MutSig

Overview

MutSig (Mutation Significance) is a statistical algorithm developed at the Broad Institute to identify genes mutated at rates significantly above the background mutation rate in cancer. It accounts for context-specific mutation rates (nucleotide context, gene expression, replication timing) and gene-specific variability to compute q-values for each gene. MutSig is widely used in WES-based cancer genome studies to distinguish driver genes from passenger mutations.

Used by

  • Applied to 55 DLBCL WES samples in the dlbc_broad_2012 cohort; identified 58 significantly mutated genes at FDR q <= 0.1, with a 97.9% validation rate by targeted resequencing PMID:22343534.
  • MutSig applied to identify statistically significant driver genes (SPOP, FOXA1, MED12) in 112 prostate adenocarcinoma WES samples PMID:22610119
  • Applied to 103 breast cancer tumor WES data (Broad cohort, brca_broad) to identify significantly mutated genes including PIK3CA, TP53, and AKT1 PMID:22722202
  • MutSig applied to somatic mutation data from 224 TCGA colorectal carcinoma exomes to identify 24 significantly mutated genes including novel candidates ARID1A, SOX9, AMER1 PMID:22810696
  • InVEx permutation framework (related to MutSig) applied to 121 melanoma exomes; leverages intronic mutation rates to control for high UV-induced mutation background; identified 11 significantly mutated genes PMID:22817889
  • MutSig applied to 92 medulloblastoma exomes (Broad) to identify 12 significantly mutated genes (q<0.1) including novel candidates DDX3X, GPS2, BCOR, LDB1 PMID:22820256
  • Applied to TCGA LUSC cohort (178 tumors) to identify significantly mutated genes including CDKN2A, TP53, KEAP1, NFE2L2, and MLL2 PMID:22960745
  • Applied to Broad LUAD cohort (183 tumors) to identify significantly mutated genes; nominated RBM10, U2AF1, and ARID1A as novel drivers alongside EGFR, KRAS, and STK11 PMID:22980975
  • MutSig applied to neuroblastoma WES data to identify significantly mutated genes; ALK, PTPN11, and ATRX passed significance thresholds PMID:23334666
  • MutSig analysis of 160 CLL exomes identified SF3B1, NOTCH1, DDX3X, and POT1 as significantly mutated genes beyond background rates PMID:23415222
  • MutSig significance algorithm identified 26 significantly mutated genes (FDR q<0.1) in 145 esophageal adenocarcinomas, including TP53, CDKN2A, SMAD4, PIK3CA, and novel candidates ELMO1, DOCK2, and SPART PMID:23525077
  • Used together with InVEx to identify 71 significantly mutated genes in 291 GBM exomes, including known drivers (PTEN, TP53, EGFR, PIK3CA, NF1) and novel LZTR1 PMID:24120142
  • MutSigCV applied to 177 WES + 26 WGS multiple myeloma samples; identified 11 significantly mutated genes at q<0.1 including KRAS, NRAS, BRAF, FAM46C/TENT5C, TP53, DIS3, TRAF3, CYLD, RB1, PRDM1, and IRF4 PMID:24434212
  • Applied to the Illumina WES arm of 147 rhabdomyosarcoma tumor/normal pairs; identified significantly mutated genes including HRAS, KRAS, NRAS, FGFR4, PIK3CA, NF1, FBXW7, and BCOR; combined with GATK UnifiedGenotyper for the SOLiD arm PMID:24436047
  • MutSig 1.5 applied to TCGA bladder carcinoma WES data (n=130); identified 32 significantly mutated genes at FDR<0.1, including 9 not previously reported as significantly mutated in any cancer (CDKN1A, ERCC2, RXRA, ELF3, KLF5, FOXQ1, RHOB, PAIP1, BTG2) PMID:24476821
  • MutSigCV applied to ESCC cohort (139 paired tumor/normal samples) to identify 13 significantly mutated genes at FDR q < 0.2, including novel drivers FAT1, FAT2, ZNF750, and KMT2D PMID:24686850
