BRCA1

Overview

BRCA1 is a tumor suppressor gene encoding a protein critical for homologous recombination (HR) DNA repair. Germline and somatic BRCA1 mutations predispose to breast, ovarian, and other cancers. BRCA1 alterations define homologous recombination deficiency (HRD) and sensitivity to PARP inhibitors and platinum agents. In the corpus, BRCA1 alterations are documented across HGSOC precursors, endometrial carcinoma (with racial disparities), anaplastic thyroid carcinoma, prostate cancer, and cervical cancer.

Alterations observed in the corpus

Germline BRCA1 mutations in 12 of 44 HGSOC patients in a multimodal spatial profiling study of fallopian tube precursor lesions (p53 signatures, STICs); somatic or germline BRCA1/2 alterations or epigenetic silencing account for nearly half of HGSOC exhibiting homologous recombination deficiency PMID:39386723.
Somatic BRCA1 mutations more frequent in CN-H/TP53abn endometrial carcinoma from Black patients (3% vs 0.3%) in a 1,025-patient molecular characterization study PMID:37651310.
Recurrent somatic BRCA1 mutations detected at both SNV and CNA levels in anaplastic thyroid carcinoma (ATC) in a multi-omic landscape study PMID:38412093.
BRCA1 alterations detected in 4% of advanced HCC patients by cfDNA profiling (MSK-ACCESS, 51 patients); combined BRCA1/2 alterations in 8% PMID:37769223.
Pathogenic somatic BRCA1 alterations in 1 of 3 cervical cancer patients with BRCA alterations in a 177-patient cervical cancer genomic landscape study PMID:37643132.
ATM, BRCA1, BRCA2, and CHEK2 — DDR pathway genes with driver genomic alterations predominantly in adenocarcinoma prostate cancer PDXs; NEPC showed transcriptomic DDR upregulation instead PMID:38488813.
BRCA1 mutations elevated in MSI-H/dMMR prostate cancer (higher mutation rate in MSI-H/dMMR vs TMB-L/MSS; likely passenger events rather than actionable alterations) PMID:38949888.
BRCA1 significantly over-expressed (FDR < 0.01, Welch’s t-test) in the undifferentiated nC3 cluster of high-risk neuroblastoma tumors in a single-nuclei transcriptomic study of 11 tumors; nC3 is enriched for MYCN-amplified and/or 11q-deleted genotypes PMID:34493726.
Pathogenic germline/somatic BRCA1 variants — along with other HRD-DDR gene alterations — used as the primary basis for HRD subtype assignment in a 444-patient HGSOC multimodal risk-stratification study; HRD status alone yielded only modest OS discrimination (concordance index 0.52) PMID:35764743.
Germline pathogenic BRCA1 alterations in 1.8% of PAAD overall; strong selection for biallelic LOH in carriers; co-occurrence with somatic TP53 mutations (P = 4 × 10⁻⁷) in a 2,336-tumor PDAC genomic cohort PMID:39753968.
BRCA1 alterations detected in 6 cases (3%) in a cfDNA study of metastatic urothelial carcinoma (mUC, n=200 patients, CALGB 90601); pooled into underpowered DDR analysis PMID:40256659.
Germline P/LP variants identified as incidental findings in KIT/PDGFRA-mutant GISTs in paired tumor-normal sequencing PMID:36593350
Germline/somatic mutations define HRD-Dup subtype with tandem duplications in HGSOC; 36/116 patients with LOH in any HLA class I gene in validation cohort PMID:36517593
BRCA1 screened as DDR candidate in FBXO7 synthetic lethality study; referenced for PARP inhibitor SL paradigm PMID:36334560
BRCA1 oncogenic mutations in 3 GBC patients (OncoKB level 3B); associated with HRD and PARP inhibitor eligibility PMID:36228155
Found mutated or epigenetically silenced in ~20% of HGSOC tumors in TCGA integrated genomic analysis of ovarian carcinoma PMID:21720365
BRCA1 somatic mutations identified in breast cancer WES of 100 tumors as part of the driver gene landscape PMID:22722201
Mutated in breast cancer (TCGA, 510 tumors); BRCA1 mutations enriched in basal-like subtype, associated with triple-negative phenotype and genomic instability PMID:23000897
Two missense mutations observed in ACC WES cohort (n=60); classified in the DNA-damage response pathway PMID:23685749
Inactivating mutation contributing to G2/M checkpoint pathway alteration in transitional cell carcinoma (TCC) of the bladder PMID:24121792
Zero of 23 pancreatic acinar carcinomas showed BRCA1 locus methylation by qMSP; no somatic mutations identified PMID:24293293
HBOC gene included in the standard multigene panel for hereditary/familial gastric cancer risk stratification PMID:24816255
Truncating somatic mutation in one ERCC2-WT cisplatin responder in muscle-invasive urothelial carcinoma; absent in non-responders PMID:25096233
Direct EWS::FLI1 transcriptional target (binding to exons 11 and 15) in Ewing sarcoma; upregulated in EF-heMSCs and primary Ewing tumors but functionally compromised (reduced phospho-BRCA1, dispersed foci, defective DDR by comet assay) — supports BRCA1-loss-of-function-despite-elevated-expression model of Ewing chemosensitivity PMID:25186949
Mutations in ~3–5% of CCA; provides rationale for PARP inhibitors and platinum agents PMID:25526346
No mutations observed in the 78-case discovery cohort of gastric cancer; contrast with BRCA2 which was mutated in 5.8% of cases PMID:25583476
DNA double-strand-break and Fanconi-anaemia pathway lesion enriched in high-CNV PDA clusters; nominates olaparib (PARP inhibitor) and cross-linking agents (mitomycin-C) as therapeutic candidates PMID:25855536
Biallelic loss (somatic + germline) in mCRPC contributing to 19.3% DNA-repair pathway aggregate; part of 22.7% broader DNA-repair alteration rate PMID:26000489
1 germline frameshift (V923, ClinVar RCV000083190.3) in primary prostate cancer; BRCA1 loss contributes to the 19% DNA-repair-gene-defect prevalence supporting PARP-inhibitor candidacy PMID:26544944
BRCA1 included in the Fanconi anemia pathway gene set upregulated in high-cell-cycle-progression mCRPC tumors (linked to RB1 loss/E2F1 activation); homozygous deleterious BRCA1 events were used as part of the DNA-repair-defect classifier predicting longer carboplatin response (P = 0.02) PMID:26928463
Inactivating/germline mutations identified in breast cancer within the METABRIC 2,433-sample cohort; pathogenic germline classification performed in-cohort; flagged as cross-cancer driver PMID:27161491
BRCA1 pathogenic germline variants enriched in young lung cancer (OR=4.1); specific variant p.Cys47Arg reported by Donner et al. PMID:27346245
Germline BRCA1 frameshift variants found in two pediatric patients (nested stromal epithelial liver tumor and ependymoma); returned as ACMG secondary findings with breast-cancer health-maintenance flag PMID:28007021
BRCA1 is recruited to DSBs via TRMT10A pSer28; BRCA1 recruitment (but not protein abundance) is impaired by TRMT10A or USP10 loss, and BRCA1 knockdown phenocopies TRMT10A loss for PARPi sensitivity in prostate cancer PMID:28068672
3 likely-inactivating truncating mutations (0.3%) in LUAD (MSK-IMPACT, n=860); level 2B actionability based on olaparib approval in BRCA-mutant ovarian carcinoma; no patient received matched PARP-inhibitor therapy PMID:28336552
Less frequent DDR alteration in high-grade non-muscle-invasive bladder cancer (NMIBC), contributing to the 30% DDR-altered fraction; DDR-altered tumors carry markedly elevated mutational burden supporting checkpoint immunotherapy PMID:28583311
BRCA1 enriched in Cluster 1 of cholangiocarcinoma (p < 0.05) PMID:28667006
BRCA1 germline PPGMs significantly enriched vs. ExAC in MET500 pan-cancer metastatic cohort (5 PPGM carriers); HR deficiency from BRCA1 alterations implies PARP inhibitor sensitivity PMID:28783718
BRCA1 is a germline DDR gene contributing to the 27% combined HR-deficiency rate in prostate cancer; combined germline+somatic frequency drives PARP-inhibitor and platinum sensitivity rationale PMID:28825054
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Alterations in BRCA1 observed in 22% of MSI-H vs 1% of MSS mCRC tumors in a 1,122-patient panel sequencing cohort PMID:29316426.
One missense BRCA1 LP/PV was identified in a pediatric cancer predisposition cohort (n=372); burden test was non-significant (OR=1.9, p=0.406). PMID:29489754

