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Gene mutations causing susceptibility to heriditary non-polyposis colorectal cancer (HNPCC): incidence, detection, and clinical consequences

Objective



The true incidence of HNPCC can only be determined by direct mutational analysis of unbiased prospective series of individuals. This will be accomplished by acquiring tumour and normal tissue from the great majority of all patients with colorectal carcinoma or adenoma in a 1.25 million subpopulation of Finland and the entire 260,000 population of the Modena district. These specimens will be analyzed for mutations in the known DNA mismatch repair genes; the initial screening of likely HNPCC cases will be by determining microsatellite instability status of the tutors. Germline mutations characteristic of HNPCC are present when normal tissue is heterozygous for the mutation. The number of specimens studied after 2-year prospective collection periods will be approximately 1360 carcinomas and 3400 adenomas. The number of germline mutations found will directly determine the incidence of HNPCC in these populations. To determine the type of mutation and genotype-phenotype correlations members of families already diagnosed with HNPCC will be analyzed. The partners have contacts with a total of 142 such families comprising 440 affected individuals and 1214 individuals over the age of 18 with a 50% genetic risk of being a mutation carrier. In each family the responsible gene mutation will be determined; a convenient test for that mutation designed, and all consenting patients and at-risk individuals counselled, tested, and re-counselled. Once the mutation status of each individual is determined, the natural history of the disease will be re-examined by correlating the mutation status with the penetrance, expressivity, and organ spectrum of involvement. Methods for the counselling and handling of mutation carriers will be designed and tested.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

N/A
Address
3,Haartmaninkatu
00014 Helsinki
Finland

Participants (2)

KAROLINSKA INSTITUTE
Sweden
Address
Karolinska Hospital
171 76 Stockholm
UNIVERSITY OF MODENA AND REGGIO EMILIA
Italy
Address
71,Largo Del Pozzo 71
41100 Modena