A CIViC Gene Summary is created to provide a high-level overview of clinical relevance of cancer variants for the gene. Gene Summaries in CIViC focus on emphasizing the clinical relevance from a molecular perspective rather than describing the biological function of the gene unless necessary to contextualize its clinical relevance in cancer. Gene Summaries include relevant cancer subtypes, specific treatments for the gene’s associated variants, pathway interactions, functional alterations caused by the variants in the gene, and normal/abnormal functions of the gene with associated roles in oncogenesis CC0-1.0 CIViC gene help@civicdb.org PyOBO v0.12.13-dev-207b46e9 on 2025-10-30T20:26:19.725451 by https://github.com/biopragmatics/pyobo/blob/main/src/pyobo/sources/civic_gene.py 2025-10-01 https://civicdb.org/ https://civic.readthedocs.io/en/latest/_images/CIViC_logo_for-light-bg_LG_v5a1.png has ontology root term has 3' gene has 5' gene factor fusion gene ALK amplifications, fusions and mutations have been shown to be driving events in non-small cell lung cancer. While crizontinib has demonstrated efficacy in treating the amplification, mutations in ALK have been shown to confer resistance to current tyrosine kinase inhibitors. Second-generation TKI's have seen varied success in treating these resistant cases, and the HSP90 inhibitor 17-AAG has been shown to be cytostatic in ALK-altered cell lines. ALK1 CD246 NBLST3 ALK Cyclin D has been shown in many cancer types to be misregulated. Well established for their oncogenic properties, the cyclins and the cyclin-dependent kinases (CDK's) they activate have been the focus of major research and development efforts over the past decade. The methods by which the cyclins are misregulated are widely variable, ranging from genomic amplification to changes in promoter methylation. Cyclin D3 loss has been reported in T-ALL, a seemingly unique trend when compared to the amplifcations and overexpressions of the other cyclin D's. In a mouse study, the targeted therapeutic palbociclib significantly increased the median survival of the cyclin D3 knockouts. CCND3 MRD29 SEB SETBP1 ABLL ARG ABL2 DAZAP1 H731 PDCD4 Cyclin E, while currenly not as widely implicated as its cyclin D counterparts, has been implicated in various carcinomas, including breast, gastric, stomach and colorectal. High levels of cyclin E, either by gene amplification or overexpression, have been shown to lead to poorer prognosis in gastic carcinoma, and these measurements are correlated with later stage disease. In lung cancer, neoplastic cells with higher levels of the cyclin E/CDK2 complex are more radiosensitive than their more lowly expressed counterparts. CCNE pCCNE1 CCNE1 APR-1 APR1 MAGEH MAGEH1 HBP231 HIF-1 HIP-1 HSPC069 HYPB KMT3A LLS MRD70 RAPAS SET2 p231HBP SETD2 ETOHI2 HSA242976 RANSE3L RN3 RNASE3L RNASEN DROSHA AIARV FTDALS4 IIAE8 NAK T2K TBK1 CD274, also commonly referred to as PDL1, is a ligand that binds with the receptor PD1, commonly found on T-cells, and acts to block T-cell activation. PD1 expression has been observed in a variety of cancers including melanoma and non-small cell lung cancer. The interaction of PD1/PDL1 is hypothesized to be a possible mechanism for the tumor to escape immune response. A number of checkpoint blockade inhibitors including pembrolizumab and nivolumab have been developed that target the PD1/PDL1 interaction in order to allow T-cells to recognize tumor cells without being deactivated by the tumor. B7-H B7H1 PD-L1 PDCD1L1 PDCD1LG1 PDL1 hPD-L1 CD274 CAMEL CT2 CT6.2 CT6.2a CT6.2b ESO2 LAGE-1 LAGE2B CTAG2 AIID DIETER IPEX JM2 PIDX XPID FOXP3 MRT2 MRT2A CRBN SFTA5 SFTPJ CLDN18 DD5 EDD EDD1 HYD UBR5 CBP KAT3A MKHK1 RSTS RSTS1 CREBBP ABS MPLPF DDX41 CDK6, along with its partner CDK4, are key players in cell cycle progression. The complex has been implicated in a number of cancer types, and is the focus of therapeutic research and development. One targeted therapy for CDK inhibition is palbociclib, which may slow the growth of advanced stage breast cancers. It has also been shown, in mouse, that CDK inhibition may sensitize mutant PIK3CA tumors to PI3K inhibitors. MCPH12 PLSTIRE CDK6 CRKL BCNS2 JBTS32 PRO1280 SUFUH SUFUXL SUFU CRK7 CRKR CRKRS CDK12 HBXAP RSF-1 XAP8 p325 RSF1 CTIP1 DILOS EVI9 HBFQTL5 SMARCM1 ZNF856 BCL11A LRP1B is a putative tumor suppressor and a member of the low-density lipoprotein (LDL) receptor family. The LDL receptor family have roles related to clearance of extracellular ligand and are proposed to be involved in extracellular signal transduction. silencing and down-expression of LRP1B as been observed in renal cell carcinoma and thyroid cancer. Further Deletion of LRP1B has been associated with chemotherapy resistance in high-grade serous cancers. LRP-1B LRP-DIT LRPDIT LRP1B GENE-33 MIG-6 MIG6 RALT ERRFI1 CSF-1 MCSF PG-M-CSF CSF1 AOVD3 ECSM4 MRB ROBO4 CD114 GCSFR SCN7 CSF3R BILIQTL1 GNT1 HUG-BR1 UDPGT UDPGT 1-1 UGT1 UGT1A UGT1A1 ANOP2 MAA2 MCOPS2 BCOR FAAP43 PHF9 POG FANCL CT6.1 CTAG CTAG1 ESO1 LAGE-2 LAGE2B NY-ESO-1 CTAG1B ACTA ASMA CFTD CFTD1 CFTDM CMYO2A CMYO2B CMYO2C CMYP2A CMYP2B CMYP2C MPFD NEM1 NEM2 NEM3 SHPM ACTA1 CTGF HCS24 IBP-8 IGFBP8 NOV2 CCN2 ALPS5 CD CD152 CELIAC3 CTLA-4 GRD4 GSE IDDM12 CTLA4 MTH2 NUDT15D NUDT15 CTNNB EVR7 MRD19 NEDSDV armadillo CTNNB1 AGO CDC4 DEDHIL FBW6 FBW7 FBX30 FBXO30 FBXW6 SEL-10 SEL10 hAgo hCdc4 FBXW7 CDK4, along with its partner CDK6, are key players in cell cycle progression. The complex has been implicated in a number of cancer types, and is the focus of therapeutic research and development. One targeted therapy for CDK inhibition is palbociclib, which may slow the growth of advanced stage breast cancers. It has also been shown, in mouse, that CDK inhibition may sensitize mutant PIK3CA tumors to PI3K inhibitors. CMM3 PSK-J3 CDK4 BKRNS BNS BRWS1 CSMH DDS1 PS1TP5BP1 THC8 ACTB CT13 HAGE DDX43 C6orf67 CDC50A TMEM30A YTM1 WDR12 CT84 HEL164 Nori-3 SPK TOPK PBK CPD6 CYP2D CYP2D7AP CYP2D7BP CYP2D7P2 CYP2D8P2 CYP2DL1 CYPIID6 P450-DB1 P450C2D P450DB1 CYP2D6 YHHQ1 p12 POLE4 C11orf30 GL002 EMSY CYSLT2 CYSLT2R GPCR21 HG57 HPN321 KPG_011 PSEC0146 hGPCR21 CYSLTR2 APOLLON BRUCE BIRC6 KLHL14 ACBD1 ACBP CCK-RP EP DBI KIAA1524 NOCIVA p90 CIP2A CRC18 CRCR1 HGPPS2 IGDCC1 MRMV1 NTN1R1 DCC AUTS18 HELSNF1 IDDAM CHD8 CDKN2A loss has been shown to be a significant event in a number of cancer types. While no targeted therapeutic has been engaged in clinical trials, the prognostic impact has been studied by a number of meta-analyses. In majority of cases CDKN2A is inactivated by homozygous deletions. One of the mechanisms by which loss of CDKN2A can occur is by hypermethylation of the promoter region for the gene. However, the prognostic impact of promoter hypermethylation has been relatively ambiguous. Many studies have suggesting poorer prognostic outcome for patients with hypermethylation in colorectal, liver, and younger lung cancer patients. This being said, there is still research to be done before this becomes a widely-accepted prognostic indicator. Additionally, CDKN2A (p16) expression is a surrogate marker for HPV infection. As such, CDKN2A expression is prognostic in Oropharyngeal and probably also non-oropharyngeal head and neck squamous cell carcinomas. ARF CAI2 CDK4I CDKN2 CMM2 INK4 INK4A MLM MTS-1 MTS1 P14 P14ARF P16 P16-INK4A P16INK4 P16INK4A P19 P19ARF TP16 CDKN2A CHED CHED1 CHED2 EUROIMAGE566589 PPCD1 ZNF339 OVOL2 HALR KLEFS2 MLL3 KMT2C DDIT1 GADD45 GADD45A BTBD25 IMD60 BACH2 CAP-Rf DBX DDX14 DDX3 HLP2 MRX102 MRXSSB DDX3X PAPP-A2 PAPP-E PAPPE PLAC3 SSDA PAPPA2 DEF1 DEFA2 HNP-1 HP-1 HP1 MRS DEFA1 HEL-S-306 MAWBP MAWDBP PBLD CRL2 CRLF2Y TSLPR CRLF2 I-kappa-B-zeta IKBZ INAP IkappaB-zeta MAIL ikB-zeta ikappaBzeta NFKBIZ MRD71 RFXDC2 RFX7 HSAN2 HSN2 KDP PPP1R167 PRKWNK1 PSK p65 WNK1 DHQU DIA4 DTD NMOR1 NMORI QR1 NQO1 BIRC7 encodes the protein Livin which is a member of the inhibitor of apoptosis protein (IAP) family. Livin consists of a single baculoviral IAP repeat domain (BIR) and a RING domian at the C-terminus. The protein inhibits apoptosis by inhibiting proteolytic activation of capsases. Overexpression of Livin has been observed in a variety of cancers including lung, colon, and prostate compared to most normal adult tissues and has been proposed as a putative therapeutic target. KIAP LIVIN ML-IAP MLIAP RNF50 BIRC7 GALNT15 GalNac-T10 GalNac-T14 GALNT14 Grc3 NET6 NOL9 'AML with mutated CEBPA' is a provisional entity in the WHO classification of acute myeloid leukemia (AML) and is recommended to be tested for in patients with AML. CEBPA mutations are particularly associated with cytogenetically normal AML (CN-AML). CEBPA is an intronless gene that is required for granulocyte formation in mice. N-terminal nonsense mutations result in a dominant negative C/EBP-alpha protein while C-terminal mutations reduce the DNA-binding potential of this transcription factor. CEBPA mutations are associated with a favorable prognosis, however, NPM1 