Methyl-thio-adenosine phosphorylase (MTAP) is an essential enzyme for the purine salvage metabolism. In cancer, MTAP deficiency (MTAPdef) confers susceptibility to novel agents inhibiting the protein arginine methyl-transferase 5 (PRMT5) pathway. MTAPdef is a recurrent event in tumors with CDKN2A/B loss as these genes are closely located in chromosome 9p. In this study, we aim at investigating the main clinical characteristics of patients with gastrointestinal (GI) cancers harboring MTAP alterations.
We retrospectively collected next generation sequencing (NGS) results obtained through the FoundationOne CDx assay (Foundation Medicine), performed in GI tumors from July 2019 to January 2022. Cancers of the digestive system (esophagus to anus), liver, pancreas, and biliary tract were included.
493 GI cancer patients NGS reports were available (351 colorectal, 80 pancreatic, 47 gastroesophageal, 15 other) and MTAP alterations were found in 26 (5%). Median age was 61 and 73% were males. Most patients (14/26, 54%) were metastatic at diagnosis. Most commonly primary sites were pancreatic (11/26, 42%), colorectal (6/26, 23%) and gastro-esophageal (4/26, 15%). MTAP alterations was most prevalent in pancreatic cancers (14%, 11/80) and biliary tract (3/10, 30%). Adenocarcinoma was the most common histology (25/26, 96%), a minority of which mucinous (3/26, 12%). MTAP loss was the main deleterious alteration (21/26, 81%), although in colorectal cancer 5/6 alterations were mutations (3 as pathogenic: splice site 34-1G>A, A191fs*6, MTAP-CDKN2B truncation; 2 as variants of unknown significance). All cases of MTAP loss were concomitant with CDKN2A/B loss. In all pancreatic cancers, MTAPdef coexisted with a KRAS mutation. Two colorectal cancers harbored a hypermutated phenotype due to microsatellite instability and a POLE mutation, respectively. Median overall survival was 15.7 months; 16.2 for pancreatic and 21.7 for colorectal cancer patients.
MTAP alterations can be found in 5% of GI adenocarcinomas with a higher prevalence in biliopancreatic cancers. Their actionability beyond gene loss warrants further investigation.
The authors.
Fondazione Oncologia Niguarda Onlus.
A. Amatu: Financial Interests, Personal, Advisory Board: Roche, Bayer; Financial Interests, Personal, Other, Honoraria: CheckmAb. A. Bardelli: Financial Interests, Personal, Advisory Board: Neophore, Inivata; Financial Interests, Personal, Stocks/Shares: Neophore; Financial Interests, Personal, Other, Research support: AstraZeneca, Boehringer Ingelheim. S. Siena: Financial Interests, Personal, Advisory Board: Agenus, AstraZeneca, Bayer, BMS, CheckmAb, Daiichi Sankyo, Guardant Health, Menarini, Merck, Novartis, Roche-Genentech, Seagen. A. Sartore Bianchi: Financial Interests, Personal, Advisory Board: Amgen, Bayer, Novartis, Sanofi, Servier. All other authors have declared no conflicts of interest.