The Landscape and Prognosis of Microsatellite Stable (MSS) Esophageal, Gastro-Esophageal Junction and Gastric Adenocarcinomas with High Tumor Mutation Burden (TMB)

Abstract

Background

A minority of patients with MSS tumors present a high tumor mutation burden (TMB) without underlying MMR defects.

Methods

Publicly available genomic series were assessed for identification of patients with MSS gastric gastroesophageal junction, and esophageal adenocarcinomas and a high TMB, defined as more than 10 mutations per Mb. These were compared with MSS cancers and a low TMB for genetic alterations and for survival outcomes.

Results

Patients with MSS cancers with high TMB in the MSK series were older but did not differ in other clinicopathologic parameters compared with MSS patients with low TMB. Mutations in tumor suppressors TP53 and APC and oncogenes KRAS and ERBB4 as well as amplifications of ERBB2 were more prevalent in the high TMB group of MSS cancers. Mutations in DDR associated genes, in epigenetic modifiers and in genes associated with immune response were more prevalent in the hIgh TMB group patients. However, high TMB was not associated with an improved survival in MSS gastric/gastroesophageal junction/esophageal adenocarcinomas (Log Rank p = 0.5).

Conclusion

MSS Gastric/gastroesophageal junction/esophageal adenocarcinomas with TMB above 10 mutations per Mb possess a genomic landscape with increased alteration frequencies in common gastroesophageal cancer genes and pathways.

Keywords:

• Mismatch repair
• genomic types
• immunotherapy
• tumor mutation burden
• molecular pathogenesis

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.