and FLT3 mutations should also be assessed in CN-AML patients as concurrent mutations may have prognostic implications. C/EBP-alpha CEBP CEBPA ACTL6 ARPN-BETA Arp4 BAF53A INO80K SMARCN1 ACTL6A C21 DC42 IRA1 MRD41 TBLR1 TBL1XR1 BROVCA5 FANCN PNCA3 PALB2 ADCADN AIM CXXC9 DNMT HSN1E MCMT m.HsaI DNMT1 DHP DHPDHASE DPD DYPD DPYD SLX3 MUS81 FBX11 IDDFBA PRMT9 UBR6 UG063H01 VIT1 FBXO11 DEP.2 DEPDC2 P-REX2 PPP1R129 PREX2 DBDR DRD1B DRD1L2 DRD5 CXXC6 LCX bA119F7.1 TET1 ACTRI ACVR1A ACVRLK2 ALK2 FOP SKR1 TSRI ACVR1 B7DC Btdc CD273 PD-L2 PDCD1L2 PDL2 bA574F11.2 PDCD1LG2 RNF140 hDx-1 DTX1 PAC-1 PAC1 DUSP2 HH19 MKP3 PYST1 DUSP6 EDSS1 LNIR PRR4 PVRL4 nectin-4 NECTIN4 COE1 EBF O/E-1 OLF1 EBF1 BACH1 FANCJ OF BRIP1 CD363 CHEDG1 D1S3362 ECGF1 EDG-1 EDG1 S1P1 S1PR1 HV1 VSOP HVCN1 BENTA BIMP3 CARMA1 IMD11 IMD11A PPBL CARD11 ELF-1 EPLG6 HEK7-L LERK-6 LERK6 EFNA2 HOMG4 URG EGF CD366 HAVcr-2 KIM-3 SPTCL TIM3 TIMD-3 TIMD3 Tim-3 HAVCR2 EIF1A EIF1AP1 EIF4C eIF-1A eIF-4C EIF1AX DDX2A EIF-4A EIF4A eIF-4A-I eIF4A-I EIF4A1 H2B/S H2BFAiii H2BFT H2BK HIST1H2BK H2BC12 4E-BP1 4EBP1 BP-1 PHAS-I EIF4EBP1 EST182763 MRP7 SIMRP7 ABCC10 KLHL6 C9orf26 DVS27 IL1F11 NF-HEV NFEHEV IL33 SLFN8/9 SLFN11 CAPZIP MK2S4 RCSD1 AUG ENT1 hENT1 SLC29A1 NAPRT1 PP3856 NAPRT KAT3B MKHK2 RSTS2 p300 EP300 ECYT4 HIF2A HLF MOP2 PASD2 bHLHe73 EPAS1 BDPLT22 CAPB DRT EK5 EPHT3 ERK Hek5 PCBC Tyro5 EPHB2 CMAVM2 HFASD HTK LMPHM7 MYK1 TYRO11 EPHB4 EPO-R EPOR ErbB-3 FERLK HER3 LCCS2 MDA-BF-1 VSCN1 c-erbB-3 c-erbB3 erbB3-S p180-ErbB3 p45-sErbB3 p85-sErbB3 ERBB3 ErbB4 (HER4) is one of the four members in the EGFR subfamily of receptor tyrosine kinases. Ligands include EGF, epiregulin, betacellulin and the neuregulins (Sundvall et. al.). Of these, NRG3 and NRG4 exclusively bind HER4 (Hynes et. al.). Mutations in ERBB4 have been identified in various cancer types including melanoma, lung adenocarcinoma and medulloblastoma. A therapeutic value of these aberrations still remains unknown (Arteaga et. al.). ALS19 HER4 p180erbB4 ERBB4 ORP10 OSBP9 OSBPL10 COFS4 RAD10 UV20 ERCC1 ERCC2 functions as a DNA repair gene involved in separating the double helix via 5’-3’ helicase activity. It forms a part of the transcription factor II Human (TFIIH) complex and is ATP-dependent. The TFIIH complex is known to be involved in the nucleotide excision repair pathway (NER) which can repair DNA damage caused by chemotherapeutic treatment and basal transcription. ERCC2 variants have been observed in a variety of cancers. A number of studies have suggested ERCC2 variants can act as biomarkers to predict response to neoadjuvant treatment, and cancer prognosis. Additionally the Lys751Gln polymorphism has been observed to increase risk in a number of cancer types; however, results have been conflicting. COFS2 EM9 TFIIH TTD TTD1 XPD ERCC2 EPR ER Ep EREG COFS3 ERCC5-201 ERCM2 UVDR XPG XPGC ERCC5 ARMD5 CKN2 COFS COFS1 CSB CSB-PGBD3 POF11 RAD26 UVSS1 ERCC6 ER-BETA ESR-BETA ESRB ESTRB Erb NR3A2 ODG8 ESR2 ETS-1 EWSR2 c-ets-1 p54 ETS1 ETS2IT1 ETS2 ER81 ETV1 E1A-F E1AF PEA3 PEAS3 ETV4 ERM ETV5 TEL TEL/ABL THC5 ETV6 AML1-EVI-1 EVI1 KMT8E MDS1 MDS1-EVI1 PRDM3 RUSAT2 MECOM H3 H3.2 H3/M H3C13 H3C15 H3F2 H3FM H3FN HIST2H3C H3C14 DNMT3A is one of several epigenetic modifiers identified as recurrently mutated in acute myeloid leukemia (AML). DNMT3A mutations are associated with cytogenetically normal AML. In vitro experiments indicate that the R882H mutation acts in a dominant negative manner to disrupt the de novo methyltransferase activity of wildtype homotetramers. AML patient bone marrow harboring R882 mutations were similarly demonstrated to be hypomethylated compared to patients with wildtype DNMT3A. These studies also indicated that non-R882 DNMT3A mutations may act in a functionally distinct manner from R882 mutations. Alternative mechanisms indicate independent prognostic outcomes and treatment protocols may need to be considered for these two classes of DNMT3A mutations. DNMT3A2 HESJAS M.HsaIIIA TBRS DNMT3A FA FA-H FA1 FAA FACA FAH FANCH FANCA FA3 FAC FACC FANCC CDHF7 CDHR8 FAT ME5 hFat1 FAT1 HCRP1 PQBP2 SPG53 VPS37A PMR1 PRM1 VPO2 PXDNL CD32 CD32A CDw32 FCG2 FCGR2 FCGR2A1 FcGR FcgammaRIIa IGFR2 FCGR2A FAM123B OSCS WTX AMER1 CD32 CD32B FCG2 FCGR2 FCGR2C FcGRIIB FcRII-c FcgammaRIIb IGFR2 FCGR2B CD16 CD16-II CD16A FCG3 FCGR3 FCGRIII FCR-10 FCRIII FCRIIIA FcGRIIIA IGFR3 IMD20 FCGR3A FOXN6 FOXR2 BFGF FGF-2 FGFB HBGF-2 FGF2 FGF3 is a member of the basic fibroblast growth factor (FGF) gene family and was first identified based on it's similarity to the mouse proto-oncogene int-2. Amplifications of this gene and the surrounding region (11q13) have been observed in various cancers including breast cancer, esophogeal cancer, melanoma, bladder cancer and hepatocellular carcinoma (HCC). Lower tumor grade and stage have been associated with FGF3 amplifications in HCC; however, this event is fairly rare in this tumor type. HBGF-3 INT2 FGF3 DEE90 FGF-13 FGF2 FHF-2 FHF2 LINC00889 XLID110 FGF13 FGFR1 is a member of the Fibroblast Growth Factor family, comprising of 4 receptors and 18 Ligands. FGFR1 signalling downstream functions mainly via PI3K and MAPK pathways (Turner et. al.). Several ways of involvement of FGFR1 in cancer have been proposed: auto- and paracrine activation, amplification and overexpression (Marshall et. al, Weiss et. al., Cheng et. al.). Especially amplification of FGFR1 in lung cancer is an emerging treatment target with clinical studies currently ongoing (e.g. NCT01004224). However, FGFR1 amplification does not always correlate with protein expression and predictive biomarkers still remain to be defined in clinic (von Mässenhausen et. al.). Mutation of FGFR1 seems to be less common, but has been described in glioblastoma, pilocytic astrocytomas and Ewing's sarcoma (Rand et. al., Jones et. al., Agelopoulos et. al.). BFGFR CD331 CEK ECCL FGFBR FGFR-1 FLG FLT-2 FLT2 HBGFR HH2 HRTFDS KAL2 N-SAM OGD bFGF-R-1 FGFR1 CD334 JTK2 TKF FGFR4 EGFR is widely recognized for its importance in cancer. Amplification and mutations have been shown to be driving events in many cancer types. Its role in non-small cell lung cancer, glioblastoma and basal-like breast cancers has spurred many research and drug development efforts. Tyrosine kinase inhibitors have shown efficacy in EGFR amplfied tumors, most notably gefitinib and erlotinib. Mutations in EGFR have been shown to confer resistance to these drugs, particularly the variant T790M, which has been functionally characterized as a resistance marker for both of these drugs. The later generation TKI's have seen some success in treating these resistant cases, and targeted sequencing of the EGFR locus has become a common practice in treatment of non-small cell lung cancer. Overproduction of ligands is another possible mechanism of activation of EGFR. ERBB ligands include EGF, TGF-a, AREG, EPG, BTC, HB-EGF, EPR and NRG1-4 (for detailed information please refer to the respective ligand section). ERBB ERBB1 ERRP HER1 NISBD2 PIG61 mENA EGFR ACDMPV FKHL5 FREAC1 FOXF1 FKHL14 LD MFH-1 MFH1 FOXC2 FKH1 FKHR FOXO1A FOXO1 AF6q21 FKHRL1 FKHRL1P2 FOXO2 FOXO3A FOXO3 FL FLG3L FLT3L FLT3LG CHTD7 FLT-4 FLT41 LMPH1A LMPHM1 PCL VEGFR-3 VEGFR3 FLT4 CIG ED-B FINC FN FNZ GFND GFND2 LETS MSF SMDCF FN1 FPTB FNTB AP-1 C-FOS p55 FOS AP-1 G0S3 GOS3 GOSB FOSB BAF200 CSS6 SMARCF3 ZIPZAP p200 ARID2 C1orf86 FP7162 FAAP20 ADPRT ADPRT 1 ADPRT1 ARTD1 PARP PARP-1 PARS PPOL Poly-PARP pADPRT-1 PARP1 BHD DENND8B FLCL FLCN AKT1, also referred to as protein kinase B, is a known oncogene. AKT activation relies on the PI3K pathway, and is recognized as a critical node in the pathway. The E17 hotspot is the most characterized of AKT1 mutations, and has been shown to result in activation of the protein. Mutations in AKT1 have also been shown to confer resistance to allosteric kinase inhibitors in vitro. AKT PKB PKB-ALPHA PRKBA RAC RAC-ALPHA AKT1 ERBB2, commonly referred to as HER2, is amplified and/or overexpressed in 20-30% of invasive breast carcinomas. HER2-positive breast cancer is treated in a separate manner from other subtypes of breast cancer and commonly presents as more aggressive disease. Metastatic HER2-positive breast cancer is now commonly treated with HER2-targeted therapy. Apart from being amplified/overexpressed, ERBB2 activating mutations have been shown to have clinical importance in HER2-negative breast cancer. These mutations have shown sensitivity to the tyrosine kinase inhibitor neratinib, and highlight the importance of clinical sequencing efforts in treating breast cancer. CD340 HER-2 HER-2/neu HER2 MLN 19 MLN-19 NEU NGL TKR1 VSCN2 c-ERB-2 c-ERB2 p185(erbB2) ERBB2 IMD77 MPG1 MPS1 Mpg-1 P-2 MPEG1 AVO3 PIA hAVO3 RICTOR mTOR deregulation has been observed in many cancer types. As a part of the PI3K/Akt pathway, there is a broad interest in mTOR biology across cancer types. mTOR inhibition has been investigated for nearly a decade. Everolimus, temsirolimus and zotarolimus are three of the more