{"entity":{"id":"paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016","kind":"paper","name":"Inherited DNA-repair gene mutations in men with metastatic prostate cancer","aka":["Pritchard 2016","germline DNA repair metastatic prostate 11.8 percent"],"tldr":"Nearly one man in eight with prostate cancer that has spread carries an inherited fault in a DNA repair gene, most often BRCA2. Family history and age at diagnosis did not predict who: the only way to find them is to test everybody.","summary":"Colin Pritchard, Peter Nelson, Joaquin Mateo and colleagues recruited 692 men with documented metastatic prostate cancer, unselected for family history or age at diagnosis, and used multiplex sequencing to look for germline mutations in 20 DNA repair genes associated with autosomal dominant cancer predisposition syndromes.\n\nThe result is one of the cleanest arguments for universal testing in oncology. The mutation frequency was 11.8 percent in metastatic disease against 4.6 percent in 499 men with localised disease and 2.7 percent in 53,105 people in the Exome Aggregation Consortium without a known cancer diagnosis, and it did not differ according to whether there was a family history of prostate cancer or according to age at diagnosis. A selective testing policy based on family history would therefore miss most carriers.","asOf":"2026-09-25","links":[{"label":"N Engl J Med 2016","url":"https://doi.org/10.1056/nejmoa1603144"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/27433846/"},{"label":"Pritchard et al., N Engl J Med 2016: inherited DNA-repair gene mutations in 692 men with metastatic prostate cancer unselected for family history","url":"https://doi.org/10.1056/NEJMoa1603144"}],"tags":["prostate-evidence"],"related":["paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015","paper-mateo-toparp-a-olaparib-dna-repair-nejm-2015","paper-struewing-brca-founder-mutations-ashkenazi-nejm-1997","idea-prev-reflex-germline-testing","prostate-roadmap"],"cancers":["prostate","prostate-mhspc","prostate-mcrpc"],"sections":["diagnostics","prevention","targeted-therapy"],"technologies":["germline-testing","cgp"],"targets":["brca","atm","chek2","palb2","rad51d"],"drugs":[],"companies":[],"institutions":["fred-hutch","royal-marsden"],"pathways":["homologous-recombination-repair","ddr"],"terms":["hrd","ngs","germline-vs-somatic","gbrca-mutation","lynch-syndrome"],"trials":[],"people":[],"bottlenecks":["b-hereditary-risk","b-biomarker-validation","b-care-fragmentation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2016,"doi":"10.1056/nejmoa1603144","pmid":"27433846","authors":"Pritchard CC, Mateo J, Walsh MF, et al.","paperType":"observational","findings":["84 presumed deleterious germline DNA repair gene mutations were identified in 82 of 692 men (11.8 percent) with metastatic prostate cancer.","Mutations were found in 16 genes: BRCA2 in 37 men (5.3 percent), ATM in 11 (1.6 percent), CHEK2 in 10 (1.9 percent of 534 men with data), BRCA1 in 6 (0.9 percent), RAD51D in 3 (0.4 percent) and PALB2 in 3 (0.4 percent).","Mutation frequencies did not differ according to whether a family history of prostate cancer was present or according to age at diagnosis.","The 11.8 percent frequency significantly exceeded the 4.6 percent prevalence among 499 men with localised prostate cancer, including high-risk disease (P less than 0.001).","It also exceeded the 2.7 percent prevalence in the Exome Aggregation Consortium, which includes 53,105 people without a known cancer diagnosis (P less than 0.001)."],"whatItMeans":"The evidence that made germline testing standard for every man with metastatic prostate cancer, whatever his family history. It changes his treatment, because PARP inhibitors and platinum work better in these tumours, and it changes his relatives' screening, because BRCA2 carries breast, ovarian and pancreatic risk as well.","caveats":["Men recruited at academic centres with an interest in genetics, so ascertainment is not fully unselected despite the design.","20 genes on the panel; a wider panel would find more variants of uncertain significance without necessarily finding more actionable ones.","The clinical benefit of finding a CHEK2 or ATM variant is much less well established than for BRCA2; ATM tumours respond poorly to PARP inhibitors, as TRITON3 showed."],"changedPractice":true,"participants":692},"route":"/key-papers/paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016/","neighbours":{"paper":[{"id":"paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015","kind":"paper","name":"SU2C-PCF: integrative clinical genomics of advanced prostate cancer","route":"/key-papers/paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015/"},{"id":"paper-struewing-brca-founder-mutations-ashkenazi-nejm-1997","kind":"paper","name":"The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews","route":"/key-papers/paper-struewing-brca-founder-mutations-ashkenazi-nejm-1997/"},{"id":"paper-mateo-toparp-a-olaparib-dna-repair-nejm-2015","kind":"paper","name":"TOPARP-A: DNA-repair defects and olaparib in metastatic prostate cancer","route":"/key-papers/paper-mateo-toparp-a-olaparib-dna-repair-nejm-2015/"},{"id":"paper-conti-trans-ancestry-gwas-prostate-nat-genet-2021","kind":"paper","name":"Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction","route":"/key-papers/paper-conti-trans-ancestry-gwas-prostate-nat-genet-2021/"},{"id":"paper-fizazi-triton3-rucaparib-nejm-2023","kind":"paper","name":"TRITON3: rucaparib or physician's choice in metastatic castration-resistant prostate cancer","route":"/key-papers/paper-fizazi-triton3-rucaparib-nejm-2023/"}],"idea":[{"id":"idea-prev-reflex-germline-testing","kind":"idea","name":"Automatic germline testing for every cancer type where it changes care","route":"/ideas/idea-prev-reflex-germline-testing/"},{"id":"idea-prostate-hrr-testing-at-metastatic-diagnosis","kind":"idea","name":"Test every man for DNA repair faults on the day his prostate cancer is found to have spread, not three treatments later","route":"/ideas/idea-prostate-hrr-testing-at-metastatic-diagnosis/"}],"roadmap":[{"id":"prostate-roadmap","kind":"roadmap","name":"Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch","route":"/roadmaps/prostate-roadmap/"}],"cancer":[{"id":"prostate-mcrpc","kind":"cancer","name":"Metastatic castration-resistant prostate cancer","route":"/cancers/prostate-mcrpc/"},{"id":"prostate-mhspc","kind":"cancer","name":"Metastatic hormone-sensitive prostate cancer","route":"/cancers/prostate-mhspc/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"section":[{"id":"diagnostics","kind":"section","name":"Diagnostics & Biomarkers","route":"/fronts/diagnostics/"},{"id":"prevention","kind":"section","name":"Prevention & Risk","route":"/fronts/prevention/"},{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"germline-testing","kind":"technology","name":"Germline (hereditary) testing","route":"/technologies/germline-testing/"}],"target":[{"id":"atm","kind":"target","name":"ATM","route":"/targets/atm/"},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"},{"id":"chek2","kind":"target","name":"CHEK2","route":"/targets/chek2/"},{"id":"palb2","kind":"target","name":"PALB2","route":"/targets/palb2/"},{"id":"rad51d","kind":"target","name":"RAD51D","route":"/targets/rad51d/"}],"institution":[{"id":"fred-hutch","kind":"institution","name":"Fred Hutchinson Cancer Center","route":"/institutions/fred-hutch/"},{"id":"royal-marsden","kind":"institution","name":"The Royal Marsden","route":"/institutions/royal-marsden/"}],"pathway":[{"id":"ddr","kind":"pathway","name":"DNA damage response & homologous recombination","route":"/pathways/ddr/"},{"id":"homologous-recombination-repair","kind":"pathway","name":"Double-strand break repair: HR versus end joining","route":"/pathways/homologous-recombination-repair/"}],"term":[{"id":"gbrca-mutation","kind":"term","name":"Germline BRCA mutation (gBRCA)","route":"/terms/gbrca-mutation/"},{"id":"germline-vs-somatic","kind":"term","name":"Germline vs somatic mutations","route":"/terms/germline-vs-somatic/"},{"id":"hrd","kind":"term","name":"Homologous recombination deficiency (HRD)","route":"/terms/hrd/"},{"id":"lynch-syndrome","kind":"term","name":"Lynch syndrome","route":"/terms/lynch-syndrome/"},{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"}],"bottleneck":[{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"},{"id":"b-care-fragmentation","kind":"bottleneck","name":"Fragmented care and guideline gaps","route":"/bottlenecks/b-care-fragmentation/"},{"id":"b-hereditary-risk","kind":"bottleneck","name":"Inherited risk is mostly unidentified","route":"/bottlenecks/b-hereditary-risk/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}],"biomarker":[{"id":"brca-germline","kind":"biomarker","name":"Germline BRCA1/2 pathogenic variant (gBRCAm)","route":"/biomarkers/brca-germline/"},{"id":"hrr-gene-mutation","kind":"biomarker","name":"Homologous recombination repair gene mutation in prostate cancer","route":"/biomarkers/hrr-gene-mutation/"}]}}