Clinical and genomic characterisation of mismatch repair deficient pancreatic adenocarcinoma
| Autor: | Robert E. Denroche, Scott R. Berry, Raymond Woo-Jun Jang, Sandra Fischer, George Zogopoulos, Steven Gallinger, Yifan Wang, Ayelet Borgida, Daniel J. Renouf, Julie M. Wilson, Joanna M. Karasinska, David F. Schaeffer, Robert C. Grant, Anna Dodd, Rebecca M. Prince, Jennifer J. Knox, Klaudia M Nowak, Gun Ho Jang, James T. Topham, Amy Zhang, Grainne M. O'Kane, Diane M. Simeone, Spring Holter, Faiyaz Notta |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Oncology medicine.medical_specialty medicine.diagnostic_test business.industry Gastroenterology Cancer Microsatellite instability medicine.disease medicine.disease_cause Lynch syndrome 03 medical and health sciences 030104 developmental biology 0302 clinical medicine 030220 oncology & carcinogenesis Internal medicine Pancreatic cancer medicine Adenocarcinoma DNA mismatch repair KRAS business Genetic testing |
| Zdroj: | Gut. 70:1894-1903 |
| ISSN: | 1468-3288 0017-5749 |
| Popis: | ObjectiveTo describe the clinical, pathological and genomic characteristics of pancreatic cancer with DNA mismatch repair deficiency (MMRD) and proficiency (MMRP).DesignWe 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)).Results12 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.ConclusionsMMRD 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. |
| Databáze: | OpenAIRE |
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