commonly used mTOR inhibitors used in clinical treatment today, with modest success. FRAP FRAP1 FRAP2 RAFT1 RAPT1 SKS MTOR ESR1 has been a focus in breast cancer for quite some time, but is also clinically relevant in endometrial, ovarian and other cancer types. The identification of ER-positive breast cancers that are resistant to hormone therapy have inspired clinical sequencing efforts to shed light on the mechanisms of this resistance. A number of mutations in the ligand binding domain of ESR1 have been implicated in hormone resistance and anti-estrogen therapies. These observations have spurred efforts to develop therapeutics that stimulate ESR1 protein degradation (e.g. Fulvestrant), rather than acting as a small molecule antagonist. These agents are currently in clinical trials and have seen some success. ER ESR ESRA ESTRR Era NR3A1 ESR1 PNCA5 RABL3 P2Y8 P2RY8 AXLLG AXSF GAS6 ERYF1 GATA-1 GF-1 GF1 HAEADA NF-E1 NFE1 XLANP XLTDA XLTT GATA1 HDR HDRS GATA3 The FGFR proteins are involved in a wide array of pathways known to play a signficant role in cancer. Activation of these receptors can lead to activation of the RAS-MAPK pathway and the PI3K-AKT pathway, among others. The mechanisms by which FGFR can be misregulated vary between cancers. Amplification of the receptors has been observed in lung and breast cancers, coding mutations and deletions have been seen in many cancers, and more recently, FGFR fusions that lead to pathway actiation have been demonstrated to have oncogenic potential across multiple cancer types. The targeted therapeutics ponatinib, dovitinib and pazopanib have seen success in treating over-active FGFR signalling, prompting use of diagnostic sequencing targeting the FGFR genes, especially in lung cancer patients. BBDS BEK BFR-1 CD332 CEK3 CFD1 ECT1 JWS K-SAM KGFR TK14 TK25 FGFR2 ACLP AEBP1 BOAT BOAT1 ATXN1L B4GAL-T1 CDG2D CLDLFIB GGTB2 GT1 GTB beta4Gal-T1 B4GALT1 The FGFR proteins are involved in a wide array of pathways known to play a signficant role in cancer. Activation of these receptors can lead to activation of the RAS-MAPK pathway and the PI3K-AKT pathway, among others. The mechanisms by which FGFR can be misregulated vary between cancers. Amplification of the receptors has been observed in lung and breast cancers, coding mutations and deletions have been seen in many cancers, and more recently, FGFR fusions that lead to pathway actiation have been demonstrated to have oncogenic potential across multiple cancer types. The targeted therapeutics ponatinib, dovitinib and pazopanib have seen success in treating over-active FGFR signalling, prompting use of diagnostic sequencing targeting the FGFR genes, especially in lung cancer patients. ACH CD333 CEK2 HSFGFR3EX JTK4 FGFR3 FBH FBH2 FHH2 GNA-11 HG1K HHC2 HYPOC2 GNA11 GIP GNAI2B HG1C H_LUCA15.1 H_LUCA16.1 GNAI2 CMAL CMC1 G-ALPHA-q GAQ SWS GNAQ AHO C20orf45 GNAS1 GPSA GSA GSP NESP PITA3 POH SCG6 SgVI GNAS FLT3 is an important cytokine receptor involved in normal hematopoiesis. Mutations in this gene are common in acute myeloid leukemia (AML) and screening for mutations in this gene has been recommended by the World Health Organization in patients with AML, particularly in cases of cytogenetically normal AML (CN-AML). FLT3 mutations commonly co-occur with mutations such as NPM1 that are associated with CN-AML and likely modulate prognostic impact. While FLT3-ITD mutations have been associated with poorer prognosis in AML, the prognostic impact of FLT3-TKD mutations are still up for debate. CD135 FLK-2 FLK2 STK1 FLT3 EML6 GRF-1 GRLF1 P190-A P190A p190ARhoGAP p190RhoGAP ARHGAP35 DFN7 FAEES3 GST3 GSTP HEL-S-22 PI GSTP1 GTBP GTMBP HNPCC5 HSAP LYNCH5 MMRCS3 MSH-6 p160 MSH6 MIRN21 hsa-mir-21 miR-21 miRNA21 MIR21 MIRN218-1 mir-218-1 MIR218-1 GATA2 is a transcription factor involved in stem cell maintenance with key roles in hematopoietic development. GATA2 mutations are associated with a variety of inherited and acquired immune disorders including myelodysplastic syndrome and acute myeloid leukemia. In addition to a role in hematopoiesis, the maintenance GATA2 expression has been implicated as a requirement in KRAS-driven non-small cell lung cancer. Preclinical models have indicated therapeutic benefit from targeting GATA2-mediated pathways in the context of KRAS-driven NSCLC. DCML IMD21 MONOMAC NFE1B GATA2 H1.2 H1C H1F2 H1s-1 HIST1H1C H1-2 H1.3 H1D H1F3 H1s-2 HIST1H1D H1-3 H1 H1.5 H1B H1F5 H1s-3 HIST1H1B H1-5 H2B.1B H2B/a H2B/b H2B/g H2B/h H2B/k H2B/l H2BFA H2BFB H2BFG H2BFH H2BFK H2BFL HIRIP2 HIST1H2BC HIST1H2BD HIST1H2BE HIST1H2BF HIST1H2BG HIST1H2BI dJ221C16.6 H2BC5 BRYLIB1 H3-3B H3.3A H3F3 H3F3A H3-3A BRYLIB2 H3-3A H3.3B H3F3B H3-3B HIHGHH PKBB PKBBETA PRKBB RAC-BETA AKT2 CD113t-C ECYT6 beta-globin HBB HD2 KDAC2 RPD3 YAF1 HDAC2 CD166 MEMD ALCAM DFNB39 F-TCF HGFB HPTA SF HGF ARIA GGF GGF2 HGL HRG HRG1 HRGA MST131 MSTP131 NDF NRG1-IT2 SMDF NRG1 HIF-1-alpha HIF-1A HIF-1alpha HIF1 HIF1-ALPHA MOP1 PASD8 bHLHe78 HIF1A IDH1 mutations have been observed in a number of cancer types, including sarcomas, hematologic malignancies, colon cancer and brain cancer. Mutations in the two isocitrate dehydrogenase enzymes involved in cytoplasmic (IDH1) and mitochondrial (IDH2) conversion of alpha-ketoglutarate to D-2-hydroxyglutarate have been described as mutually exclusive in many of these cancer types. The most frequent mutations involve R132 (IDH1) and R172 (IDH2) involve the active site and result in neomorphic enzyme activity. The implications of mutations in this gene vary greatly by cancer type. In myelodysplastic syndromes and acute myeloid leukemia (AML), IDH1 mutations have been associated with worse outcome, shorter overall survival, and normal karyotype. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Unlike the association with cytogenetically normal AML, in glioblastoma, IDH1 mutations have been associated with specific cytogenetic abnormalities, 1p and 19q deletions. HEL-216 HEL-S-26 IDCD IDH IDP IDPC PICD IDH1 HLAA HLA-A AS B-4901 HLAB HLA-B D6S204 HLA-JY3 HLAC HLC-C MHC PSORS1 HLA-C HLA-DRA1 HLA-DRA HMOX1D HO-1 HSP32 bK286B10 HMOX1 ARIA ECSM2 ECSCR HNRPH HNRPH1 NEDCDS hnRNPH HNRNPH1 DEE54 EIEE54 GRIP120 HNRNPU-AS1 HNRPU SAF-A SAFA U21.1 hnRNP U pp120 HNRNPU IDH2 mutations have been observed in a number of cancer types, including sarcomas, hematologic malignancies, colon cancer and brain cancer. Mutations in the two isocitrate dehydrogenase enzymes involved in cytoplasmic (IDH1) and mitochondrial (IDH2) conversion of alpha-ketoglutarate to D-2-hydroxyglutarate have been described as mutually exclusive in many of these cancer types. The most frequent mutations involve R132 (IDH1) and R172 (IDH2) involve the active site and result in neomorphic enzyme activity. Although IDH2 (R172) mutations are associated with poorer overall prognosis in AML patients, its utility as a prognostic marker in MDS is still under debate. Additionally, IDH2 (R140) has been associated with improved overall survival in AML. IDH2 mutations have been associated with improved prognosis in gliomas. D2HGA2 ICD-M IDH IDH-2 IDHM IDP IDPM mNADP-IDH IDH2 HOX3I HOXC10 HOX4 HOX4E HOX5.4 HOXD8 C-BAS/HAS C-H-RAS C-HA-RAS1 CTLO H-RASIDX HAMSV HRAS1 RASH1 p21ras HRAS BIP GRP78 HEL-S-89n HSPA5 CMT2F HEL-S-102 HMN2B HMND3 HS.76067 HSP27 HSP28 Hsp25 SRP27 HSPB1 JAK2 is a kinase that is misregulated or mutated in a number of myeloproliferative diseases and cancers. The mutation V617F is the most clinically relevant variant, and is seen in around half of myeloproliferative disorders. The variant is a known activating mutation, and activated JAK2 is sufficient to drive myeloproliferative disorders in mouse models. V617F, while most recurrent, is not the only mechanism by which JAK2 can be activated in patients. JAK2 is now one of the first diagnostic markers tested upon diagnosis with a myeloproliferative disorder. JTK10 JAK2 150-225 DFNA56 GMEM GP HXB JI TN TN-C TNC H-ICSBP ICSBP ICSBP1 IMD32A IMD32B IRF-8 IRF8 HEIR-1 bHLHb25 ID3 CD119 IFNGR IMD27A IMD27B IFNGR1 CD221 IGFIR IGFR JTK13 IGF1R c-KIT activation has been shown to have oncogenic activity in gastrointestinal stromal tumors (GISTs), melanomas, lung cancer, and other tumor types. The targeted therapeutics nilotinib and sunitinib have shown efficacy in treating KIT overactive patients, and are in late-stage trials in melanoma and GIST. KIT overactivity can be the result of many genomic events from genomic amplification to overexpression to missense mutations. Missense mutations have been shown to be key players in mediating clinical response and acquired resistance in patients being treated with these targeted therapeutics. C-Kit CD117 MASTC PBT SCFR KIT CD124 IL-4RA IL4RA IL4R BSF-2 BSF2 CDF HGF HSF IFN-beta-2 IFNB2 IL-6 IL6 CD127 CDW127 IL-7R-alpha IL-7Ralpha IL7RA IL7Ralpha ILRA IMD104 lnc-IL7R sIL-7R IL7R ARAF has recently become increasingly considered for its oncogenic potential. Its potential as a target for informing clinical action was demonstrated by a single case of advanced lung adenocarcinoma harboring an S214C mutation that, when treated with sorafenib, acheived near-complete clinical remission. This finding has brought new focus on ARAF as a marker that should be assayed for in cancer treatment. A-RAF ARAF1 PKS2 RAFA1 ARAF Mutations in the RAS family of proteins are frequently observed across cancer types. The amino acid positions that account for the overwhelming majority of these mutations are G12, G13 and Q61. The different protein isoforms, despite their raw similarity, also behave very differently when expressed in non-native tissue types, likely due to differences in the C-terminal hyper-variable regions. Mis-regulation of isoform expression has been shown to be a driving event in cancer, as well as missense mutations at the three hotspots previously mentioned. While highly recurrent in cancer, attempts to target these RAS mutants with inhibitors have not been successful, and has not yet become common practice in the clinic. The prognostic implications for KRAS mutations vary between cancer types, but have been shown to be associated with poor outcome in colorectal cancer, non-small cell lung cancer, and others. 