A brave new world of cancer screening

Abstract

A brave new world of cancer screening he development of colorectal cancer has a clear molecular genetic basis. The last five years has T resulted in an explosion of information emanating from a number of laboratories studying genes involved in the development of this common cancer. Initial data were codified as a paradigm by Fearon and Vogelstein who proposed that colorectal cancer was the end result of cumulative mutations to a restricted set of genes such as p53, DCC (Deleted in Colon Cancer), APC (Adenomatous Polyposis Coli) and Ras.' It is now clear that 75% of colorectal cancers are associated with mutations to the p53 and APC loci and almost half of the cancers also carry a mutated ras gene. It is possible to detect these mutations in small biopsy samples and even stool samples may provide information about the presence of mutations at these loci.Recently a number of exciting new developments have occurred in colorectal cancer genetics. Many additional proto-oncogenes and tumour suppressor genes have been implicated in the genesis of colorectal cancer and in many instances the physiological functions of these genes are beginning to be ~n d e r s t o o d .~-~ These new findings have provided a rational explanation for the biological consequences of the genetic abnormalities and the progression to colorectal cancer. Most importantly during the last year, mutations to genes encoding DNA repair enzymes were linked to Hereditary NonPolyposis Colorectal Cancer (HNPCC).6-10 The hMLH 1 and hMSH2 genes were first identified in yeast as DNA mismatch repair enzymes and the mutations to these genes have been suggested as the cause of the accumulation of other cancerous mutations in HNPCC and sporadic colorectal cancer.In this issue of the Journal, on page 682, Van de Water et al., describe direct mutational analysis in a family with HNPCC." They examined an HNPCC kindred for a germline mutation of the mismatch repair gene hMSH2. Mutations of this gene have been implicated in up to 30% of HNPCC cases. In this kindred the specific C to T transition in codon 622 results in the creation of a new restriction enzyme site which allowed the use of relatively simple laboratory techniques to identifl unequivocally patients carrying the mutation.The study documents that all family members who developed colorectal cancer have the specific hMSH2 gene mutation. In addition, all cancer free elderly family members were mutation negative, while 40% of younger family members were mutation positive. Family members were invited to receive the results of genetic testing and those who were mutation negative were removed from regular colonoscopic surveillance. The non-carriers were also told that they would not pass the defective gene to their children.This report emphasises one possible benefit associated with genetic testing in a high risk setting for colorectal cancer predisposition. That is, current screening strategies for young family members may be enhanced or even superseded by testing for genetic abnormalities. Family members who a...