Tumors associated with Hereditary Nonpolyposis Colorectal Cancer: Defective Mismatch Repair and Familial Risk of Cancer

Abstract: Inactivation of the DNA mismatch repair (MMR) system is a tumorigenic mechanism involved in 15-20% of tumor types such as colorectal and endometrial cancer and is specifically associated with the Hereditary Nonpolyposis Colorectal Cancer (HNPCC) syndrome. These MMR defective tumors are characterized by microsatellite instability (MSI), a phenomenon that reflects alterations in length of repeated sequences, and 90% of MSI tumors show loss of immunohistochemical expression for the MMR protein affected. HNPCC yields an increased risk for several tumor types; cancer of the colorectum (80-90% lifetime risk), endometrium (40-60%), ovary (5-15%), stomach (5-15%), urinary tract, small bowel, skin, and brain. The syndrome is characterized by an early age (mean 45 years) at diagnosis and one third of the patients develop metachronous tumors. The major aims of this thesis were to assess the contribution of defective MMR to the development of the more rare tumor types associated with HNPCC and to assess cancer risks in children whose parents had developed HNPCC-associated tumors. In study I, patients who developed multiple (at least 4) primary tumors, including two colorectal cancers, were assessed for MSI and immunohistochemical expression of the MMR proteins MLH1 and MSH2. MSI was identified in 63/154 (40%) tumors, 55 of which also showed immunohistochemical loss of MMR protein expression. A concordant finding of MSI and loss of the same MMR protein, which strongly suggest HNPCC, was found in 17/45 (38%) patients, which suggests that a high fraction of such multiple tumors are caused by HNPCC. In studies II and III, the frequency of defective MMR was studied in adenocarcinomas of the small intestine and in upper urinary tract cancers (UUC). MSI was detected in 16/89 (18%) of cancers of the small intestine and in 9/194 (4%) UUC. MMR protein expression loss affected 11 cancers of the small intestine and 11 UUC. Malignant fibrous histiocytoma (MFH) represents one of the largest subsets of soft tissue sarcomas, and occasional MFHs have been described in HNPCC-families. In study IV, we assessed MMR expression in a series of 209 MFH and found loss of MSH2 and MSH6 in 2 MFH. Study V is based on the national Swedish cancer registry and analyses familial risk of HNPCC-associated tumors. Cancer risks were calculated in 204 358 offspring whose 102 814 parents had developed HNPCC-associated cancer and the risks were correlated to the age of the parent, metachronous tumors in the parent, and presence of several HNPCC-associated cancers in the family. Significantly increased risks were observed for several tumor types, including colon cancer, rectal cancer, endometrial cancer, gastric cancer, and ovarian cancer. The highest offspring risks were observed in the subgroup with multiple HNPCC-associated cancers in the parent. In summary, we have demonstrated that MMR defects are common in patients who develop multiple primary tumors, occur at similar frequencies in cancers of the small intestine and the colon, contribute to development of UUC and MFH at low frequencies, and that HNPCC-associated tumor in a parent confer an increased risk of several cancer types in the offspring, especially if the parent developed more than one cancer or cancer at a young age.