Clinical and molecular diagnosis of hereditary non-polyposis colorectal cancer: problems and pitfalls in an extended pedigree

Hereditary non-polyposis colorectal cancer (or Lynch syndrome) is an autoso mal dominant disease in which early onset colorectal carcinomas aggregate i n families together with tumours of other organs. The genetic basis of the syndrome has been clarified with the identification of mutations in several DNA mismatch repair genes (MSH2, MLH1, PMS1, PMS2 and MSH6). We describe t he clinical features and molecular characterization of a large hereditary n onpolyposis colorectal cancer family which has been followed for almost 10 years. The kindred showed a striking aggregation of colorectal tumours in 3 successive generations; most of these neoplasms developed before the age o f 50 years and were localized in the proximal colon. Molecular tests (carri ed out in ten individuals) showed specific alterations at the MLH1 gene, co nsisting in the insertion of a T nucleotide between bases 2,269 and 2,270; the mutation caused frameshift of the open reading frame and synthesis of a polypeptide longer than normal. The only tumour that could be analysed was positive for microsatellite instability. Physicians should become more con fident with hereditary tumours and their implications, which are not limite d to a single individual but concern all family members at risk of cancer T his family approach is different, and requires more expertise than the trad itional individual approach. Common problems encountered in Hereditary Non- polyposis Colorectal Cancer families include: A) poor collaboration of subj ects at risk (a situation which may cause some conflict between the doctor' s duty to inform patients about their risk of disease and the rights of pat ients to choose and decide about their health); B) definition of the most a ppropriate surveillance programme for a given family (how many investigatio ns to propose to the patients, and how often); C) possible interaction betw een genes and environmental factors (for instance, a gene carrier - in this family - developed an endometrial carcinoma after standard tamoxifen adjuv ant therapy for breast cancer).