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DNA repair genes. Inheriting a broken copy raises breast and ovarian cancer risk, but tumours that lose them become uniquely vulnerable to PARP inhibitors and platinum.
BRCA1 and BRCA2 are homologous recombination repair genes; a tumour that loses both copies must rely on error-prone repair, which makes it uniquely vulnerable to PARP inhibitors and platinum. Germline BRCA1/2 mutations account for roughly 5 to 10 percent of breast cancers and about 15 percent of ovarian cancers, with 10 to 20 percent of triple-negative breast cancers (mostly BRCA1) and 3 to 5 percent of HR-positive cases (mostly BRCA2); BRCA2 alterations occur in 8 to 12 percent of metastatic prostate cancers and germline BRCA1/2 in 5 to 8 percent of pancreatic cancers. Homologous recombination deficiency (HRD) extends the phenotype to BRCA-wild-type tumours and is measured by genomic scars (myChoice CDx). HRD predicts benefit from PARP inhibitors and platinum, though the best assay and cut-off remain debated. The same genes guide both prevention and treatment.
In plain words · DNA repair genes. Inheriting a broken copy raises breast and ovarian cancer risk, but tumours that lose them become uniquely vulnerable to PARP inhibitors and platinum.
Backbone ribbon from PDB 7KK4. RCSB PDB 7KK4. The ribbon widens where the chain is folded into a regular pattern and narrows where it is a loose loop.
Backbone ribbon with the bound drug in ball-and-stick (pink carbons). The wireframe view adds the pocket residues within 5 Å as a thin cage.
DNA repair genes. Inheriting a broken copy raises breast and ovarian cancer risk, but tumours that lose them become uniquely vulnerable to PARP inhibitors and platinum.
Homologous recombination repair; loss forces reliance on error-prone pathways.
6 products aim at BRCA1 / BRCA2 (HRD): small molecules and other agents. Because the protein is lost rather than overactive, drugs either restore its function or exploit the weakness its loss leaves (synthetic lethality).
Germline variant: UniProt lists Breast cancer (BC); Breast cancer (BC) under involvement in disease, and the record is a tumour suppressor; the medicines linked to it act through the loss (synthetic lethality) or use the variant to pick patients. HPA BRCA1: RNA low tissue specificity; blood lineage group enriched (dendritic cells 11 nTPM, granulocytes 11 nTPM, monocytes 15 nTPM); high antibody staining in 1 normal tissue; highest cancer staining breast cancer (4 of 12 high). HPA BRCA2: RNA tissue enhanced (bone marrow 5 nTPM, lymphoid tissue 4 nTPM, testis 3 nTPM); no normal tissue stained high; highest cancer staining melanoma (3 of 11 high). Distribution: 5 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Breast cancer (all types), Ovarian cancer, Prostate cancer, Pancreatic ductal adenocarcinoma, Biliary tract cancer (all types)); Open Targets associates it with 35 specific cancer types at or above 0.5 (breast cancer, hereditary breast ovarian cancer syndrome, ovarian cancer, breast-ovarian cancer, familial, susceptibility to, 1, breast carcinoma, BRCA1-related cancer predisposition and more). (Rule 2 of scripts/fetch-target-specificity.ts.)
Sources: UniProt P38398; UniProt P51587; Human Protein Atlas BRCA1 tissue; Human Protein Atlas BRCA2 tissue; Open Targets ENSG00000012048 associations; Open Targets ENSG00000139618 associations
What a pathology or genomic report can say about this target, each with the thresholds approvals use.
Cell lines and mouse models for this target →
Homologous recombination repair; loss forces reliance on error-prone pathways.
RNA: low tissue specificity, detected in all normal tissues. Blood: group enriched (dendritic cells 11 nTPM, granulocytes 11 nTPM, monocytes 15 nTPM).
Medium: Adrenal gland, Appendix, Bone marrow, Breast, Caudate, Cerebellum, Cerebral cortex, Cervix.
Medium only: carcinoid, endometrial cancer, liver cancer, pancreatic cancer.
RNA: tissue enhanced (bone marrow 5 nTPM, lymphoid tissue 4 nTPM, testis 3 nTPM), detected in some normal tissues.
No normal tissue stained high.
Medium only: breast cancer, carcinoid, colorectal cancer, endometrial cancer.
