RT Journal Article
SR Electronic
T1 Clinical and genomic characterisation of mismatch repair deficient pancreatic adenocarcinoma
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP gutjnl-2020-320730
DO 10.1136/gutjnl-2020-320730
A1 Robert C Grant
A1 Robert Denroche
A1 Gun Ho Jang
A1 Klaudia M Nowak
A1 Amy Zhang
A1 Ayelet Borgida
A1 Spring Holter
A1 James T Topham
A1 Julie Wilson
A1 Anna Dodd
A1 Raymond Jang
A1 Rebecca Prince
A1 Joanna M Karasinska
A1 David F Schaeffer
A1 Yifan Wang
A1 George Zogopoulos
A1 Scott Berry
A1 Diane Simeone
A1 Daniel J Renouf
A1 Faiyaz Notta
A1 Grainne O'Kane
A1 Jennifer Knox
A1 Sandra Fischer
A1 Steven Gallinger
YR 2020
UL http://gut.bmj.com/content/early/2020/09/14/gutjnl-2020-320730.abstract
AB Objective To describe the clinical, pathological and genomic characteristics of pancreatic cancer with DNA mismatch repair deficiency (MMRD) and proficiency (MMRP).Design We identified patients with MMRD and MMRP pancreatic cancer in a clinical cohort (N=1213, 519 with genetic testing, 53 with immunohistochemistry (IHC)) and a genomic cohort (N=288 with whole-genome sequencing (WGS)).Results 12 out of 1213 (1.0%) in the clinical cohort were MMRD by IHC or WGS. Of the 14 patients with Lynch syndrome, 3 (21.4%) had an MMRP pancreatic cancer by IHC, and 4 (28.6%) were excluded because tissue was unavailable for testing. MMRD cancers had longer overall survival after surgery (weighted HR after coarsened exact matching 0.11, 95% CI 0.02 to 0.78, p=0.001). One patient with an unresectable MMRD cancer has an ongoing partial response 3 years after starting treatment with PD-L1/CTLA-4 inhibition. This tumour showed none of the classical histopathological features of MMRD. 9 out of 288 (3.1%) tumours with WGS were MMRD. Despite markedly higher tumour mutational burden and neoantigen loads, MMRD cancers were significantly less likely to have mutations in usual pancreatic cancer driver genes like KRAS and SMAD4, but more likely to have mutations in genes that drive cancers with microsatellite instability like ACV2RA and JAK1. MMRD tumours were significantly more likely to have a basal-like transcriptional programme and elevated transcriptional markers of immunogenicity.Conclusions MMRD pancreatic cancers have distinct clinical, pathological and genomic profiles. Patients with MMRD pancreatic cancer should be considered for basket trials targeting enhanced immunogenicity or the unique genomic drivers in these malignancies.