  • MutSigCV applied to 215 non-hypermutated gastric adenocarcinomas (stad_tcga_pub) identified 25 significantly mutated genes including TP53, ARID1A, KRAS, PIK3CA, RNF43, APC, CTNNB1, SMAD4; expanded analysis including indels added RNF43, B2M, NF1 PMID:25079317
  • MutSig2CV applied to 412 lung adenocarcinomas (luad_tcga_pub, 230 TCGA + 182 published) identified 18 significantly mutated genes; newly identified RIT1 activating mutations and MGA loss-of-function (mutually exclusive with MYC amplification) PMID:25079552
  • MutSigCV applied to 50 muscle-invasive urothelial carcinoma tumors; identified ERCC2, TP53, RB1, KDM6A, and ARID1A as significantly mutated genes. PMID:25096233
  • Used in the TCGA ChRCC study to identify significantly mutated genes in 66 tumors; nominated TP53 (32%) and PTEN (9%) as the only statistically significant drivers. PMID:25155756
  • MutSig CV v1.4 applied to aggressive cSCC WES (39 tumors) despite extreme UV-driven mutation burden (median 61.2 mutations/Mb); identified 11 significant driver genes at q<0.1, including TP53, CDKN2A, NOTCH1, NOTCH2, AJUBA, HRAS, CASP8 PMID:25303977
  • Identified 7 significantly mutated genes (q<0.1) in 402 papillary thyroid carcinomas: BRAF, NRAS, HRAS, KRAS, EIF1AX, PPM1D, CHEK2; EIF1AX was a novel PTC driver (q=5.3×10⁻⁸) PMID:25417114
  • MutSigCV identified 16 significantly mutated genes (q<0.2) in 78 gastric adenocarcinomas, including TP53, ARID1A, CDH1, APC, RHOA, PIK3CA, SMAD4, MYC, and KRAS; 13 were mutated in ≥5% of tumors PMID:25583476
  • Applied (versions 1.5, 2.0, and CV; most significant of three taken) to identify recurrently mutated genes in 29 metastatic cSCC tumors from DFCI-ONCOPANEL-1 sequencing; identified TP53 (79%), CDKN2A (48%), NOTCH1/2/4, and chromatin-remodeling genes as significantly mutated PMID:25589618
  • MutSigCV applied to TCGA HNSC WES data (n=279); identified 11 significantly mutated genes at q<0.1 including TP53, CDKN2A, FAT1, PIK3CA, NOTCH1, KMT2D, NSD1, CASP8, AJUBA, NFE2L2, and HLA-A; additional trend-significant genes at q<1 PMID:25631445
  • MutSigCV used to identify 14 significantly mutated genes (q < 0.05) in 243 HCC exomes including TP53, CTNNB1, AXIN1, and TERT-pathway genes. PMID:25822088
  • MutSigCV applied to 109 microdissected PDA exomes identifying 24 significantly mutated genes at ≥3.5% frequency; meta-analysis with 99-case ICGC cohort (208-case total) added ATM, ARID2, TGFBR2, ACVR1B. PMID:25855536
  • MutSig used to assess recurrence of somatic mutations in 150 mCRPC cases, identifying TP53 as most selectively enriched versus primary prostate cancer (q<0.001). PMID:26000489
  • MutSig (Q < 0.1) and InVEx (Bonferroni p < 0.05) together called 42 and 13 significantly mutated genes respectively in 318 melanoma WES cases, including novel SMGs RAC1, DDX3X, MRPS31, and RPS27. PMID:26091043
  • Applied to the TCGA breast ILC/IDC cohort (n=817) for significantly mutated gene discovery; identified ILC-enriched drivers CDH1, TBX3, RUNX1, PIK3CA, and FOXA1, plus IDC-enriched TP53 and MYC amplification PMID:26451490
  • Used to identify 44 recurrently mutated genes across 538 CLL whole-exomes (CLL8 trial), achieving 94%/61% power at 3%/2% mutation frequency; discovered novel drivers RPS15, IKZF3, MGA, BRAF (non-V600E), and MAP2K1 PMID:26466571
  • Applied as MutSigCV to identify 13 significantly mutated genes (q < 0.1) in 333 primary prostate adenocarcinomas including SPOP, TP53, FOXA1, PTEN, MED12, CDKN1B, and newly identified BRAF, HRAS, AKT1, CTNNB1, ATM, ZMYM3, NKX3-1 PMID:26544944.
  • MutSig-CV identified 19 significantly mutated genes in periampullary tumors (ampullary, distal bile-duct, duodenal adenocarcinoma), plus 3 additional genes (PBRM1, RECQL4, KDM6A) by inactivation-bias test; MSI cases excluded PMID:26804919
