Hereditary Nonpolyposis Colorectal Cancer - Molecular Genetics and Biology of Associated Tumors

This thesis focuses on one of the most common types of hereditary cancer, hereditary nonpolyposis colorectal cancer (HNPCC). This syndrome is characterized by an autosomal dominant inheritance, an increased risk for several types of cancer (especially cancer of the colorectum, small bowel, endometrium, ovary and urinary tract), early age at diagnosis, and frequent development of multiple primary malignancies. HNPCC is caused by a germline mutation in one of several DNA mismatch-repair (MMR) genes. In paper I, we screened 16 families with suspected HNPCC for germline MMR gene mutations and found a diverse spectrum of mutations, involving the MMR genes MLH1, MSH2 and MSH6. A defective MMR is associated with microsatellite instability (MSI) in the tumor tissue and with somatic mutations in repeated sequences in several cancer-associated genes. In paper II, we studied the occurrence of such alterations in 24 tumors from 14 individuals in an HNPCC family with a germline MSH2 mutation and found an extensive intra- and inter-individual variation. Paper III demonstrates intratumoral heterogeneity of repeat-mutations in 10 macroscopically different areas of a colon carcinoma in a patient with a germline MLH1 mutation. The variation in the somatic mutations in repeat-containing genes suggests that these alterations are important for tumor progression rather than initiation and that the accumulation of mutations, rather than the specific alterations, drives HNPCC tumorigenesis. MMR defects play a role also in the development of sporadic (non-hereditary) cancer and are found in about 15% of colon cancers. In paper IV, we investigated rectal cancer patients regarding a family history of cancer and MSI in the tumor tissue. Only 3/165 (2%) of the tumors had MSI and all 3 patients were found to carry germline HNPCC-causing mutations. We conclude that MSI is rare in rectal cancer, but, when present, strongly indicates HNPCC. In paper V, we studied MSI and immunohistochemical expression of the MMR proteins in small bowel adenocarcinomas and found MSI in 11/70 (16%) tumors, 7 of which showed loss of MMR expression. Defective MMR thus contributes to small bowel carcinogenesis in a fraction of the tumors similar to colon cancer. In paper VI, we studied a population-based series of women who developed the two most common cancer types in HNPCC, colorectal cancer and endometrial cancer, before age 50. MSI was demonstrated in 75% of the tumors and concordant loss of the same MMR protein in both tumors, suggesting an underlying MMR gene mutation, was found in 12/27 patients. In summary, this thesis presents novel HNPCC-causing mutations, demonstrates variability among somatic mutations in repeat-containing genes in HNPCC-tumors, delineates the contribution of defective MMR in rectal cancer and small bowel cancer and points to a high risk of HNPCC among women with colorectal and endometrial cancer at young age