'C-K-RAS C-K-RAS CFC2 K-RAS2A K-RAS2B K-RAS4A K-RAS4B K-Ras K-Ras 2 KI-RAS KRAS1 KRAS2 NS NS3 OES RALD RASK2 c-Ki-ras c-Ki-ras2 KRAS C7 IFI10 INP10 IP-10 SCYB10 crg-2 gIP-10 mob-1 CXCL10 LSIRF MUM1 NF-EM5 SHEP8 IRF4 IP3-3KB IP3K IP3K-B IP3KB PIG37 ITPKB AIIDE JAK1A JAK1B JTK3 JAK1 JAK-3 JAK3_HUMAN JAKL L-JAK LJAK JAK3 AP-1 AP1 c-Jun cJUN p39 JUN MAP2K1 is a dual-specificity kinase known for it's involvement in the ERK pathway by activation of ERK1 and ERK2. MAP2K1 activating mutations have been observed in a number of cancers including ovarian, melanoma and lung. These activating mutations are generally found in the N-terminal negative regulatory region or the ATP-binding region of the N-terminal lobe. Inhibitors of MEK genes have been shown to inhibit tumor growth in these cases. CFC3 MAPKK1 MEK1 MEL MKK1 PRKMK1 MAP2K1 CD309 FLK1 VEGFR VEGFR2 KDR MEF2D CWS4 KILLIN KLLN CK-18 CYK18 K18 KRT18 CD223 LAG3 C1orf215 LAP18 Lag OP18 PP17 PP19 PR22 SMN STMN1 CD295 LEP-R LEPRD OB-R OBR LEPR BANDDOS C-FMS CD115 CSF-1R CSFR FIM2 FMS GPSC HDLS HDLS1 M-CSF-R CSF1R TNFC TNFSF3 TNLG1C p33 LTB JTK8 SAIDV p53Lyn p56Lyn LYN EGP-1 EGP1 GA733-1 GA7331 GP50 M1S1 TROP2 TACSTD2 Ber-Ep4 BerEp4 DIAR5 EGP-2 EGP314 EGP40 ESA HNPCC8 KS1/4 KSA LYNCH8 M4S1 MIC18 MK-1 MOC-31 TACSTD1 TROP1 EPCAM CHTD8 JV18 JV18-1 LDS6 MADH2 MADR2 hMAD-2 hSMAD2 SMAD2 HSPC193 HsT17436 JV15-2 LDS1C LDS3 MADH3 hMAD-3 hSMAD3 mad3 SMAD3 RSRFR2 MEF2B CT1.4 MAGE-41 MAGE-X2 MAGE4 MAGE4A MAGE4B MAGEA4 MGMT BCL2L3 EAT MCL1-ES MCL1L MCL1S Mcl-1 TM bcl2-L-3 mcl1/EAT MCL1 ACTFS HDMX LSKB hdm2 MDM2 BMFS6 HDMX MDMX MRP1 MDM4 C5DELq14.3 DEL5q14.3 NEDHSIL MEF2C MAPKKK1 MEKK MEKK 1 MEKK1 SRXY6 MAP3K1 MEAI SCG2 MEN1 AML with mutated NPM1 is a provisional entity in the WHO classification of AML and is recommended to be tested in patients with cytogenetically normal AML (CN-AML). FLT3 mutations should be evaluated concurrently as they have prognostic consequences. NPM1 mutations are concentrated in exon 12, most frequently W288fs which results in cytoplasmic sequestration of the protein. Exon 12 NPM1 mutations in the absence of FLT3-ITD are associated with good prognostic outcomes. Mice expressing the Npm1-W288fs mutation develop myeloproliferative neoplasms but not overt leukemia, indicating it may require additional mutations to promote leukemic development. B23 NPM NPM1 C2TA CIITAIV MHC2D1 MHC2TA NLRA CIITA CMM8 COMMAD MI MITF-A WS2 WS2A bHLHe32 MITF KIA MIB- MIB-1 PPP1R105 MKI67 AIP1 API2 CIAP2 HAIP1 HIAP1 IAP-1 MALT2 MIHC RNF49 c-IAP2 BIRC3 MLH1 is a tumor suppressor gene involved in DNA mismatch repair. Germline mutations in this gene are known to cause Lynch syndrome. The most common malignancies in Lynch syndrome are colorectal and endometrial carcinomas. In addition to germline mutations, somatic mutations in this gene have been described in colorectal and endometrial cancers. COCA2 FCC2 HNPCC HNPCC2 LYNCH2 MLH-1 MMRCS1 hMLH1 MLH1 ALL-1 ALL1 CXXC7 GAS7 HRX HTRX HTRX1 MLL MLL1 MLL1A TRX1 WDSTS KMT2A CLG4 CLG4A MMP-2 MMP-II MONA TBE-1 MMP2 API4 EPR-1 BIRC5 CLG4B GELB MANDP2 MMP-9 MMP9 CEBALID MGCR MGCR1 MGCR1-PEN dJ353E16.2 MN1 C-MPL CD110 MPLV THCYT2 THPOR TPOR MPL ATLD HNGS1 MRE11A MRE11B MRE11 Mutations in the RAS family of proteins have frequently been observed across cancer types. The amino acid positions G12, G13 and Q61 account for the overwhelming majority of these mutations. The isoforms, despite their raw similarity, also behave very differently when expressed in non-native tissue types, likely due to differences in the C-terminal hyper-variable regions. Mis-regulation of isoform expression has been shown to be a driving event in cancer, as well as missense mutations at the three hotspots previously mentioned. While highly recurrent in cancer, targeting these RAS mutants has also been very elusive, and has not yet become common practice in the clinic. ALPS4 CMNS KRAS N-ras NCMS NRAS1 NS6 NRAS COCA1 FCC1 HNPCC HNPCC1 LCFS2 LYNCH1 MMRCS2 MSH-2 hMSH2 MSH2 DUP FAP4 MRP1 MSH3 BDMF DMSFH DMSMFH HEL-249 LGMBF MSAP c86fus MTAP MTHFR PIK3CA is the most recurrently mutated gene in breast cancer, and has been found to important in a number of cancer types. An integral part of the PI3K pathway, PIK3CA has long been described as an oncogene, with two main hotspots for activating mutations, the 542/545 region of the helical domain, and the 1047 region of the kinase domain. PIK3CA, and its interaction with the AKT and mTOR pathways, is the subject of an immense amount of research and development, and PI3K inhibition has seen some limited success in recent clinical trials. While monotherapies seem to be limited in their potential, there is a recent interest in pursuing PI3K inhibition as part of a combination therapy regiment with inhibition partners including TKI's, MEK inhibitors, PARP inhibitors, and in breast cancer, aromatase inhibitors. CCM4 CLAPO CLOVE CWS5 HMH MCAP MCM MCMTC PI3K PI3K-alpha p110-alpha PIK3CA Cmyb c-myb c-myb_CDS efg MYB A-MYB AMYB MYBL1 MRTL MYCC bHLHe39 c-Myc MYC L-Myc LMYC MYCL1 bHLHe38 MYCL FGLDS1 MODED MPAPA MYCNsORF MYCNsPEP N-myc NMYC ODED bHLHe37 MYCN IMD68 MYD88D WM1 MYD88 ALPS1A APO-1 APT1 CD95 FAS1 FASTM TNFRSF6 FAS CMYO17 CMYP17 MYF3 MYOD MYODRIF PUM bHLHc1 MYOD1 Commonly mutated in GI tract tumors, PDGFR family genes (mutually exclusive to KIT mutations) are a hallmark of gastrointestinal stromal tumors. Gene fusions involving the PDGFRA kinase domain are highly correlated with eosinophilia, and the WHO classifies myeloid and lymphoid neoplasms with these characteristics as a distinct disorder. Mutations in the 842 region of PDGFRA have been often found to confer resistance to the tyrosine kinase inhibitor, imatinib. CD140A PDGFR-2 PDGFR2 PDGFRA AT-V1 AT-V2 ATV NBS NBS1 P95 hNbs1 NBN CAS-L CAS2 CASL CASS2 HEF1 NEDD9 NFNS VRNF WSS NF1 ACN BANF SCH SWNV merlin-1 NF2 HEBP1 IMDDHH NRF2 Nrf-2 NFE2L2 EDAID2 IKBA MAD-3 NFKBI NFKBIA IKBE NFKBIE AR AREGB CRDGF SDGF AREG The PML-RARA fusion is the result of a recurrent, balanced translocation between chromosomes 15 and 17, denoted as t(15;17)(q22;q12), and a diagnostic event in acute promyelocytic leukemia (APL). Both in vitro and in vivo studies have shown sensitivity to ATRA (all-trans retinoic acid) in APL patients harboring the PML-RARA fusion. Recent interest has been shown in combining ATRA and arsenic trioxide for treating these patients, and early results seem promising. However, newly discovered mutations in the B2 domain of PML have started to show conferred resistance to ATRA in these patients. MYL PP8675 RNF71 TRIM19 PML AGS2 HJCYS hN2 NOTCH2 CADASIL CADASIL1 CASIL IMF2 LMNS NOTCH3 CALJA CD73 E5NT NT NT5 NTE eN eNT NT5E MTC TRK TRK1 TRKA Trk-A p140-TrkA NTRK1 DEE58 EIEE58 GP145-TrkB OBHD TRKB trk-B NTRK2 GP145-TrkC TRKC gp145(trkC) NTRK3 ARH12 ARHA EDFAOB RHO12 RHOH12 RHOA ABL1 is most relevant to cancer in its role in the BCR-ABL fusion protein that has become a signature of chronic myeloid leukemia (CML). Cells harboring this fusion have shown sensitivity to imatinib, greatly improving the prognostic outlook of the disease. However, additional mutations in ABL1 have been shown to confer resistance to imatinib. In these resistance cases, second-generation tyrosine kinase inhibitors such as dasatinib and nilotinib have exhibited some efficacy and are currently undergoing clinical trials for treating acquired resistance in CML. ABL BCR-ABL CHDSKM JTK7 bcr/abl c-ABL c-ABL1 p150 v-abl ABL1 HSORC1 ORC1L PARC1 ORC1 PTEN is a multi-functional tumor suppressor that is very commonly lost in human cancer. Observed in prostate cancer, glioblastoma, endometrial, lung and breast cancer to varying degrees. Up to 70% of prostate cancer patients have been observed to have loss of expression of the gene. It is a part of the PI3K/AKT/mTOR pathway and mTOR inhibitors have been relatively ineffective in treating patients with PTEN loss. New appoaches using microRNAs are currently being investigated. 