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 1894
OP 1903
DO 10.1136/gutjnl-2020-320730
VO 70
IS 10
A1 Grant, Robert C
A1 Denroche, Robert
A1 Jang, Gun Ho
A1 Nowak, Klaudia M
A1 Zhang, Amy
A1 Borgida, Ayelet
A1 Holter, Spring
A1 Topham, James T
A1 Wilson, Julie
A1 Dodd, Anna
A1 Jang, Raymond
A1 Prince, Rebecca
A1 Karasinska, Joanna M
A1 Schaeffer, David F
A1 Wang, Yifan
A1 Zogopoulos, George
A1 Berry, Scott
A1 Simeone, Diane
A1 Renouf, Daniel J
A1 Notta, Faiyaz
A1 O'Kane, Grainne
A1 Knox, Jennifer
A1 Fischer, Sandra
A1 Gallinger, Steven
YR 2021
UL http://gut.bmj.com/content/70/10/1894.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.Data are available in a public, open access repository. Genomic data will be uploaded to the European Genome-Phenome Archive (https://ega-archive.org/) upon publication and available for use.