Clinicopathological Characterisation of Alterations in Gastrointestinal Cancers

Background: Methylthioadenosine phosphorylase (MTAP) is an essential metabolic enzyme in the purine and methionine salvage pathway. In cancer, gene copy number loss ( loss) confers a selective dependency on the related protein arginine methyltransferase 5. The impact of alterations in gastrointestinal (GI) cancers remains unknown although hypothetically druggable. Here, we aim to investigate the prevalence, clinicopathological features and prognosis of loss GI cancers.

Methods: Cases with alterations were retrieved from The Cancer Genome Atlas (TCGA) and a real-world cohort of GI cancers profiled by next-generation sequencing. If alterations other than loss were found, immunohistochemistry was performed. Finally, we set a case-control study to assess loss prognostic impact.

Results: Findings across the TCGA dataset (N=1363 patients) and our cohort (N=508) were consistent. Gene loss was the most common alteration (9.4%), mostly co-occurring with loss (97.7%). Biliopancreatic and gastro-oesophageal cancers had the highest prevalence of loss (20.5% and 12.7%, respectively), being mostly microsatellite stable (99.2%). In colorectal cancer, loss was rare (1.1%), while most alterations were mutations (5/7, 71.4%); among the latter, only truncation led to protein loss, thus potentially actionable. loss did not confer worse prognosis.

Conclusions: alterations are found in 5%-10% of GI cancers, most frequently biliopancreatic and gastro-oesophageal. loss is the most common alteration, identified almost exclusively in MSS, loss, upper-GI cancers. Other alterations were found in colorectal cancer, but unlikely to cause protein loss and drug susceptibility.