Deletion mapping reveals two regions of chromosome 8 allele loss in colorectal carcinomas.

Colorectal carcinogenesis is associated with the accumulation of genetic changes involving both dominant oncogenes and tumor suppressor genes. Although at least four different genes have been implicated in the process, the detection of allele loss from other regions of the genome suggests the involvement of additional genes. The short arm of chromosome 8 is one of these regions; loss of heterozygosity occurs at rates ranging from 30 to 50%. To define the region of common deletion containing the putative tumor suppressor gene, we analyzed a series of 87 carcinomas for allele loss in different regions of the short arm of chromosome 8 by using Southern blot analysis and a panel of polymorphic probes. We found allele loss in 33% of our cases, which involves two separate regions, one in the p-terminal region of the chromosome, 8p23.1-pter, where 45% of informative cases demonstrated loss, and the other in the mid-p region, at 8p21, where 31% of cases showed allele loss. No tumors showed loss of heterozygosity for both regions. These findings suggest the presence of two discrete genes related to colorectal carcinogenesis on the short arm of chromosome 8.

Evidence for a common molecular pathogenesis in colorectal, gastric, and pancreatic cancer.

We examined tissue extracted from 19 gastric, 7 pancreatic, and 23 colorectal carcinoma specimens to determine the comparative incidence of allele loss on chromosomes 5, 17, and 18 and that of KRAS2 point mutations. Chromosome 5 allele loss occurred at the same frequency in all three gastrointestinal tumors (approximately 30%), whereas chromosome 17 and 18 allele losses were seen at a significantly lower frequency in gastric (20%) and pancreatic (0%) malignancies than in colorectal cancer (57%). Point mutations in KRAS2 were seen in 83% of pancreatic and 52% of colon cancers, but not in gastric cancer specimens. In pancreatic tumors, these mutations were always found in the second nucleotide of codon 12. In colorectal cancer, the distribution was more variable, involving the second nucleotide of codon 13 and both the first and second nucleotides of codon 12. These results suggest that inactivation of the adenomatous polyposis coli gene on chromosome 5 may be an initiating step for carcinomas of the stomach and pancreas as well as of the colon, but that the genes involved in tumor progression events may be tissue- or tumor-specific.

Evidence for a new tumor-suppressor gene involved in gastrointestinal malignancies.

Inactivation or loss of tumor-suppressor genes is believed to lead to the development or progression of malignancies. To determine whether a tumor-suppressor gene is located on chromosome 8, DNA was extracted from tumor and normal tissue of colorectal, gastric, and pancreatic specimens, and allele loss was investigated by Southern hybridization techniques with the chromosome 8 probe D8S7. Twenty-five percent of pancreatic carcinomas, 50% of gastric carcinomas, and 50% of colorectal carcinomas were found to have lost an allele on chromosome 8. These findings suggest the presence of a tumor-suppressor gene on chromosome 8, which is involved in colorectal carcinoma, gastric carcinoma, and pancreatic carcinoma. Definition of the frequency with which this tumor-suppressor gene is involved in gastrointestinal malignancies will await the study of many patients who are classified as informative and the use of multiple probes for chromosome 8.