  • MutSigCV identified 75 significantly mutated genes in 1,122 diffuse gliomas, 45 of which were novel glioma associations; applied within the TCGA pan-glioma study PMID:26824661
  • Used to identify significantly mutated genes in 114 metastatic CRPC biopsies; confirmed TP53 and RB1 as top altered genes differentiating CRPC-NE from CRPC-Adeno PMID:26855148
  • MutSigCV applied to 488 non-hypermutated CRCs, identifying 90 significantly mutated genes (73 novel for CRC); hypermutator threshold = 12 mutations/Mb PMID:27149842
  • MutSig2CV applied to 660 lung ADC and 484 lung SqCC exomes; identified 38 SMGs in ADC and 20 in SqCC (q < 0.1); 14 additional SMGs in the pan-lung joint analysis PMID:27158780
  • MutSig used for driver gene identification (FDR<0.1) in 216 metastatic breast cancer exomes, yielding 12 significantly mutated genes including ESR1 and RB1 as metastasis-specific drivers PMID:28027327.
  • MutSigCV2.0 applied to identify significantly mutated genes in 164 oesophageal carcinomas, yielding TP53, NFE2L2, KMT2D, ZNF750, NOTCH1, TGFBR2 in ESCC and TP53, CDKN2A, ARID1A, SMAD4, ERBB2 in EAC PMID:28052061.
  • MutSig2 applied to 173 PCPG tumors identifying five significant somatic driver genes (q < 0.05): HRAS, NF1, EPAS1, RET, and the novel driver CSDE1 PMID:28162975.
  • MutSigCV used alongside IntOGen to identify 32 significantly mutated genes (SMGs) at q < 0.1 in 489 CCA cases, including four newly nominated driver genes: RASA1, STK11, MAP2K4, and SF3B1 PMID:28667006
  • Driver detection tool used alongside GenomeMuSiC and IntOGen to call SMGs across 491 medulloblastoma cases, assigning driver events to 76% of Group 3 and 82% of Group 4 patients PMID:28726821
  • MutSig 2CV applied to 412 BLCA tumors identifying 58 significantly mutated genes (q<0.1); 34 were new vs the prior 131-tumor cohort, including KMT2C (18%), ATM (14%), CREBBP (12%) PMID:28988769
  • MuSiC (Genome MuSiC) and MutSig 2CV applied to 206 TCGA sarcomas identifying only 3 significantly mutated genes (FDR<0.05): TP53, ATRX, RB1 PMID:29100075
  • MutSig2CV identified PBRM1 as the only recurrently mutated gene enriched in anti-PD-1 responders (9/11 vs 3/13 CB vs NCB; p=0.012) in 35 metastatic CCRCC WES samples PMID:29301960
  • Applied with MuSiC to identify 47 significantly recurrently mutated genes in 1,027 MSS colorectal adenocarcinomas, including APC (79%), TP53 (78%), KRAS (44%), PIK3CA (18%), and SMAD4 (16%) PMID:29316426
  • MutSig2CV (P < 3.5e-5) applied to KIRC PASS variants from the MC3 open-access MAF; identified 10 SMGs; the unfiltered MAF inflated the list to 1,203 SMGs, demonstrating the necessity of stringent filtering PMID:29596782
  • MutSig2CV (integrating MutSigCV, MutSigFN, MutSigCL) applied to 1,013 prostate WES samples with additional biological filters (≥10 altered samples, allelic-fraction floors, length/expression/oncogenic-variant filters); identified 97 SMGs PMID:29610475

Notes

  • MutSig relies on a background mutation model; covariates include expression levels, replication timing, and trinucleotide context.
  • At a q <= 0.1 threshold in the DLBCL study, confirmed known drivers (MYD88, CARD11, EZH2, CREBBP, CD79B, TP53) and identified novel candidates (MEF2B, KMT2D, BTG1, GNA13, ACTB, P2RY8, TNFRSF14) PMID:22343534.
  • A complementary rare-driver analysis using mutational clustering and evolutionary conservation identified KRAS, BRAF, NOTCH1, and SYK as likely drivers not captured by MutSig alone PMID:22343534.
  • Not a sequencing panel; lacks a cBioPortal genePanelId.

Sources

  • PMID:22343534 — DLBCL WES study where MutSig identified 58 significantly mutated genes.

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