HPA BRCA2 tissue · HPA BRCA2 pathology · HPA protein class: Essential proteins
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Triple-negative breast cancer | 15-20% | Germline BRCA1/2 | BRCA1 predominant | Wikipedia |
| Ovarian cancer | 15-20% | Germline BRCA1/2; ~25% including somatic | Wikipedia | |
| Prostate cancer | 8-12% | Germline or somatic BRCA2 (metastatic) | cBioPortal (TCGA) | |
| Triple-negative breast cancer | 7-11% | Germline pathogenic variant | 8.5% of 1,824 TNBC patients unselected for family history (Couch 2015); 11.1% of 207 registry patients (Sharma 2014); BRCA1 and BRCA2 together 17.2% (50 of 291) in GeparSixto (Hahnen 2017) and 11.2% (Couch 2015); pathogenic variants in the TNBC risk genes BARD1, BRCA1, BRCA2, PALB2 and RAD51D in 12.0% of 10,901 patients, 3.7% outside BRCA1/2 (Shimelis 2018). Biallelic loss of BRCA1 or BRCA2 in 29 of 237 whole genomes, 20 germline and 9 somatic (Staaf 2019). | doi.org |
| Prostate cancer | 3-11% | Inactivating mutation, germline or somatic, plus deep deletion | cBioPortal mutation: 8 of 494, 1.6%, in prad_tcga_pan_can_atlas_2018; 29 of 1,013, 2.9%, in prad_p1000; 19 of 424, 4.5%, in prad_mcspc_mskcc_2020; 91 of 2,260, 4.0%, in prostate_msk_2024; 37 of 444, 8.3%, in prad_su2c_2019; 10 of 150, 6.7%, in prad_su2c_2015. Deep deletion adds 2.2 to 11.5% (17 of 489, 3.5%, in prad_tcga_pan_can_atlas_2018; 13 of 444, 2.9%, in prad_su2c_2019; 7 of 61, 11.5%, in prad_mich). Germline: 37 of 692 men with metastatic disease unselected for family history, 5.3% (Pritchard 2016). | cBioPortal (TCGA) |
| Pancreatic ductal adenocarcinoma | 5-8% | Germline BRCA1/2 | cBioPortal (TCGA) | |
| HR-positive / HER2-negative breast cancer | 3-5% | Germline BRCA1/2 | BRCA2 predominant | Wikipedia |
| Triple-negative breast cancer | 3-4% | Germline pathogenic variant | 2.7% of 1,824 unselected patients (Couch 2015); 4.3% of 207 (Sharma 2014); somatic calls in 5 of 123, 4.1%, in brca_tcga_pan_can_atlas_2018, 7 of 299, 2.3%, in brca_metabric and 8 of 176, 4.5%, in breast_msk_2018 (cBioPortal). Metastatic TNBCs carried somatic biallelic loss-of-function mutations in homologous recombination genes in 7% against 2% of early TNBCs (Bertucci 2019). | doi.org |
| Gallbladder cancer | 1-5% | Mutation (somatic or germline) | BRCA2 mutation in 13 of 244 samples, 5.3%, and BRCA1 in 3 of 244, 1.2%, in cBioPortal gbc_mskcc_2022; oncogenic BRCA1/2 variants among the actionable findings (Giraldo 2022); deleterious germline variants in BRCA1, BRCA2, RAD51D, MLH1 or MSH2 in 11% (16 of 146) of biliary tract cancer patients (Wardell 2018); gallbladder tumours had the highest rate of homologous recombination repair deficiency among biliary sites (Weinberg 2019). | cBioPortal (TCGA) |
| Pancreatic ductal adenocarcinoma | 1.4-2% | Germline pathogenic variant | 1.9% of 3,030 patients against 0.3% of controls, odds ratio 6.20 (Hu 2018); 12 of 854 apparently sporadic patients, 1.4% (Shindo 2017); 4 of 289 resected patients (Yurgelun 2019); 49 of 71 BRCA carriers in a three-centre series were BRCA2 (Golan 2014). Tumour sequencing (germline and somatic together): 67 of 2,336, 2.9%, in pdac_msk_2024; 8 of 383, 2.1%, in paad_qcmg_uq_2016; 11 of 395, 2.8%, in pancreas_msk_2024; 2 of 179 in paad_tcga_pan_can_atlas_2018 (cBioPortal). POLO screened 3,315 metastatic patients to randomise 154 germline BRCA1/2 carriers (Golan 2019). | doi.org |
| Prostate cancer | 0.2-2% | Inactivating mutation, germline or somatic | cBioPortal mutation: 1 of 494, 0.2%, in prad_tcga_pan_can_atlas_2018; 6 of 1,013, 0.6%, in prad_p1000; 1 of 424, 0.2%, in prad_mcspc_mskcc_2020; 18 of 2,260, 0.8%, in prostate_msk_2024; 8 of 444, 1.8%, in prad_su2c_2019. Germline: 6 of 692, 0.9% (Pritchard 2016). | cBioPortal (TCGA) |
| Pancreatic ductal adenocarcinoma | 0.4-1% | Germline pathogenic variant | 0.6% of 3,030 against 0.2% of controls, odds ratio 2.58 (Hu 2018); 3 of 854, 0.4% (Shindo 2017); 3 of 289 (Yurgelun 2019); 21 of 71 BRCA carriers (Golan 2014). Tumour sequencing: 16 of 2,336, 0.7%, in pdac_msk_2024; 5 of 383 in paad_qcmg_uq_2016; 2 of 179 in paad_tcga_pan_can_atlas_2018 (cBioPortal). | doi.org |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
The inherited BRCA test that decides who can have PARP inhibitor pills for ovarian, breast, pancreatic and prostate cancer.
