Elucidating the molecular genetic pathways associated with intestinal type gastric carcinoma of South African patients

Abstract

Gastric cancer is one of the top five causes of cancer-related deaths worldwide, contributing to 8% of total cancer cases and 10% of total cancer-related deaths. There is a gender bias in the occurrence of gastric cancer, with a male-to-female ratio of 2:1. In South Africa, gastric cancer incidence in the general population is notably lower, at an age standardised rate (ASR) of 4.1 per 100 000 males, when compared to 42.4 per 100 000 males in Eastern Asia and 9 per 100 000 males in Western Europe. The incidence rates also differ among various ethnic groups in South Africa, ranging from 2.1 in black males to 6.85 in white males. Two main mechanisms of gastric cancer development: chromosomal instability (CIN) and microsatellite instability (MSI), have been described. In cells where CIN occurs, a high rate of aneuploidy and loss of heterozygosity is observed. In MSI, the mismatch repair machinery is dysfunctional, leading to the accumulation of replication errors, often in short sequence repeats. Such instability causes many downstream frameshift mutations in coding regions of genes that function in important cellular control pathways. There is no information regarding the molecular mechanisms involved in gastric carcinogenesis in South Africans. In order to determine to what extent the MSI mechanism is involved in gastric cancers of South African patients, MSI analysis was performed on tumours from 74 Black and 16 White patients. MSI-high (MSI-H) gastric tumours were subsequently investigated for frameshift mutations in 11 genes that are involved in the development of MSI-H cancers. The mean age at diagnosis of the Black patients (57.12±12.41 years) was significantly (p< 0.05). This is in keeping with the classification of the mismatch repair genes as “caretaker” genes, as opposed to “gatekeeper” genes. When caretaker genes are mutated it leads to the accumulation of mutations in various genes that over time eventually lead to cancer. In the case of gatekeeper genes, which play a direct role in cancer prevention, their inactivation leads to cancer in a much shorter timeframe. Nine of the 11 genes with coding repeat sequences were shown to contain previously defined frameshift mutations within the 13 MSI-H tumours. Genes involved in cell growth and differentiation pathways (TGFBR2, ACVR2, and RNF43) were found to be most heavily affected. In the TGFBR2 gene, one bp (c.383delA) and/or two bp (c.382_383delAA) frameshift mutations were present in all MSI-H tumours. Frameshift mutations in ACVR2A and RNF43 were observed in 76.9% and 61.4% of tumours respectively. A gene in the translational fidelity pathway, RPL22, was mutated in 84.6% of tumours. No frameshifts were detected in the miRNA processing (TARBP2) and export (XPO5) pathway genes. To the best of our knowledge, this is the first study of the molecular mechanisms involved in gastric cancer in South Africans. We have shown that the MSI mechanism is involved in the development of 14.9% of gastric cancers of Black patients and 12.5% of gastric cancers in White patients.