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Pancreatic cancer frustrates patients, clinicians and scientists. Five-year overall survival is the worst among common cancers, stubbornly remaining below 10%.1 Despite large international efforts offering unprecedented insights into pancreatic cancer biology in the last 10 years,2 patients with pancreatic cancer have not experienced the exciting translational advances in screening and treatment recently observed in other cancers, with few notable exceptions.3
DNA mismatch repair deficiency (MMRD) overlaps with the most important current areas of cancer research: precision therapy, which describes treatments that target specific biological features of cancers, and immunotherapy, which are treatments that unleash the native immune system against cancer. MMRD encompasses germline or somatic defects in MLH1, MSH2, MSH6 and PMS2, leading to distinctive genome-wide alterations such as microsatellite instability and high tumour mutational burden.4 Pembrolizumab, an immune-checkpoint inhibitor of programmed cell death protein 1, was the first approved cancer therapy with the indication defined by a molecular feature, rather than cancer type.5
Microsatellite instability/defective mismatch repair (MSI/dMMR) has been extensively studied in some cancer types, such as colorectal and endometrial cancer, but little is known about this molecular alteration in pancreatic ductal adenocarcinoma (PDAC). Notably, in 2021, two manuscripts related to this topic have been published in two different issues of Gut. The first paper is by Luchini et al, and represents a systematic review of all published material on MSI/dMMR in PDAC, coupled with a comparative analysis with existing databases, such as the Surveillance, Epidemiology and End Results Program (SEER) and the Cancer Genome Atlas (TCGA) project.6 The second manuscript is by Grant et al, and represents the largest original study on MSI/dMMR PDAC, providing new genomic data on this tumour entity, including mutational and transcriptomic profiles.7 A summary image of recent advances on MSI/dMMR in …
Contributors All authors analysed data and wrote the commentary.
Funding This study is supported by Associazione Italiana Ricerca sul Cancro (AIRC 5×1000 n. 12182), Fondazione Cariverona: Oncology Biobank Project 'Antonio Schiavi' (prot. 203885/2017), Fondazione Italiana Malattie Pancreas (FIMP, Ministero Salute, J38D19000690001), Ontario Institute for Cancer Research (PanCuRx Translational Research Initiative) through funding provided by the Government of Ontario, the Wallace McCain Centre for Pancreatic Cancer supported by the Princess Margaret Cancer Foundation, the Terry Fox Research Institute, the Canadian Cancer Society Research Institute and the Pancreatic Cancer Canada Foundation. The study was also supported by a charitable donation from the Canadian Friends of the Hebrew University (Alex U. Soyka).
Competing interests CL has been a paid expert-consultant on microsatellite instability for BioScience Communications (New York, New York, USA).
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.
Provenance and peer review Commissioned; internally peer reviewed.