Cancers of the upper gastro-intestinal tract: a review of somatic mutation distributions

Arch Iran Med. 2014 Apr;17(4):286-92.

Abstract

Cancers of the upper gastro-intestinal tract (UGIT) comprise esophageal, esophago-gastric junction, stomach and duodenal cancers. Together, these cancers represent over 1.5 million cases and are the cause of about 1.25 million deaths annually. This group of cancers encompasses diseases with marked disparities in etiology, geographic distribution, histopathological features and frequency. Based on histological origin, squamous cell carcinoma of the esophagus (ESCC), which arises through a dysplasia-carcinoma sequence within the squamous mucosa, is a completely different cancer than junction, stomach and duodenal cancers, which develop within glandular epithelia through cascades involving inflammation, metaplasia, dysplasia and carcinoma. At the frontline between these two histological domains, cancers of the esophago-gastric junction constitute a mixed group of glandular tumors including distal esophageal adenocarcinomas and cancers arising within the most proximal part of the stomach - the cardia. Most of UGIT cancers are sporadic, although familial susceptibility genes have been identified for stomach and rare cases of ESCC. We have used the COSMIC database (http://www.sanger.ac.uk/genetics/CGP/cosmic/) to identify genes commonly mutated in UGIT cancers. Regardless of etiology and histopathology, three genes are mutated in at least 5% of UGIT cancers: TP53, CDKN2a and PIK3CA. Another three genes, NFE2L2, PTCH1 and NOTCH1, are mutated in ESCC only. Conversely, genes of the RAS family and of the CDH1/APC/CTNNB1 pathway are mutated only in non-squamous cancers, with differences in mutated genes according to topography. We review the potential functional significance of these observations for understanding mechanisms of UGIT carcinogenesis.

Publication types

  • Review

MeSH terms

  • Adenocarcinoma / genetics*
  • Carcinoma, Squamous Cell / genetics*
  • Class I Phosphatidylinositol 3-Kinases
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Duodenal Neoplasms / genetics*
  • Esophageal Neoplasms / genetics*
  • Esophagogastric Junction
  • Genetic Predisposition to Disease
  • Humans
  • Mutation*
  • NF-E2-Related Factor 2 / genetics
  • Patched Receptors
  • Patched-1 Receptor
  • Phosphatidylinositol 3-Kinases / genetics
  • Receptor, Notch1 / genetics
  • Receptors, Cell Surface / genetics
  • Stomach Neoplasms / genetics*
  • Tumor Suppressor Protein p53 / genetics
  • ras Proteins / genetics

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • NOTCH1 protein, human
  • PTCH1 protein, human
  • Patched Receptors
  • Patched-1 Receptor
  • Receptor, Notch1
  • Receptors, Cell Surface
  • Tumor Suppressor Protein p53
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • ras Proteins