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

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