10q23del BZS CWS1 DEC GLM2 MHAM MMAC1 PTEN1 PTENbeta PTENgama TEP1 PTEN AR-JP LPRS2 PARK2 PDJ PRKN ALL3 BSAP PAX-5 PAX5 HEL-S-85 HNRPE1 HNRPX hnRNP-E1 hnRNP-X PCBP1 ATLD2 PCNA CARLo-3 PCAT8 PRNCR1 IBGC5 PDGF-2 PDGF2 SIS SSV c-sis PDGFB CD140B IBGC4 IMF1 JTK12 KOGS PDGFR PDGFR-1 PDGFR1 PENTT PDGFRB RET mutations and the RET fusion RET-PTC lead to activation of this tyrosine kinase receptor and are associated with thyroid cancers. RET point mutations are the most common mutations identified in medullary thyroid cancer (MTC) with germline and somatic mutations in RET associated with hereditary and sporadic forms, respectively. The most common somatic form mutation is M918T (exon 16) and a variety of other mutations effecting exons 10, 11 and 15 have been described. The prognostic significance of these mutations have been hotly debated in the field, however, data suggests that some RET mutation may confer drug resistance. Highly selective and well-tolerated RET inhibitors, selpercatinib (LOXO-292) and pralsetinib (BLU-667), have been FDA approved recently for the treatment of RET fusion-positive non-small-cell lung cancer, RET fusion-positive thyroid cancer and RET-mutant medullary thyroid cancer. CDHF12 CDHR16 HSCR1 MEN2A MEN2B MTC1 PTC RET-ELE1 RET ABC20 CD243 CLCS GP170 MDR1 P-GP PGY1 p-170 ABCB1 STAG2-AS1 P110BETA PI3K PI3KBETA PIK3C1 PIK3CB PIM PIM1 AGM7 GRB1 IMD36 p85 p85-ALPHA p85alpha PIK3R1 MPPH MPPH1 P85B p85 p85-BETA p85beta PIK3R2 RUNX1 is a transcription factor that forms a complex with the cofactor CBFB. This complex provides stability to the RUNX1 protein which is involved in the generation of hematopoietic stem cells and for their differentiation into myeloid and lymphoid lines. Loss of RUNX1 function has been shown to impair differentiation between myeloid and lymphoid lines often resulting in the development of leukemia. AML1 AML1-EVI-1 AMLCR1 CBF2alpha CBFA2 EVI-1 PEBP2aB PEBP2alpha RUNX1 IDAA NCKAP3 PLC-II PLC1 PLC148 PLCgamma1 PLCG1 APLAID FCAS3 PLC-IV PLC-gamma-2 PLCG2 PLK STPK13 PLK1 ASH1 HASH1 MASH1 bHLHa46 ASCL1 HNPCC4 LYNCH4 MLH4 MMRCS4 PMS-2 PMS2CL PMSL2 PMS2 CDC2 CRCS10 IMD120 MDPL POLD POLD1 CRCS12 FILS IMAGEI POLE1 POLE SF3B1 mutations have been described in several myeloid malignancies, predominantly myelodysplastic syndromes (MDS), as well as other hematologic malignancies, breast cancer, and uveal melanoma (UM). SF3B1 is one of several genes involved in RNA splicing that has been identified as recurrently mutated in MDS and other malignanices. The mutations affecting SF3B1 are typically heterozygous, point mutations suspected to be functionally deleterious with R625 and K700E described as a major mutation hotspots. MDS patients with SF3B1 mutations have been reported to have better overall and event-free survival than their wildtype counterparts. Additionally, these mutations are highly associated with subtypes of MDS characterized by ringed sideroblasts (refractory anemia with ringed sideroblasts and refractory cytopenia with multilineage dysplasia and ring sideroblasts). In UM patients, SF3B1 mutations have been reported to be associated with chromosome 3 disomy, which defines a subgroup with low risk of metastasis. Hsh155 MDS PRP10 PRPF10 SAP155 SF3b155 SF3B1 BOB1 OBF-1 OBF1 OCAB POU2AF1 OCT2 OTF2 Oct-2 POU2F2 OCT3 OCT4 OTF-3 OTF3 OTF4 Oct-3 Oct-4 Oct3/4 POU5F1 ASNSD TS11 ASNS HJS2 MRD36 PP2A-Aalpha PP2AA PP2AAALPHA PR65A PPP2R1A B55A B55ALPHA PR52A PR55A PR55alpha PPP2R2A TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010). To fulfill its proper biological function four TP53 polypeptides must form a tetramer which functions as a transcription factor, therefore even if one out of four polypeptides has inactivating mutation it may lead to dominant negative phenotype of variable degree. While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. The significance of many polymorphisms for susceptibility and prognosis of disease is still very much up for debate. BCC7 BMFS5 LFS1 P53 TRP53 TP53 ASS CTLN1 ASS1 AMPK AMPK2 AMPKa2 PRKAA PRKAA2 ACRDYS1 ADOHR CAR CNC CNC1 PKR1 PPNAD1 PRKAR1 Prkar1alpha TSE1 PRKAR1A PKC-beta PKCB PKCI(2) PKCbeta PRKCB1 PRKCB2 PRKCB DNA-PKC DNA-PKcs DNAPK DNAPKc DNPK1 HYRC HYRC1 IMD26 XRCC7 p350 PRKDC ERK ERK-2 ERK2 ERT1 MAPK2 NS13 P42MAPK PRKM1 PRKM2 p38 p40 p41 p41mapk p42-MAPK MAPK1 CFC4 MAPKK2 MEK2 MKK2 PRKMK2 MAP2K2 JNKK2 MAPKK7 MEK MEK 7 MKK7 PRKMK7 SAPKK-4 SAPKK4 MAP2K7 ARTS CMTX5 DFN2 DFNX1 PPRibP PRS-I PRSI PRPS1 LAM TSC TSC1 ALDD D6S216 D6S216E JMP LMP7 NKJO PRAAS1 PSMB5i RING10 PSMB8 AF AF-1 ASF MCB1 Rpn10 S5A pUB-R5 PSMD4 BCNS BCNS1 NBCCS PTC PTC1 PTCH PTCH1 COX-2 COX2 GRIPGHS PGG/HS PGHS-2 PHS-2 hCox-2 PTGS2 HCP HCPH HPTP1C PTP-1C SH-PTP1 SHP-1 SHP-1L SHP1 PTPN6 BPTP3 CFC JMML METCDS NS1 PTP-1D PTP2C SH-PTP2 SH-PTP3 SHP2 PTPN11 PTP-PEST PTPG1 PTPN12 HPTP-BETA HPTPB PTPB R-PTP-BETA VEPTP PTPRB HPTP HPTPD HPTPDELTA PTPD R-PTP-delta RPTPDELTA PTPRD BNAH2 LAR PTPRF LAM PPP1R160 TSC4 TSC2 The RAC1 P29S mutation is the third most common protein-coding hotspot mutation in melanomas, ocurring in 4-9%. A preclinical study has shown that this mutation confers resistance to BRAF inhibition in-vitro. MIG5 MRD48 Rac-1 TC-25 p21-Rac1 RAC1 HHR23B HR23B P58 RAD23B BROVCA3 FANCO R51H3 RAD51L2 RAD51C R51H2 RAD51L1 REC2 RAD51B BROVCA4 R51H3 RAD51L3 TRAD RAD51D CMD1NN CRAF NS5 Raf-1 c-Raf RAF1 CM-AVM CMAVM CMAVM1 GAP PKWS RASA RASGAP p120 p120GAP p120RASGAP RASA1 OSRC PPP1R130 RB p105-Rb p110-RB1 pRb pp110 RB1 U2AF1 is one of several spliceosome complex genes frequently mutated in a variety of hematologic malignancies, particularly de novo myelodysplastic syndromes (MDS), as well as solid tumors such as lung and pancreatic cancers. Two hotspot mutations (S34 and Q157) occur within the two zinc-finger domains of the U2AF1 protein. These mutations have been associated with altered splicing patterns in vitro and in vivo. U2AF1 mutations in MDS have been associated with an increased risk of transformation to secondary acute myeloid leukemia, however, the impact of these mutations on overall survival has been an area of debate. FP793 RN RNU2AF1 U2AF35 U2AFBP U2AF1 RHEB2 RHEB NS8 RIBB RIT ROC1 RIT1 WT1 is a tumor suppressor gene associated with the development of Wilms' Tumor, from which it was named. Mutations in exon 7 and 9 of WT1 have been recurrently identified in acute myeloid leukemia and associated with poorer prognosis and chemotherapy resistance. AWT1 GUD NPHS4 WAGR WIT-2 WT-1 WT33 WT1 ROS1 is a receptor tyrosine kinase that is frequently involved in genetic rearrangement in a variety of human cancers (e.g. NSCLC, gastric cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, angiosarcoma...). The resulting fusion protein harbors the constitutively active ROS1 kinase domain and drives cellular proliferation (Davies et. al.). In NSCLC about 1% harbor a ROS1 rearrangement. These patients are predominantely female and have a lower T-stage (Warth et. al.). Treatment with crizotinib leads to a reported objective response rate of appr. 70% and a median duration of response of 18 months (Shaw et. al.). Resistance mechanisms to crizotinib have been described and involve mutations in the kinase domain. More selective inhibitors of ROS1 might overcome this resistance (Davare et. al.). MCF3 ROS c-ros-1 ROS1 BRAF mutations are found to be recurrent in many cancer types. Of these, the mutation of valine 600 to glutamic acid (V600E) is the most prevalent. V600E has been determined to be an activating mutation, and cells that harbor it, along with other V600 mutations are sensitive to the BRAF inhibitor dabrafenib. It is also common to use MEK inhibition as a substitute for BRAF inhibitors, and the MEK inhibitor trametinib has seen some success in BRAF mutant melanomas. BRAF mutations have also been correlated with poor prognosis in many cancer types, although there is at least one study that questions this conclusion in papillary thyroid cancer. Oncogenic BRAF mutations are divided into three categories that determine their sensitivity to inhibitors. Class 1 BRAF mutations (V600) are RAS-independent, signal as monomers and are sensitive to current RAF monomer inhibitors. Class 2 BRAF mutations (K601E, K601N, K601T, L597Q, L597V, G469A, G469V, G469R, G464V, G464E, and fusions) are RAS-independent, signaling as constitutive dimers and are resistant to vemurafenib. Such mutants may be sensitive to novel RAF dimer inhibitors or MEK inhibitors. Class 3 BRAF mutations (D287H, V459L, G466V, G466E, G466A, S467L, G469E, N581S, N581I, D594N, D594G, D594A, D594H, F595L, G596D, and G596R) with low or absent kinase activity are RAS-dependent and they activate ERK by increasing their binding to activated RAS and wild-type CRAF. Class 3 BRAF mutations coexist with mutations in RAS or