Gastric carcinoma. Which chromosomes are involved?

Gastric carcinoma

P.A. Wright, G.T. Williams

The molecular study of gastric carcinoma has much to offer the medical scientist, pathologist, clinician, and patient. Morphological classifications are not completely satisfactory in predicting biological and clinical behaviour. Molecular diagnostic markers are needed to discriminate between inflammation and neoplasia in biopsy and cytology specimens, to show invasion in those biopsies currently difficult to interpret, to define disease subgroups with differing natural history or response to various treatments, and to identify high risk groups for surveillance. It is hoped that molecular analysis of the disease will identify new therapeutic targets for more precise and effective treatments with fewer side effects.

The genes underlying inherited susceptibility to gastric carcinoma have not yet been identified, and the molecular mechanisms of cancer promotion by environmental influences, such as diet and Helicobacter pylori infection, await elucidation. Some progress has been made, however, in identifying abnormalities of oncogenes, tumour suppressor genes, and growth factors including their receptors and related gene products. This will provide a structural framework for analysing molecular mechanisms of disease development. Comparisons can now be made between gastric carcinoma and other cancers (particularly colorectal cancer), between diffuse and intestinal morphological types of gastric carcinoma, and between early and advanced cases. Many of the problems which have limited progress are now being resolved.

Which chromosomes are involved?

Early cytogenetic studies were done on malignant effusions from very advanced cases so it was unsurprising that a large variety of iiromosomal aberrations were found, differing from case to case. Jiore recent studies of solid tumour material have also found parked heterogeneity both between cases and within each case, but two studies, have reported frequent breakpoints at 3p21, which is the site of deletions in lung cancer and may involve a phosphatase tumour suppressor. Rodriguez et al. found translocations and deletions of llpl3-15 (often abnormal in other solid tumours) in four of five cases, two involving reciprocal translocations of 3p21. They observed the same rearrangement in adenocar-cinomas of the lower oesophagus, supporting the view that these cancers are similar in pathogenesis to gastric carcinomas, as they usually arise in the metaplastic glandular mucosa of Barrett's oesophagus. A cytogenetic analysis of nine cases of Barrett's metaplasia, however, did not find chromosomal abnormalities at either the llpl3-15 or 3p21 sites.

Chromosomal losses important in the pathogenesis of cancers can be studied by using DNA polymorphism marker techniques to identify separately maternal and paternal alleles (comparable with HLA typing). Patients are informative if their constitutional DNA (from peripheral blood, or hair roots) shows two patterns—one for each allele. Allele loss is indicated if one of these disappears in tumour tissue, and may signify loss of a tumour suppressor gene. Studies on gastric carcinomas were relatively few and analysed only small numbers of tumours, most finding a low level of deletion. The high proportion of stromal cells in many gastric cancers, particularly the diffuse type, may have caused a dilution of tumour DNA and consequent failure to detect allele loss. A recent study by Sano et al. selected cases comprising over 50% of tumour cells microscopically assessed on immediately adjacent tissue, and found a much higher rate of allele loss. Deletion of 5q was found only in well differentiated cases and not in undifferentiated tumours. The 5q sites correspond with the sites of the familial adenomatous polyposis (APC) gene, also deleted in some spontaneous colon carcinomas, and the adjacent mutated in colon carcinoma (MCC) gene. In contrast, both types of gastric tumour showed a 60% rate of allele loss on 17p at the site of the p53 gene. Extrapolating from this, we would then expect to find mutations of the p53 gene in both cancer types, but 5q gene mutations only in differentiated carcinomas. Paradoxically, Horii et al. have found APC gene mutations in only diffuse or poorly differentiated types, out not in differentiated intestinal types of gastric carcinoma, in a study of 44 tumours. It will be interesting to see if this curious paradox is clarified by other studies in progress.

Allele loss has also been reported in the 18q chromosomal site of the deleted in colon cancer (DCC) gene in a series of intestinal type gastric carcinomas (diffuse cancers were not examined). 18q deletions were found in over 60% of informative cases including many early intramucosal cases, compared to 17p losses (p53 gene) found at a lower rate and in more advanced cases. Thus the overall pattern of allele loss in gastric cancers shows many similarities with colon cancer, with losses at 5q, 18q, and 17p, with 17p loss associated with progression.

Ras oncogenes and proteins

The ras protein p21 is encoded by three ras genes