{"entity":{"id":"paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019","kind":"paper","name":"Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers","aka":[],"tldr":"Targeted sequencing of 3,594 pancreatic cancers, the largest such series, found KRAS in 88%, a drug-matchable alteration in 17%, BRCA or FANC repair gene changes in 14%, and microsatellite instability or very high mutation burden in only 0.5%.","summary":"Targeted genomic profiling of 3,594 pancreatic ductal adenocarcinoma samples from an international cohort covered up to 315 cancer genes and the introns of 28 rearranged genes, with tumour mutation burden over 1.14 megabases (high at 20 or more per megabase) and MSI over 114 loci. KRAS, TP53, CDKN2A and SMAD4 were the most frequently altered genes; KRAS was mutated in 88%. Among KRAS wild-type tumours, actionable MAPK pathway alterations (n = 132; 4%) included gene fusions (51), amplifications (35), missense mutations (30) and deletions (16), mostly in receptor tyrosine kinase, RAS or MAPK genes. Beyond TP53, DNA damage repair alterations (BRCA and FANC) were found in 14%. MSI-high and/or TMB-high phenotypes were detected in 0.5% of 2,563 and 1,021 evaluated. FGF23, CCND2, PIK3CA and FGF6 alterations were commoner in IPMN-associated cancers. Overall 17% carried alterations that might make tumours susceptible to existing agents.","asOf":"2026-09-24","links":[{"label":"Singhi et al., Gastroenterology 2019: targeted profiling of 3,594 pancreatic ductal adenocarcinomas","url":"https://doi.org/10.1053/j.gastro.2019.02.037"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30836094/"}],"tags":[],"related":[],"cancers":["pancreatic","kras-wild-type-pdac","msi-high-pdac"],"sections":[],"technologies":["tmb-testing","msi-mmr-testing"],"targets":["kras","tp53","cdkn2a","smad4","brca"],"drugs":["foundationone-cdx"],"companies":[],"institutions":["upmc-hillman"],"pathways":[],"terms":["tmb","msi","ngs"],"trials":[],"people":["anirban-maitra","talia-golan"],"bottlenecks":[],"keyPapers":[],"journals":["gastroenterology"],"dependsOn":[],"notes":[],"journal":"Gastroenterology","year":2019,"doi":"10.1053/j.gastro.2019.02.037","pmid":"30836094","authors":"Singhi AD, George B, Greenbowe JR, et al.","paperType":"real-world","findings":["KRAS 88%; KRAS wild-type tumours carry MAPK pathway fusions, amplifications and mutations (4% of all).","BRCA and FANC alterations 14%; MSI-high and/or TMB-high 0.5%.","17% with alterations matched to existing drugs."],"whatItMeans":"It fixed the working numbers for a comprehensive panel in pancreatic cancer: a hit worth acting on in about one patient in six, most of it in repair genes and the KRAS wild-type minority.","caveats":["Commercial referral cohort (FoundationOne); germline status not separated from somatic.","TMB-high defined at 20, not the 10 used for the tumour-agnostic label."],"changedPractice":false,"participants":3594},"route":"/key-papers/paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019/","neighbours":{"cancer":[{"id":"kras-wild-type-pdac","kind":"cancer","name":"KRAS wild-type pancreatic ductal adenocarcinoma","route":"/cancers/kras-wild-type-pdac/"},{"id":"msi-high-pdac","kind":"cancer","name":"Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma","route":"/cancers/msi-high-pdac/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"}],"technology":[{"id":"msi-mmr-testing","kind":"technology","name":"MSI and mismatch-repair testing","route":"/technologies/msi-mmr-testing/"},{"id":"tmb-testing","kind":"technology","name":"Tumour mutational burden testing","route":"/technologies/tmb-testing/"}],"target":[{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"},{"id":"cdkn2a","kind":"target","name":"CDKN2A","route":"/targets/cdkn2a/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"mmr","kind":"target","name":"Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)","route":"/targets/mmr/"},{"id":"smad4","kind":"target","name":"SMAD4","route":"/targets/smad4/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"drug":[{"id":"foundationone-cdx","kind":"drug","name":"FoundationOne CDx / Liquid CDx","route":"/drugs/foundationone-cdx/"}],"institution":[{"id":"upmc-hillman","kind":"institution","name":"UPMC Hillman Cancer Center","route":"/institutions/upmc-hillman/"}],"term":[{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"}],"person":[{"id":"anirban-maitra","kind":"person","name":"Anirban Maitra","route":"/people/anirban-maitra/"},{"id":"talia-golan","kind":"person","name":"Talia Golan","route":"/people/talia-golan/"}],"journal":[{"id":"gastroenterology","kind":"journal","name":"Gastroenterology","route":"/journals/gastroenterology/"}],"biomarker":[{"id":"kras-g12c","kind":"biomarker","name":"KRAS G12C","route":"/biomarkers/kras-g12c/"},{"id":"tmb-high","kind":"biomarker","name":"TMB-high (tumour mutational burden >= 10 mutations per megabase)","route":"/biomarkers/tmb-high/"}]}}