NF1 in melanoma may be treated with MEK inhibitors. In epithelial tumors such as CRC or NSCLC may be effectively treated with combinations that include inhibitors of receptor tyrosine kinase. B-RAF1 B-raf BRAF-1 BRAF1 NS7 RAFB1 BRAF NOTCH1 is one of four known genes encoding the NOTCH family of proteins, a group of receptors involved in the Notch signaling pathway. NOTCH proteins are characterized by N-terminal EGF-like repeats followed by LNR domains which form a complex with ligands to prevent signaling. The Notch signaling pathway is involved in processes related to cell fate specification, differentiation, proliferation, and survival. Activation of Notch has been shown to be correlative with mammary tumorgenesis in mice and increased expression of Notch receptors has been observed in a variety of cancer types including cervical, colon, head and neck, lung, renal, pancreatic, leukemia, and breast cancer. A number of treatment modalities have been explored related to Notch inhibition especially in breast cancer with mixed results. AOS5 AOVD1 TAN1 hN1 NOTCH1 S6 eS6 RPS6 PEOB6 R1 RIR1 RR1 RRM1 C2orf48 R2 RR2 RR2M RRM2 NEF S100 S100-B S100beta S100B MIG20a NTRKR3 TKT TYRO10 WRCN DDR2 ADCAII OPCA3 SCA7 SGF73 ATXN7 BFIS5 CERIII CIAT DEE13 EIEE13 MED MYOCL2 NaCh6 Nav1.6 PN4 SCN8A ABCD-3 C3Xkine CXC3 CXC3C NTN NTT SCYD1 fractalkine neurotactin CX3CL1 CMD1GG FP MC2DN1 NDAXOA PGL5 PPGL5 SDH1 SDH2 SDHF SDHA CWS2 IP MC2DN4 PGL4 PPGL4 SDH SDH1 SDH2 SDHIP SDHB PWD WC1 WD WND ATP7B Mesenchymal Epithelial Transition MET is a prototypical receptor tyrosine kinase. Its ligand is Hepatocyte Growth Factor (HGF). MET alterations are drivers of human cancer. Amplification and resulting overexpression has been reported in several cancers, and make the receptor's activity independent of HGF. Gene fusions also decouple kinase activity from the cell membrane and render it constitutively active. Finally, exclusion of the juxtamembrane (JM) domain of the kinase by "skipping" of exon 14 activates the kinase. FDA-approved selective MET inhibitors, including tepotinib and capmatinib, have shown efficacy in cancers with exon 14 skipping mutations or MET amplification. AUTS9 DA11 DFNB97 HGFR RCCP2 c-Met MET JNKK JNKK1 MAPKK4 MEK4 MKK4 PRKMK4 SAPKK-1 SAPKK1 SEK1 SERK1 SKK1 MAP2K4 PR264 SC-35 SC35 SFRS2 SFRS2A SRp30b SRSF2 SGK SGK1 FCTCS FRP1 MEC1 SCKL SCKL1 ATR JMS MRX52 RAD54 RAD54L XH2 XNP ZNF-HX ATRX ARK AXL3 JTK11 Tyro7 UFO AXL BAF190 BIS BRM NCBRS SNF2 SNF2L2 SNF2LA SWI2 Sth1p hBRM hSNF2a SMARCA2 BAF47 CSS3 INI-1 INI1 MRD15 PPP1R144 RDT RTPS1 SNF5 SNF5L1 SWNTS1 Sfh1p Snr1 hSNFS SMARCB1 CRJS FZD11 Gx PHLS SMOH SMO AMYLD6 IMD43 MHC1D4 B2M Fusions between EWSR1 and multiple 3` partners are regularly identified in soft tissue sarcomas and can aid in differential diagnosis. The fusion product usually contains the N-terminal transcription-activating domain of EWSR1 and the C-terminal DNA-binding domain of the fusion partner, generating a novel transcription factor. EWS EWS-FLI1 bK984G1.4 EWSR1 GF1 GGF1 GINGF HGF NS4 SOS-1 SOS1 DOM PCWH SOX-10 WS2E WS4 WS4C SOX10 BARD1 SS-5-R SST5 SSTR5 IMD75 KIAA1546 MDS TET2 BCL2L4 BAX CANDF7 IMD31A IMD31B IMD31C ISGF-3 STAT91 STAT1 ADMIO ADMIO1 APRF HIES STAT3 GHISID2 STAT5 STAT5B D12S1644 HIES6 IL-4-STAT STAT6B STAT6C STAT6 EST EST-1 ST1E1 STE SULT1E1 LKB1 PJS hLKB1 STK11 IMD82 p72-Syk SYK SAVA T TFT TBXT 12CC4 HSPC215 MFH QRF1 hFKH1B FOXP1 VETD TBX2 COII MTCO2 COX2 MTND1 ND1 AGM8 AGM8A AGM8B E2A E47 ITF1 TCF-3 VDIR bHLHb21 p75 TCF3 AREB6 BZP DELTAEF1 FECD6 NIL2A PPCD3 TCF8 ZFHEP ZFHX1A ZEB1 SC1 TCF-19 TCF19 BCL5 BCL6A LAZ3 ZBTB27 ZNF51 BCL6 BCL7 SMARCJ1 BCL7A C-Rel HIVEN86A IMD92 REL BCM BCMA CD269 TNFRSF13A TNFRSF17 CD202B GLC3E TIE-2 TIE2 VMCM VMCM1 TEK HEL-S-71p PRO1557 PRO2086 TFQTL1 TF AP-4 bHLHc41 TFAP4 ARP-1 ARP1 CHTD4 COUPTF2 COUPTFB COUPTFII NF-E3 SRXX5 SVP40 TFCOUP2 NR2F2 MRXSPF RCCP2 RCCX1 TFEA bHLHe33 TFE3 ITF P1B TFI TFF3 TFGA TGFA BGCAN betaglycan TGFBR3 EDSCLL3 TSP2 THBS2 CLGI EPA EPO HCI TIMP TIMP-1 TIMP1 Von Hippel-Lindau (VHL) disease is characterized by heterozygous germline mutation in VHL gene on chromosome 3p. Patients are predisposed to developing hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal cell carcinoma; pheochromocytoma, pancreatic cysts and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and broad ligament cysts. Cerebellar hemangioblastomas may be associated with headache, vomiting, gait disturbances, or ataxia. Spinal hemangioblastomas and related syrinx usually present with pain. Sensory and motor loss may develop with cord compression. Retinal hemangioblastomas may be the initial manifestation of VHL disease and can cause vision loss. Renal cell carcinoma occurs in about 70% of individuals with VHL and is the leading cause of mortality. Pheochromocytomas can be asymptomatic but may cause sustained or episodic hypertension. Pancreatic lesions often remain asymptomatic and rarely cause endocrine or exocrine insufficiency. Endolymphatic sac tumors can cause hearing loss of varying severity, which can be a presenting symptom. Cystadenomas of the epididymis are relatively common. They rarely cause problems, unless bilateral, in which case they may result in infertility. The VHL gene product encodes pVHL, which binds to elongin C, elongin B, cullin-2 and Rbx1. This complex catalyzes the polyubiquitinylation of specific proteins and targets them for degradation by proteosomes. For example, under normoxic conditions, hydroxylated hypoxia-inducble factor alpha subunits (HIFα) binds pVHL targets HIFα for degradation. Under hypoxic conditions, HIF1α is not hydroxylated, pVHL does not bind, and HIF1α subunits accumulate. HIF1α forms heterodimers with HIF1β and activates transcription of a variety of hypoxia-inducible genes (i.e., VEGF, EPO, TGFα, PDGFβ). Likewise, when pVHL is absent or mutated, HIF1α subunits accumulate, resulting in cell proliferation and the neovascularization of tumors characteristic of VHL disease. Pathogenic variants in VHL either prevent its expression (i.e., deletions, frameshifts, nonsense mutations, and splice site mutations) or lead to the expression of an abnormal protein (i.e., missense mutations). Missense mutations that destabilize packing of the alpha-helical domains, decrease the stability of the alpha-beta domain interface, interfere with binding of elongin C and HIF1α, or disrupt hydrophobic core residues result in loss of HIF regulation and are more likely to result in VHL type 1 (no predisposition to pheochromocytoma). Missense mutations that result in pVHL that is normal with respect to HIF regulation are more likely to be associated with VHL with clinical pheochromocytoma. Acquired somatic pathogenic variants in VHL may give rise to sporadic VHL-type tumors (i.e., clear cell RCC and hemangioblastoma) without other associated tumors characteristic of the hereditary disease. It should be noted that >90% of the most common form of kidney cancer (clear cell renal cell carcinoma) are associated with bi-allelic somatic mutation in the VHL gene, and is the rationale for the anti-angiogenic therapy for RCC patients. HRCA1 RCA1 VHL1 pVHL VHL PRSS10 TMPRSS2 FX PTMB4 TB4X TMSB4 TMSB4X A20 AIFBL1 AISBL OTUD7C TNFA1P2 TNFAIP3 TOPI TOP1 TOP2 TOP2alpha TOPIIA TP2A TOP2A 53BP1 TDRD30 p202 p53BP1 TP53BP1 HRF TCTP p02 p23 TPT1 ECGP GP96 GRP94 HEL-S-125m HEL35 TRA1 HSP90B1 BGP BGP1 BGPI CEACAM1 Bcl-2 PPP1R50 BCL2 BLIMP-1 BLIMP1 PRDI-BF1 PRDM1 TSPYL TSPYL1 MODY11 BLK IMD35 JTK1 TYK2 DKCD HST422 TMS TS TYMS ATN CMM8 OCA1 OCA1A OCAIA SHEP3 TYR HHR6A MRXS30 MRXSN RAD6A UBC2 UBE2A BRCA1 mutations in the germline have become a hallmark for hereditary breast and ovarian cancers. Variants that have been demonstrated to reduce the function of the protein have been shown to increase the risk for these cancers, as well as prostate and pancreatic cancer. These findings have been the impetus for the increased popularity of genetic testing of healthy individuals to assess risk. Recent studies in ovarian cancer have also demonstrated that BRCA mutation status can predict treatment response. A number of trials assessing BRCA mutation status have shown an improved response to platinum agents, and more recently has led to the FDA-approval of PARP inhibitors for BRCA-positive ovarian cancers. These studies have resulted in the Society of Gynecologic Oncology to recommend germline BRCA testing in all patients with a diagnosis of ovarian cancer. BRCAI BRCC1 BROVCA1 FANCS IRIS PNCA4 PPP1R53 PSCP RNF53 BRCA1 C11orf43 GRDF IGF-II PP9974 SRS3 IGF2 CONDBA NOR-90 UBF UBF-1 UBF1 UBF2 UBTF GNT1 UGT UGT1 UGT1A@ UGT1A KABUK2 UTX bA386N14.2 KDM6A L-VEGF MVCD1 VEGF VPF VEGFA Flt4-L LMPH1D LMPHM4 VRP VEGFC OP-1 BMP7 AIK ARK1 AURA BTAK PPP1R47 STK15 STK6 STK7 AURKA WEE1A WEE1hu WEE1 KMT3F KMT3G MMSET RAUST REIIBP TRX5 WHS WHSC1 NSD2 HWNT11 WNT11 CRM-1 CRM1 emb exp1 XPO1 RCC SCAR26 XRCC1 CMM6 XRCC3 HsT441 P61-YES Yes c-yes YES1 Tumor mutational burden (TMB) refers to the total number