Search

Background and objective. Hereditary nonpolyposis colorectal cancer (HNPCC) is the most frequent form of hereditary colorectal cancer. In addition to the high lifetime risk for colorectal cancer in mutation carriers, there is also a remarkably increased risk for endometrial cancer (EC). Methods. In this retrospective study, clinical and molecular approach to the individual decision making as to whether or not to perform a prophylactic hysterectomy in a subset of HNPCC patients is discussed. 147 female patients meeting at least one criterion of the Bethesda guidelines were included in this analysis between 1995 and 2003. After clinical and genetic counseling, patients gave informed written consent and microsatellite analysis, immunohistochemistry and sequencing of the mismatch repair genes MLH1 , MSH2 and MSH6 was performed. Results. 11 of the analyzed patients had a personal history of EC and had undergone previous hysterectomy at ages 26 to 62 years. Prophylactic hysterectomy with oophorectomy was considered in postmenopausal women meeting the Amsterdam criteria and/or carrying a disease causing mismatch repair gene mutation who were operated on because of diagnosed colorectal cancer in our center for hereditary cancer. This procedure was performed in 4 patients. None of them had shown any symptoms of a gynecologic malignancy. Preoperative gynecological examination showed no evidence for EC or ovarian cancer in these patients. Postoperative histological examination showed EC stage T1b N0 M0 in 2 patients. Conclusions. Since the efficiency of gynecological surveillance is uncertain, prophylactic hysterectomy could be an option for a subset of HNPCC patients and mutation carriers.

Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in the folate metabolism, which affects DNA synthesis and methylation. Low enzyme activity may reduce the capacity of DNA methylation, and possibly reduce uracil misincorporation into DNA, which can result in double strand breaks. Both processes may be critical for the oncogenic transformation of human cells. Two common amino acid-changing and enzyme activity-reducing nucleotide polymorphisms (677C→T/Ala222Val and 1298A→C/Glu428Ala) have been described in MTHFR . We performed estimations of the relative risk associated with these two polymorphisms in samples from 287 colorectal cancer patients, compared to 346 healthy controls. Relative risk were further determined for subpopulations of cancer patients having sporadic ( n =227) or suspected/verified hereditary disease ( n =60) and tumours exhibiting high-level microsatellite instability ( n =41) or not ( n =246). No significant differences for the relative risk of colorectal cancer were observed for the MTHFR genotypes either alone or in combination in the analysed cohorts, although the frequency of the 1298AA+AC genotypes was increased among the 60 cases with hereditary disease. Whereas our results do not support an association of high enzyme activity and increased risk of colorectal cancer in general, we can not exclude an association of patients with hereditary disease and the MTHFR 1298A→C variant.