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Clinical and genomic characterisation of mismatch repair deficient pancreatic adenocarcinoma
  1. Robert C Grant1,2,
  2. Robert Denroche1,
  3. Gun Ho Jang1,
  4. Klaudia M Nowak3,
  5. Amy Zhang1,
  6. Ayelet Borgida4,
  7. Spring Holter4,
  8. James T Topham5,
  9. Julie Wilson1,
  10. Anna Dodd2,
  11. Raymond Jang2,
  12. Rebecca Prince2,
  13. Joanna M Karasinska5,
  14. David F Schaeffer5,
  15. Yifan Wang6,
  16. George Zogopoulos6,
  17. Scott Berry7,
  18. Diane Simeone8,
  19. Daniel J Renouf5,9,
  20. Faiyaz Notta1,
  21. Grainne O'Kane2,
  22. Jennifer Knox2,
  23. Sandra Fischer3,
  24. Steven Gallinger1,2,4
  1. 1Ontario Institute for Cancer Research, Toronto, Ontario, Canada
  2. 2Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada
  3. 3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  4. 4Ontario Pancreas Cancer Study, Mount Sinai Hospital, Toronto, Ontario, Canada
  5. 5Pancreas Centre BC, Vancouver, Ontario, Canada
  6. 6Goodman Cancer Research Centre, Montreal, Quebec, Canada
  7. 7Department of Oncology, Queen's University, Kingston, Ontario, Canada
  8. 8NYU Langone Health, New York City, New York, USA
  9. 9BC Cancer Agency, Vancouver, British Columbia, Canada
  1. Correspondence to Dr Steven Gallinger, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Steven.Gallinger{at}uhn.ca

Abstract

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.

  • cancer genetics
  • cancer immunobiology
  • cancer syndromes
  • pancreatic cancer
  • molecular genetics
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Footnotes

  • Twitter @KMN_GIPath

  • Contributors Study concept and design: RCG, RD, GHJ, FN, GOK, JK, SEF, SG. Contribution and collection of data: AZ, AB, SH, JTT, JMW, AD, RJ, RP, JK, DS, YW, GZ, SRB, DMS, DJR, FN, GOM, JK, SEF, SG. Analysis and interpretation: GH, RD, GHJ, AZ. Drafting of the manuscript: RG, SG. Critical revision of the manuscript for important intellectual content: all authors.

  • Funding This study was funded by generous donations from the Princess Margaret Cancer Centre and Toronto General Hospital Foundations.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement 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.

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