GENETIC EPIDEMIOLOGY OF HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER

Lynch syndrome or Hereditary non-polyposis colorectal cancer (HNPCC) has recently received considerable attention either for its clinical implication or for the characterization of the molecular basis. HNPCC is an autosomal dominant disorder featured by the development of early onset colorectal malignancies frequently localized in the proximal colon, synchronous and metachronous lesions of the large bowel, and association with tumors of other organs, especially endometrium, stomach and urinary tract. In typical cases the clinical diagnosis may be relatively easy, but in many other instancies small size of families, possible low penetrance, variable expressivity, and frequency of phenocopies may render the identification of Lynch syndrome extremely complex. Molecular biology will be of considerable help in diagnosis HNPCC, since at least four genes have recently been identified whose mutations are closely associated with the development of this phenotype. Various studies in different races and continents seem to indicate that the frequency of Lynch syndrome is in the order of 1 to 5% of all colorectal malignancies. In most of these investigations the clinical guideline for the definition of HNPCC were the so-called ''Amsterdam Criteria'', proposed by the International Collaborative group on HNPCC. In some of these series, gene mutation were found in 50-70% of the families. However, the problem is much more complex owing to the existence - in a given population - of ''suspected'' HNPCC families and juvenile cases that might represent possible first mutations of a HNPCC kindred. Molecular studies should make clear how many of these families are true HNPCC and how many represent spurious aggregates of cancer. Finally, segregation analysis repetedly showed that the autosomal dominant model was the most plausible type of transmission in HNPCC families, though more complex models (i.e., codominant) cannot be excluded and deserve further investigations.