A tumour test that measures DNA-repair scarring so that women with ovarian cancer beyond BRCA carriers can benefit from PARP inhibitors.
Olaparib was the first PARP inhibitor, and turned an inherited BRCA mutation from a risk factor into a drug target, including after surgery in breast cancer.
A PARP inhibitor for BRCA-mutated ovarian and prostate cancer whose original maker went bankrupt; still available, with a narrowed label.
Talazoparib is a PARP inhibitor that traps PARP on DNA about 100 times more strongly than olaparib, which is why it works at a 1 mg daily dose. It is approved for germline BRCA-mutant HER2-negative breast cancer and, with enzalutamide, for HRR-mutant castration-resistant prostate cancer; anaemia is its dominant side effect.
Veliparib is a PARP inhibitor that AbbVie tested with chemotherapy in breast cancer. It added nothing to carboplatin before surgery (BrighTNess) and lengthened progression-free but not overall survival with carboplatin and paclitaxel in inherited BRCA advanced disease (BROCADE3), so it was never licensed.
The 48 most recent of 69 papers; see them all →
This is what the NHS R208 pathway yields in practice: a one-in-seven positive rate among the eligible, at the cost of clinician time spent on eligibility scoring.
Answers the two questions that hung over adjuvant olaparib, durability and late leukaemia, in its favour; the remaining question is whether carriers who also received pembrolizumab or capecitabine, whom the trial did not study, get the same benefit.
An argument for universal rather than criteria-based germline testing at diagnosis, with turnaround fast enough to inform surgery; for TNBC patients, who are already eligible, the lesson is timing.
Chile has the world's highest gallbladder cancer mortality and until this paper almost no tumour genomics; the lower TP53 rate and high TSC2 and NOTCH1 hint at a different mutational grammar, but the panel and sample size mean the figures need replication.
For TNBC, which is diagnosed young and is the PARP inhibitor-eligible subtype, the guideline makes germline testing part of the diagnostic workup rather than a referral decision.
The randomised proof for PARP inhibition in BRCA-altered prostate cancer, and the clearest evidence that the homologous recombination repair gene list should not be used as a single yes-or-no test. ATM-altered disease needs a different answer, and does not yet have one.
Confirms that the TROP2 antibody-drug conjugates are given without a TROP2 test and that PD-L1 remains the one selection assay in metastatic triple-negative disease, which is why assay harmonisation matters.
The reference Western cohort for gallbladder cancer frequencies, deposited on cBioPortal as gbc_mskcc_2022, where the per-gene sample counts on OnCo were read. It supports panel testing at diagnosis: one patient in three has a targetable finding.
Query for this target: (TITLE:"BRCA1 / BRCA2" OR ABSTRACT:"BRCA1 / BRCA2" OR TITLE:"HRD" OR ABSTRACT:"HRD" OR TITLE:"BRCA1" OR ABSTRACT:"BRCA1" OR TITLE:"BRCA2" OR ABSTRACT:"BRCA2") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about BRCA1 / BRCA2 (HRD), not a curated reading list.
Shares Christopher Lord, Jonathan A. Ledermann, Thomas Helleday, Alan D. D'Andrea.
Shares Genomic hallmarks and structural variation in metastatic prostate cancer, Circulating tumour DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer, Genomic analysis of circulating tumour DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms, Circulating tumour DNA fraction (and what a negative plasma result means) and the tag biomarker.
Shares Comprehensive molecular characterization of gallbladder carcinoma and potential targets for intervention, Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers, Gallbladder cancer, Triple-negative breast cancer (TNBC) and the tag biomarker.
Shares HRD-positive (genomic instability score), Tumour (somatic or germline) BRCA1/2 mutation and HRR gene alterations, High-grade serous ovarian cancer, Ovarian cancer and the tag biomarker.
Shares Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations, Gallbladder cancer, Triple-negative breast cancer (TNBC), Pancreatic ductal adenocarcinoma and the tag biomarker.
Shares Comprehensive molecular characterization of gallbladder carcinoma and potential targets for intervention, Gallbladder cancer, Triple-negative breast cancer (TNBC), Pancreatic ductal adenocarcinoma and the tag biomarker.
Shares Molecular profiling of biliary cancers reveals distinct molecular alterations and potential therapeutic targets, Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update, Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem, Gallbladder cancer and the tag biomarker.
Shares Comprehensive molecular characterization of gallbladder carcinoma and potential targets for intervention, Gallbladder cancer, Pancreatic ductal adenocarcinoma and the tag biomarker.