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Tytuł:
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Clinical and genomic characterisation of mismatch repair deficient pancreatic adenocarcinoma.
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Autorzy:
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Grant RC; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.; Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.
Denroche R; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Jang GH; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Nowak KM; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Zhang A; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Borgida A; Ontario Pancreas Cancer Study, Mount Sinai Hospital, Toronto, Ontario, Canada.
Holter S; Ontario Pancreas Cancer Study, Mount Sinai Hospital, Toronto, Ontario, Canada.
Topham JT; Pancreas Centre BC, Vancouver, Ontario, Canada.
Wilson J; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Dodd A; Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.
Jang R; Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.
Prince R; Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.
Karasinska JM; Pancreas Centre BC, Vancouver, Ontario, Canada.
Schaeffer DF; Pancreas Centre BC, Vancouver, Ontario, Canada.
Wang Y; Goodman Cancer Research Centre, Montreal, Quebec, Canada.
Zogopoulos G; Goodman Cancer Research Centre, Montreal, Quebec, Canada.
Berry S; Department of Oncology, Queen's University, Kingston, Ontario, Canada.
Simeone D; NYU Langone Health, New York City, New York, USA.
Renouf DJ; Pancreas Centre BC, Vancouver, Ontario, Canada.; BC Cancer Agency, Vancouver, British Columbia, Canada.
Notta F; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
O'Kane G; Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.
Knox J; Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.
Fischer S; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Gallinger S; Ontario Institute for Cancer Research, Toronto, Ontario, Canada .; Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.; Ontario Pancreas Cancer Study, Mount Sinai Hospital, Toronto, Ontario, Canada.
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Źródło:
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Gut [Gut] 2021 Oct; Vol. 70 (10), pp. 1894-1903. Date of Electronic Publication: 2020 Sep 15.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: London, British Medical Assn.
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MeSH Terms:
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Adenocarcinoma/*genetics
DNA Repair-Deficiency Disorders/*genetics
Pancreatic Neoplasms/*genetics
Adenocarcinoma/pathology ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis/pathology ; DNA Repair-Deficiency Disorders/pathology ; Female ; Genetic Testing ; Genomics ; Humans ; Male ; Microsatellite Instability ; Mutation ; Ontario ; Pancreatic Neoplasms/pathology ; Retrospective Studies ; Whole Genome Sequencing
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Contributed Indexing:
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Keywords: cancer genetics; cancer immunobiology; cancer syndromes; molecular genetics; pancreatic cancer
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Entry Date(s):
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Date Created: 20200916 Date Completed: 20220107 Latest Revision: 20220107
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Update Code:
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20240104
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DOI:
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10.1136/gutjnl-2020-320730
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PMID:
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32933947
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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.
Competing Interests: Competing interests: None declared.
(© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)
Comment in: Gut. 2022 Jan;71(1):219-221. (PMID: 33731370)