of genomic alterations (mutations) in a tumor cell. TMB is commonly assessed by sequencing tumor DNA (e.g. panel sequencing, exome sequencing, whole genome sequencing, etc). Genomic alterations of various types are counted and TMB is often reported as mutations per megabase (mut/Mb). Higher or lower TMB values can be associated with clinically actionable information, for instance it is a biomarker for response to checkpoint inhibitor therapy in some tumor cases. Similarly it may indicate tumors with DNA damage repair defects and predict response to therapies that have been shown to be effective for such tumors. Tumor Mutation Burden TMB DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion errors, deletion, as well as base misincorporation which can arise during DNA replication. It is evolutionarily conserved. Five MMR proteins are mainly responsible for MMR: MutS-Homologs (MSH2, 3, and 6), MutL-Homolog 1 (MLH1), and Post-Meiotic Segregation 2 (PMS2). MMR deficiency can lead to microsatellite instability (MSI). MSI involves insertion or deletion of short sequences of DNA at microsatellite sequences, which are repetitive di-, tri- or tetranucleotides distributed over the genome. MSI can occur in multiple cancers including colorectal cancer and other gastrointestinal cancers, endometrial cancer, breast cancer, prostate cancer, and bladder cancer. MSI has been associated to better prognosis in colorectal cancer, and also reported to be associated with sensitivity to checkpoint inhibition therapy in some instances. Microsatellite Instability dMMR MSI Kataegis is a phenomenon characterized by localized clustering of mutations, with other non-random features such as enrichment of C>T and C>G changes on the same strand, typically ranging from a few to several hundred mutations. APOBEC (apolipo-protein B mRNA editing enzyme, catalytic polypeptide-like) enzymes are considered to have a likely role in driving kataegis in non-B cell tumors and AID (activation-induced cytidine deaminase) has been implicated in B cell tumors. Kataegis is seen in ~50% of breast tumors but has also been observed at high frequency in pan-cancer studies overall and across many individual tumor types. clustered mutagenesis mutation storms Kataegis Complex Karyotype CK Chromothripsis is presumed to occur from a single cataclysmic one-off rearrangement affecting many parts of the genome, and generating extensive genomic rearrangements. It can occur in cancer cells and in patients with congenital disease. It results in extensive DNA damage, involving tens to hundreds of DNA double-strand breaks. Next generation sequencing techniques have enabled the discovery and identification of chromothripsis. It can result in multiple loss or gain of sequence fragments and lead to breaking of tumor suppressor function, or oncogene activation via gene fusion or other mechanisms. Recent data indicate that it may be more widespread than previously realized. Some proposed mechanisms that drive chromothripsis are DNA damage to condensed chromosomes, shortened telomeres, and premature chromosome compaction before DNA replication. Chromothripsis has been linked with specific mutational signatures in some cases, and also has been associated with highly aggressive disease and worse outcomes in various tumors. Chromosome Shattering Chromothrypsis Chromothripsis DNA methylation DNA methylation signature Methylation signature HPV can drive multiple types of cancer, including oropharyngeal, anal, cervical, penile, and vaginal cancers. Cervical carcinoma is a leading cause of death from cancer worldwide. There are multiple types of HPV virus. High risk HPV subtypes include HPV-16 and HPV-18. Many of the HPV tumorigenic effects are driven by viral proteins E6 and E7. E6 inhibits apoptosis and interacts with proliferative pathways. E7 binds Rb protein, disassociating it from E2F transcription factors, which can drive early entry into S-phase of the cell cycle. Human Papillomavirus HPV MEF2D::CSF1R FGFR2::v EML4::ALK FGFR3::BAIAP2L1 v::NRG1 v::ABL1 AKAP9::BRAF CBFB::MYH11 SS18::SSX1 SS18::SSX2 SS18::SSX4 FGFR2::TACC3 TMPRSS2::ERG NPM1::ALK RANBP2::ALK DUX4::v EBF1::PDGFRB v::PDGFRA v::PDGFRB PCM1::JAK2 FIP1L1::PDGFRA TFG::ROS1 CCDC6::RET BRAF::CUL1 ZKSCAN1::BRAF EWSR1::DDIT3 FUS::DDIT3 WWTR1::CAMTA1 TNKS2::PDGFRA FGFR2::BICC1 FGFR2::AHCYL1 SQSTM1::NTRK1 ETV6::NTRK3 KIF5B::RET AGK::BRAF PAPSS1::BRAF TRIM24::BRAF v::NTRK3 LMNA::NTRK1 KMT2A::MLLT3 PAX8::PPARG PPFIBP2::BRAF KIAA1549::BRAF EWSR1::FLI1 CLTC::ALK CTLA4::CD28 ACTB::GLI1 DNAJB1::PRKACA PML::RARA BCR::ABL1 FGFR2::OGA SLC3A2::NRG1 SDC4::NRG1 EGFR::RAD51 KMT2E::ASNS STRN::ALK MACF1::BRAF CUX1::BRAF STRN::NTRK2 PDE4DIP::NTRK1 FGFR3::TACC3 P2RY8::CRLF2 EWSR1::NR4A3 TRIM63::NTRK1 DDR2::NTRK1 GON4L::NTRK1 ETV6::NTRK2 ETV6::ABL1 AGGF1::PDGFRB HEY1::NCOA2 PAX3::FOXO1 PAX7::FOXO1 NUP98::NSD1 CBFA2T3::GLIS2 ATF7IP::PDGFRB v::BRAF v::NTRK2 FAM131B::BRAF NUP214::ABL1 SSBP2::JAK2 IGH::CRLF2 MYB::GATA1 SNX2::ABL1 FOXP1::ABL1 PTK2B::KDM6A PTK2B::STAG2 DGKH::ZFAND3 IL2RB::MYH9 DEK::AFF2 KIF5B::MET FGFR1OP2::FGFR1 EML6::ALK CAD::ALK GOPC::ROS1 CD74::NRG1 APP::NRG1 NAB2::STAT6 KMT2A::v TMPRSS2::ETV1 ATF7IP::JAK2 EBF1::JAK2 PPFIBP1::JAK2 STRN3::JAK2 TPR::JAK2 ETV6::JAK2 BCR::JAK2 PAX5::JAK2 TERF2::JAK2 USP25::JAK2 ZNF274::JAK2 RFX3::JAK2 NRF1::BRAF MET::ATXN7L1 v::ABL2 EWSR1::WT1 v::JAK2 LPP::HMGA2 HMGA2::LPP BCR::PDGFRA COL1A1::PDGFB OFD1::JAK2 SMU1::JAK2 SNX29::JAK2 ZNF430::JAK2 TPM3::NTRK1 v::RET ATP1B1::NRG1 EWSR1::ATF1 NUP98::KDM5A RUNX1::RUNX1T1 TLX3::BCL11B ETV6::RUNX1 KANK1::NTRK2 RBPMS::MET GOLGA5::JAK2 BCOR::CCNB3 CIC::DUX4 RANBP2::ABL1 ZMIZ1::ABL1 CENPC::ABL1 NUP153::ABL1 LSM14A::ABL1 SFPQ::ABL1 BAG4::FGFR1 TBL1XR1::CSF1R TPR::NTRK1 TAF15::ZNF384 PAG1::ABL2 RCSD1::ABL2 KMT2A::ABI1 SSBP2::CSF1R ZC3HAV1::ABL2 ASPSCR1::TFE3 ETV6::NTRK1 VCL::NTRK2 AFAP1::NTRK2 v::TFE3 G3BP2::KIT FGFR3::v IGH::EPOR OCLN::RASGRF1 SH3PXD2A::HTRA1 CIC::LEUTX MAP3K8::v QKI::RAF1 KANK4::ALK EGFR::SEPTIN14 VOPP1::EGFR SEC61G::EGFR NTRK3::SCAPER SCP2::NTRK1 EGFR::PURB EGFR::PPARGC1A EGFR::ZNF713 EGFR::BRAF EML4::NTRK3 KIF5B::EGFR ERC1::ALK IGHA1::FGFR3 MYB::QKI CHD7::BEND2 EGFR::VSTM2A EGFR::WIF1 HIP1::ALK FBXO11::ALK EGFR::YAP1 EGFR::ZNF880 FN1::ALK TPM4::ALK DCTN1::ALK ZMYM2::FGFR1 BCR::FGFR1 TRIM24::FGFR1 ZFTA::RELA ZFTA::NCOA1 ZFTA::NCOA2 ZFTA::MAML2 MN1::ZFTA QKI::NTRK2 ESR1::CCDC170 YAP1::TFE3 v::NCOA2 CRTC1::MAML2 CRTC3::MAML2 FUS::ERG FUS::FEV EWSR1::ERG EWSR1::NFATC2 FUS::NFATC2 FGFR2::? FGFR2::KIAA1217 TNIP1::PDGFRB FGFR2::POC1B FGFR2::DBP FGFR2::FILIP1 FGFR1::TACC1 FGFR1::PLAG1 FGFR2::NRAP FGFR2::WAC FGFR2::TNS1 FGFR2::TTC28 FGFR2::CCDC6 SLC4A4::ROS1 v::TFEB UFD1-NTRK2 UFD1::NTRK2 RALGPS2::NTRK3 TCF3::PBX1 EMILIN2::PDGFD SPECC1L::NTRK3 EEF1G::ROS1 EML1::NTRK2 YAP1::MAMLD1 YAP1::FAM118B YAP1::v VPS18::NTRK3 CD74::ROS1 BCR::NTRK2 BAF180 PB1 RCC SMARCH1 PBRM1 v::NUTM1 BRD4::NUTM1 EWSR1::CREB3L1 FUS::CREB3L2 MALAT1::GLI1 MN1::BEND2 MNX1::ETV6 DEK::NUP214 NPM1::MLF1 SDC4::ROS1 NFASC::NTRK1 ETV6::FGFR3 v::DUX4 GOLGA4::RAF1 ANO10::RAF1 IQGAP1::RASGRF1 BCOR::MAML3 v::MITF VCP::TFE3 YWHAE::NUTM2A YWHAE::NUTM2B YWHAE::NUTM2E KAT6A::CREBBP FOS::v v::ALK v::FGFR1 v::NTRK1 RCSD1::ABL1 v::ROS1 MIGA1::BRAF RBM15::MRTFA KMT2A::AFDN KMT2A::MLLT10 CEP43::FGFR1 VGLL2::v KIF5B::FGFR1 SERPINE1::FOSB SLC4A4::RASGRF1 CD72::ROS1 EGFR::FGFR1 CLIP2::EGFR MYB::NFIB MEF2D::v MEF2D::BCL9 v::IRF4 TCF3::HLF IGH::IL3 IGH::DUX4 v::TFCP2 FUS::TFCP2 v::NR4A3 EGFR::SHC1 EGFR::MACF1 EGFR::GNAT3 EGFR::ERBB4 NUP98::v IGH::MYC EGFR::SUMF2 The C19MC miRNA cluster is a microRNA cluster consisting of several genes (>40 genes, >50 miRNAs). The region is ~100 kb in size on chromosome 19. C19MC MicroRNA Cluster C19MC TRPS1::PLAG1 EGFR::USP42 PICALM::MLLT10 LANCL2::EGFR v::ZNF384 The ZEB2::PDGFRB Fusion has been reported in two Ph-Like B-ALL patients. The fusions were in frame. In one patient the exon structure was reported as exon 9 of ZEB2 joined to exon 9 of PDGFRB, removing PDGFRB Extracellular Domains 1-4. In one patient, the fusion occurred together with PAX5::BZW1. One preclinical report indicates that the fusion has driver properties and may respond to imatinib or dasatinib. ZEB2-PDGFRB ZEB2::PDGFRB PAX5::BZW1 ETV6::ABL2 has been reported in at least 4 hematologic cancer cases (2 AML, one B-ALL, and one T-ALL). The studies reported the fusion to be between ETV6 exons 1 to 5 and either base pair 362 (exon 2) or base pair 425 (exon 3) of ABL2. Both of the fusion breakpoints maintain the ETV6 HLH domain as well as the ABL2 tyrosine kinase domain. ETV6-ABL2 ETV6::ARG TEL::ARG ETV6::ABL2 CIC::NUTM1 CIC::NUTM2B ATXN1::NUTM1 ATXN1::NUTM2B DOCK1::DUX4 BRF1 Berg36 ERF-1 ERF1 RNF162B TIS11B cMG1 ZFP36L1 ZABC1 ZNF217 ENX-1 ENX1 EZH2b KMT6 KMT6A WVS WVS2 EZH2 APRO1 PC3 TIS21 BTG2 CD184 D2S201E FB22 HM89 HSY3RR LAP-3 LAP3 LCR1 LESTR NPY3R NPYR NPYRL NPYY3R WHIM WHIMS WHIMS1 CXCR4 BTEB2 CKLF IKLF KLF5 C16DELp13.2 DEL16P13.2 HAFOUS HAUSP TEF1 USP7 APRO2 BTG1 ALPHATFEB BHLHE35 TCFEB TFEB HLD17 JTV-1 