Cancer types (linked)

OVT — Germline BRCA1 mutations present in HGSOC precursor studies; HRD via BRCA1/2 is the primary therapeutic vulnerability for platinum and PARP inhibitors PMID:39386723.
UCEC — Somatic BRCA1 mutations enriched in Black EC patients with CN-H/TP53abn subtype PMID:37651310.
CESC — Pathogenic somatic BRCA1 alterations in a subset of cervical cancers PMID:37643132.
THPA — Recurrent somatic BRCA1 SNVs and CNAs in anaplastic thyroid carcinoma PMID:38412093.
HCC — BRCA1/2 detected by cfDNA in 8% of advanced HCC; actionable (OncoKB level) PMID:37769223.
PRAD — DDR gene alterations in prostate cancer adenocarcinoma PDXs; MSI-H/dMMR prostate cancers show elevated BRCA1 as likely passengers PMID:38488813 PMID:38949888.
Neuroblastoma (NBL) — BRCA1 over-expression marks the high-risk undifferentiated nC3 cluster at single-nuclei resolution; significance confirmed at FDR < 0.01 PMID:34493726.

Co-occurrence and mutual exclusivity

In HGSOC, BRCA1/2 germline mutations define a subset with HRD; somatic loss via epigenetic silencing contributes to a similar proportion of HRD cases PMID:39386723.
In MSI-H/dMMR prostate cancer, elevated BRCA1/2 mutation rates may represent subclonal or passenger events rather than primary drivers PMID:38949888.

Therapeutic relevance

BRCA1 alterations are actionable (OncoKB level) across multiple cancer types; PARP inhibitors (olaparib, niraparib) and platinum-based regimens are established HRD-targeting strategies PMID:37769223.
In ATC, recurrent DDR gene alterations (BRCA1, BRCA2, ATM) rationalize investigation of PARP inhibitors in this aggressive, largely therapy-refractory cancer type PMID:38412093.

Open questions

Whether elevated BRCA1 mutation rates in MSI-H/dMMR prostate cancer represent actionable targets or passenger events needs prospective functional validation PMID:38949888.
Whether somatic BRCA1 mutations (3%) in Black CN-H/TP53abn EC are sufficient to confer HRD sensitivity to PARP inhibitors in this molecularly distinct population is untested PMID:37651310.

Sources

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