{"entity":{"id":"paper-gabai-kapara-population-brca-screening-pnas-2014","kind":"paper","name":"Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2","aka":[],"tldr":"The study that made population-wide BRCA testing defensible. Instead of measuring risk in families already known to cancer clinics, it found carriers among healthy men and then followed their female relatives, and the risk turned out to be just as high.","summary":"The objection to offering BRCA testing to everyone in a population was that the risk figures came from families referred to cancer genetics clinics, who are selected for having a lot of cancer. Ephrat Levy-Lahad and Mary-Claire King's answer was to start somewhere with no such selection. Between June 2004 and December 2010 they recruited healthy Ashkenazi Israeli men aged 30 and over with no personal history of cancer from health-screening centres and outpatient clinics: 8,222 enrolled, 8,195 (99.7 percent) were successfully genotyped for the three founder variants. Female relatives of the carriers were then enrolled and genotyped.\n\nCarrier frequency was 1.14 percent for BRCA1 and 1.03 percent for BRCA2, 2.17 percent combined. Among fully genotyped sibships, cumulative risk of breast or ovarian cancer was 0.60 by age 60 and 0.83 by age 80 for BRCA1 carriers, and 0.33 by 60 and 0.76 by 80 for BRCA2 carriers. Risk was higher in later birth cohorts: 3.8-fold higher age-specific risk for carriers born after 1958 than for those born in or before it.\n\nThe decisive number for policy is that 51 percent of the 167 carrier families had little or no relevant cancer history, so testing triggered by family history would have missed them; and only 35 percent of the 82 families that did have a high cancer burden had ever been referred for genetic counselling, in a country with universal health coverage. Israel began offering the three-variant test to every woman of Ashkenazi origin in January 2020.","asOf":"2026-09-25","links":[{"label":"PNAS 2014","url":"https://doi.org/10.1073/pnas.1415979111"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25192939/"}],"tags":[],"related":[],"cancers":["breast-hr-positive","ovarian"],"sections":["prevention"],"technologies":["germline-testing"],"targets":["brca"],"drugs":[],"companies":[],"institutions":["shaare-zedek","sheba"],"pathways":[],"terms":["founder-variant"],"trials":[],"people":["ephrat-levy-lahad","eitan-friedman"],"bottlenecks":["b-hereditary-risk"],"keyPapers":[],"journals":["pnas"],"dependsOn":[],"notes":[],"journal":"Proceedings of the National Academy of Sciences","year":2014,"doi":"10.1073/pnas.1415979111","pmid":"25192939","authors":"Gabai-Kapara E, Lahad A, Kaufman B, Friedman E, Segev S, Renbaum P, Beeri R, Gal M, Grinshpun-Cohen J, Djemal K, Mandell JB, Lee MK, Beller U, Catane R, King MC, Levy-Lahad E","paperType":"observational","findings":["Carrier frequency among 8,195 genotyped healthy Ashkenazi Israeli men: BRCA1 1.14 percent, BRCA2 1.03 percent, 2.17 percent combined.","Cumulative risk of breast or ovarian cancer by age 80: 0.83 (standard error 0.07) for BRCA1 carriers, 0.76 (0.13) for BRCA2 carriers.","Age-specific risk was 3.8-fold higher in carriers born after 1958 than in those born in or before 1958 (P = 0.006).","51 percent (85 of 167) of carrier families had little or no history of relevant cancer, so family-history criteria would not have identified them.","Only 35 percent (29 of 82) of the families with a high cancer burden had previously been referred for genetic counselling."],"whatItMeans":"This is the evidence base for offering an inherited-risk test to a whole population rather than to people who already look high risk. It is why Israel's health basket funds BRCA founder testing for every woman of Ashkenazi origin without a family history requirement, and it is quoted in every argument for doing the same elsewhere.","caveats":["Risk estimates are for three specific founder variants in one population; they do not transfer to other BRCA variants or other populations, and a negative three-variant test does not exclude inherited risk.","Ascertainment through healthy men removes clinic selection but the female relatives who agreed to be genotyped are still a volunteer sample.","The BRCA2 ovarian cancer estimate is unstable: 0.62 in fully genotyped sibships but 0.37 to 0.45 when all sibships are included with imputation."],"changedPractice":true,"participants":8195},"route":"/key-papers/paper-gabai-kapara-population-brca-screening-pnas-2014/","neighbours":{"cancer":[{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"},{"id":"ovarian","kind":"cancer","name":"Ovarian cancer","route":"/cancers/ovarian/"}],"section":[{"id":"prevention","kind":"section","name":"Prevention & Risk","route":"/fronts/prevention/"}],"technology":[{"id":"germline-testing","kind":"technology","name":"Germline (hereditary) testing","route":"/technologies/germline-testing/"}],"target":[{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"}],"institution":[{"id":"shaare-zedek","kind":"institution","name":"Shaare Zedek Medical Center","route":"/institutions/shaare-zedek/"},{"id":"sheba","kind":"institution","name":"Sheba Medical Center","route":"/institutions/sheba/"}],"term":[{"id":"founder-variant","kind":"term","name":"Founder variant","route":"/terms/founder-variant/"}],"person":[{"id":"eitan-friedman","kind":"person","name":"Eitan Friedman","route":"/people/eitan-friedman/"},{"id":"ephrat-levy-lahad","kind":"person","name":"Ephrat Levy-Lahad","route":"/people/ephrat-levy-lahad/"}],"bottleneck":[{"id":"b-hereditary-risk","kind":"bottleneck","name":"Inherited risk is mostly unidentified","route":"/bottlenecks/b-hereditary-risk/"}],"journal":[{"id":"pnas","kind":"journal","name":"Proceedings of the National Academy of Sciences","route":"/journals/pnas/"}]}}