JTV1 P38 AIMP2 AAD10 ALR BCAHH CAGL114 KABUK1 KMS MLL2 MLL4 TNRC21 KMT2D AGMX1 AT ATK BPK IGHD3 IMD1 PSCTK1 XLA BTK BTBD29 LZTR-1 NS10 NS2 SWNTS2 LZTR1 U2AF1-RS2 U2AF1L2 U2AF1RS2 URP ZC3H22 ZRSR2 DXS1272E JARID1C MRX13 MRXJ MRXSCJ MRXSJ SMCX XE169 KDM5C B120 BAF250 BAF250a BM029 C1orf4 CSS2 ELD MRD14 OSA1 P270 SMARCF1 hELD hOSA1 ARID1A AXIL ODCRCS AXIN2 H2A/l H2AFL HIST1H2AC dJ221C16.4 H2AC6 H2A.1 H2A/n H2AC11 H2AC13 H2AC15 H2AC16 H2AFN HIST1H2AM dJ193B12.1 H2AC17 BTPS2 DESMD DP2 DP2.5 DP3 GS PPP1R46 APC H3/l H3C1 H3C10 H3C11 H3C12 H3C3 H3C4 H3C6 H3C7 H3C8 H3FL HIST1H3B H3C2 BTBD32 NEDMACE NEDMIDF NSDVS1 NSDVS2 TEF2 SPOP HR54 RAD54A hHR54 hRAD54 RAD54L AIS AR8 DHTR HUMARA HYSP1 KD NR3C4 SBMA SMAX1 TFM AR FEX GPR49 GPR67 GRP49 HG38 LGR5 BOPS MDS ASXL1 AISIMD CIS1 CISH1 JAB SOCS-1 SSI-1 SSI1 TIP-3 TIP3 SOCS1 IRS-2 IRS2 Ataxia-telangiectasia (A-T) is a recessive disorder resulting from germline mutation of the A-T mutated (ATM) gene on chromosome 11q. Upon sensing double-stranded breaks (DSB), the wild-type kinase encoded by ATM initiates the DNA-damage response by phosphorylating histone H2AX and, subsequently, various other proteins, such as BRCA1 and the MRE11–RAD50–NBS1 (MRN) complex, which are recruited to the damaged site. Additionally, ATM phosphorylates p53, resulting in expression of the cyclin-dependent kinase inhibitor p21 and leading to senescence or apoptosis. Somatic variants can result in inhibition or loss of these functions and can cause resistance to therapies that rely on inducing apoptosis via DSBs. Germline variants in A-T patients result in a predisposition to cancer, most frequently hematologic or breast. PARP inhibition has been studied for its potential in treating ATM mutated breast cancer patients. AT1 ATA ATC ATD ATDC ATE TEL1 TELO1 ATM ABC31 EST90757 MLP2 MOAT-D MRP3 cMOAT2 ABCC3 ATAR CD270 HVEA HVEM LIGHTR TR2 TNFRSF14 BRCA2 mutations in the germline have become a hallmark for hereditary breast and ovarian cancers. Variants that have been demonstrated to reduce the function of the protein have been shown to increase the risk for these cancers, as well as prostate and pancreatic cancer. These findings have been the impetus for the increased popularity of genetic testing of healthy individuals to assess risk. Recent studies in ovarian cancer have also demonstrated that BRCA mutation status can predict treatment response. A number of trials assessing BRCA mutation status have shown an improved response to platinum agents, and more recently has led to the FDA-approval of PARP inhibitors for BRCA-positive ovarian cancers. These studies have resulted in the Society of Gynecologic Oncology to recommend germline BRCA testing in all patients with a diagnosis of ovarian cancer. BRCC2 BROVCA2 FACD FAD FAD1 FANCD FANCD1 GLM3 PNCA2 XRCC11 BRCA2 BAP1 is a deubiquitylase thought to be a key regulator of many cancer-associated pathways. Germline alterations in BAP1 have been characterized as predisposing variants to familial melanocytic skin tumors. These alterations also have been linked to the development of mesothelioma, uveal melanoma, cutaneous melanoma and others. Clinically, the role of BAP1 is still being investigated. However, the development of intradermal tumors known as melanocytic BAP1-associated intradermal tumors (MBAITs) are enough for a patient to be subject to more intense surveillance to catch other malignancies as early as possible. HUCEP-13 KURIS TPDS1 UBM2 UCHL2 UVM2 hucep-6 BAP1 CASH CASP8AP1 CLARP Casper FLAME FLAME-1 FLAME1 FLIP I-FLICE MRIT c-FLIP c-FLIPL c-FLIPR c-FLIPS cFLIP CFLAR AC133 CD133 CORD12 MCDR2 MSTP061 PROML1 RP41 STGD4 PROM1 DIH4 RALDH(II) RALDH2 RALDH2-T ALDH1A2 SPHK SPHK1 FBP FUBP hDH V FUBP1 CARMEN CIPER CLAP IMD37 c-E10 mE10 BCL10 MED1 TPDS2 UVM1 MBD4 LMPHM14 erg-3 p55 ERG BPES BPES1 PFRK PINTO POF3 FOXL2 CYCE2 CCNE2 AIK2 AIM-1 AIM1 ARK-2 ARK2 AurB IPL1 PPP1R48 STK-1 STK12 STK5 aurkb-sv1 aurkb-sv2 AURKB EAP1 ECRAR HPTTG PTTG TUTR1 PTTG1 CVID13 Hs.54452 IK1 IKAROS LYF1 LyF-1 PPP1R92 PRO0758 ZNFN1A1 IKZF1 CALR1 CRT HEL-S-99n RO SSA cC1qR CALR AGR16 DFNB68 EDG-5 EDG5 Gpcr13 H218 LPB2 S1P2 S1PR2 BL11 HB15 CD83 EZF GKLF KLF4 ACTR AIB-1 AIB1 CAGH16 CTG26 KAT13B RAC3 SRC-3 SRC3 TNRC14 TNRC16 TRAM-1 bHLHe42 pCIP NCOA3 GLXR GLYD PH2 GRHPR ABC15 ABCP BCRP BCRP1 BMDP CD338 CDw338 CDw388 EST157481 GOUT1 MRX MXR MXR-1 MXR1 UAQTL1 ABCG2 PAX8 is one of nine transcription factors within the PAX gene family. It has been observed to be expressed during embryonic development however expression attenuates after development in all but a few tissues. Research has indicated that over-expression of PAX proteins in general are not an initiating event in tumorgenesis however they may facilitate malignant development. PAX8 is expressed in 80-96% of all High-grade serous carcinomas (HGSC) and is commonly used as a marker for the disease. In addition PAX8 has become a useful biomarker for differentiating between mullerian mucinous and non-mullerian tumors. PAX8 has also been associated with neoplasms in the kidney and thyroid. PAX-8 PAX8 CDA3 CDAIII CDAN3 CDAN3A CHO1 KNSL5 MKLP-1 MKLP1 KIF23 NR3C3 PR PGR SYPH1 Sph1 SNCAIP ALPS2B CAP4 Casp-8 FLICE MACH MCH5 CASP8 DPC4 JIP MADH4 MYHRS SMAD4 ARCND4 HD7 HD7b HD9 HDAC HDAC7 HDAC7B HDAC9B HDAC9FL HDRP MITR HDAC9 TOX1 TOX INrf2 KLHL19 KEAP1 C-CBL CBL2 FRA11B NSLL RNF55 CBL 3M1 CUL-7 KIAA0076 dJ20C7.5 CUL7 ADMIO3 Cbl-b Nbla00127 RNF56 CBLB BAF190 BAF190A BRG1 CSS4 MRD16 OTSC12 RTPS2 SNF2 SNF2-beta SNF2L4 SNF2LB SWI2 hSNF2b SMARCA4 CMM9 DKCA2 DKCB4 EST2 PFBMFT1 TCS1 TP2 TRT hEST2 hTRT TERT FGF19 MPPH MPPH2 PKB-GAMMA PKBG PRKBG RAC-PK-gamma RAC-gamma STK-2 AKT3 CPBHM HD6 JM21 KDAC6 PPP1R90 HDAC6 BAM BIM BOD BCL2L11 IDDM20 LNK SH2B3 Cyclin D has been shown in many cancer types to be misregulated. Well established for their oncogenic properties, the cyclins, and the cyclin-dependent kinases (CDK's) they activate, have been the focus of major research and development efforts over the past decade. The methods by which the cyclins are misregulated are widely variable, ranging from genomic amplification to changes in promoter methylation. While Cyclin D2 has only been found to be significantly deregulated in glioma, Cyclin D1 seems to be a pan-cancer actor. Cyclin D misregulation has been shown to lead to poorer outcomes in a number of studies, but currently there are no FDA-approved targeted therapies. BCL1 D11S287E PRAD1 U21B31 CCND1 TTF-1 TTF-I TTF1 NBSLD RAD502 hRad50 RAD50 IGAN3 hSPRY2 SPRY2 EMLP EMP GID9 HLC-10 P44EMLP PIG5 MAEA LKLF KLF2 B4 CVID3 CD19 CDCBM CDCBM1 CFEOM3 CFEOM3A FEOM3 TUBB4 beta-4 TUBB3 B1 Bp35 CD20 CVID5 FMC7 LEU-16 S7 MS4A1 COB1 YAP YAP-1 YAP2 YAP65 YKI YAP1 MER RP38 Tyro12 c-Eyk c-mer MERTK HPC9 PSGD HOXB13 AG-2 AG2 GOB-4 HAG-2 HEL-S-116 HPC8 PDIA17 RIFTD XAG-2 AGR2 HBLRR LST-1 LST1 OATP-C OATP1B1 OATP2 OATPC SLC21A6 SLCO1B1 CFAP108 FAP108 MRD21 CTCF G13 HG1N GNA13 SCDO1 DLL3 CDW44 CSPG8 ECM-III ECMR-III H-CAM HCELL HUTCH-1 HUTCH-I Hermes-1 IN LHR MC56 MDU2 MDU3 MIC4 Pgp1 CD44 SA3 SPGF61 STAG3 HPE13 MKMS NEDXCF SA-2 SA2 SCC3B bA517O1.1 STAG2 LFA-3 LFA3 ag3 CD58 HSP105 HSP105A HSP105B NY-CO-25 HSPH1 CD27-L CD27L CD27LG LPFS3 TNFSF7 TNLG8A CD70 AGM6 B29 IGB Igbeta CD79B HsHPK MRD57 PKU-ALPHA TLK2 PIM2 R-PTP-T RPTP-rho RPTPrho PTPRT Arc-1 BCDS1 CD324 CDHE ECAD LCAM UVO CDH1 PRL-3 PRL-R PRL3 PTP4A3 CDS1 CHK2 HuCds1 LFS2 PP1425 RAD53 TPDS4 hCds1 CHEK2 LYSP100 LYSP100-A LYSP100-B SP140 Cyclin D has been shown in many cancer types to be misregulated. Well established for their oncogenic properties, the cyclins and the cyclin-dependent kinases (CDK's) they activate have been the focus of major research and development efforts over the past decade. The methods by which the cyclins are misregulated are widely variable, ranging from genomic amplification to changes in promoter methylation. While Cyclin D2 has only been found to be significantly deregulated in glioma, Cyclin D1 in particular seems to be a pan-cancer actor. Cyclin D misregulation has been shown to lead to poorer outcomes in a number of studies, and currently there are no FDA-approved targeted therapies. KIAK0002 MPPH3 CCND2 NS12 TC21 RRAS2 CDKN2 p33(CDK2) CDK2 LIS7 PSSALRE CDK5 C-2k CDC2L4 CTK1 PITALRE TAK CDK9 AFR1 RAF ZHX2 CAP20 CDKN1 CIP1 MDA-6 P21 SDI1 WAF1 p21CIP1 CDKN1A CDKN4 KIP1 MEN1B MEN4 P27KIP1 CDKN1B CDK4I INK4B MTS2 P15 TP15 p15INK4b CDKN2B DKK-1 SK DKK1 This gene, when mutated to be over-active, has been linked to chemotherapy resistance in relapsed T-cell Acute Lymphoblastic Leukemia. GMP NT5B PNT5 SPG45 SPG65 cN-II NT5C2 HIAA0929 MINT RATARS RBM15C SHARP SPEN MRD63 MRD64 Nbla00365 ZFP292 ZN-16 Zn-15 bA393I2.3 ZNF292 IDDSELD KMT2G Set1B SETD1B CDX-3 CDX2/AS CDX3 CDX2 MRD45 CIC MAD5 MXD5 MGA DCR1 Dicer Dicer1e GLOW HERNA K12H4.8-LIKE MNG1 RMSE2 aviD DICER1 SIR2 SIR2L1 SIR2alpha SIRT1 CAP CDLS6 FSHRG4 HUNK1 HUNKI MCAP BRD4 CBL-3 CBL-SL RNF57 CBLC GADD34 PPP1R15A CHK1 OZEMA21 CHEK1 CMM10 CRMCC3 GLM9 HPOT1 PFBMFT8 TPDS3 POT1 CHR15DELq24 DEL15Q24 WITKOS SIN3A