{"entity":{"id":"paper-yurgelun-germline-second-hits-resected-pancreatic-genet-med-2019","kind":"paper","name":"Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer","aka":[],"tldr":"Nearly one in ten of 289 unselected patients with resected pancreatic cancer carried an inherited cancer-gene variant, but the tumour had lost the second copy in fewer than half, which matters for whether PARP inhibitors will work.","summary":"Germline and somatic DNA from 289 patients with resected pancreatic ductal adenocarcinoma, ascertained without preselection, were analysed on a customised panel. 28 of 289 (9.7%) carried pathogenic or likely pathogenic germline variants: 21 (7.3%) in double-strand DNA damage repair genes (3 BRCA1, 4 BRCA2, 14 in ATM, BRIP1, CHEK2, NBN, PALB2, RAD50 or RAD51C), 3 Lynch syndrome and 4 other (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry found second hits in 12 of 27 (44.4%). Carriers of double-strand repair variants had superior overall survival (hazard ratio 0.54).","asOf":"2026-09-24","links":[{"label":"Yurgelun et al., Genet Med 2019: germline variants and somatic second hits in 289 resected cancers","url":"https://doi.org/10.1038/s41436-018-0009-5"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29961768/"}],"tags":[],"related":["brca-germline","brca-somatic"],"cancers":["pancreatic","resectable-pdac","brca-palb2-pdac"],"sections":[],"technologies":["germline-testing"],"targets":["brca","atm","palb2","cdkn2a"],"drugs":[],"companies":[],"institutions":["dana-farber"],"pathways":[],"terms":["germline-vs-somatic"],"trials":[],"people":["andrew-aguirre"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Genetics in Medicine","year":2019,"doi":"10.1038/s41436-018-0009-5","pmid":"29961768","authors":"Yurgelun MB, Chittenden AB, Morales-Oyarvide V, et al.","paperType":"observational","findings":["Germline variants in 9.7%; double-strand repair genes 7.3%.","Somatic second hit in 12 of 27 carriers, 44.4%.","Repair-gene carriers: overall survival hazard ratio 0.54."],"whatItMeans":"A germline result is not the whole story: without loss of the second allele the tumour may not be repair-deficient, which is why tumour sequencing and, in trials, HRD signatures are read alongside.","caveats":["Resected patients; survival advantage may reflect platinum exposure.","Second-hit assessment on a panel misses epigenetic silencing."],"changedPractice":false,"participants":289},"route":"/key-papers/paper-yurgelun-germline-second-hits-resected-pancreatic-genet-med-2019/","neighbours":{"biomarker":[{"id":"brca-germline","kind":"biomarker","name":"Germline BRCA1/2 pathogenic variant (gBRCAm)","route":"/biomarkers/brca-germline/"},{"id":"brca-somatic","kind":"biomarker","name":"Tumour (somatic or germline) BRCA1/2 mutation and HRR gene alterations","route":"/biomarkers/brca-somatic/"}],"cancer":[{"id":"brca-palb2-pdac","kind":"cancer","name":"BRCA or PALB2-mutant pancreatic ductal adenocarcinoma","route":"/cancers/brca-palb2-pdac/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"},{"id":"resectable-pdac","kind":"cancer","name":"Resectable pancreatic ductal adenocarcinoma","route":"/cancers/resectable-pdac/"}],"technology":[{"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":"cdkn2a","kind":"target","name":"CDKN2A","route":"/targets/cdkn2a/"},{"id":"palb2","kind":"target","name":"PALB2","route":"/targets/palb2/"}],"institution":[{"id":"dana-farber","kind":"institution","name":"Dana-Farber Brigham Cancer Center","route":"/institutions/dana-farber/"}],"term":[{"id":"germline-vs-somatic","kind":"term","name":"Germline vs somatic mutations","route":"/terms/germline-vs-somatic/"}],"person":[{"id":"andrew-aguirre","kind":"person","name":"Andrew J. Aguirre","route":"/people/andrew-aguirre/"}]}}