Molecular biology of gastric cancer.
Gastric cancer is one of the leading causes of cancer mortality in the world. Gastric adenocarcinomas account for more than 95% of gastric tumors, whereas gastrointestinal stromal tumors (GISTs) are the most common neoplasms of the rare gastric mesenchymal tumors. Although the incidence of mid-distal gastric adenocarcinomas is decreasing, the incidence of gastroesophageal junctional tumors and Barrett's adenocarcinomas is increasing for unknown reasons. The majority of gastric tumors are sporadic in nature. However, there are rare, inherited gastric cancer predisposition traits, such as germline p53 (Li-Fraumeni syndrome) as well as E-cadherin (CDH1) alterations in familial diffuse gastric cancers. Gastric cancer has been observed to be part of the spectrum of neoplasms associated with germline mismatch repair gene (MMR) alterations that give rise to the hereditary nonpolyposis colorectal cancer (HNPCC) entity. Comparative genomic hybridization analyses have identified several amplifications and losses of DNA copy numbers in gastric cancers. Loss of heterozygosity (LOH) studies have shown several chromosomal loci with significant allelic loss, thus indicating the possibility of harboring a tumor suppressor gene important in gastric tumorigenesis. Microsatellite instability (MIS) and associated alteration of the TGF-bIIR, IGFRII, BAX, E2F-4, hMSH3, and hMSH6 genes are found in a subset of gastric carcinomas. Cell adhesion molecule abnormalities such as those involving CDH1 may play an important role in diffuse-type gastric cancer development. Although, multiple somatic alterations have been described in gastric carcinomas at the molecular level, the significance of these changes in gastric tumorigenesis remains to be established in most instances. The critical molecular alterations in gastric cancers that may lead to advances in our armamentarium to combat this lethal disease remain to be fully characterized.
El-Rifai
Wa'el
W
Department of Medicine, Division of Gastroenterology/Hepatology, University of Virginia, Charlottesville, VA 22908, USA.
Powell
Steven M
SM
D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000209:etiology; D006801:Humans; D015994:Incidence; D008967:Molecular Biology; D009154:Mutation / Q000235:genetics; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000453:epidemiology / Q000235:genetics*; D013577:Syndrome; D014481:United States / Q000453:epidemiology