Objective-To introduce and monitor a screening programme for first degree relatives of patients with colorectal cancer based on their calculated lifetime risk.Design-Lifetime risks were calculated for first degree relatives of patients with colorectal cancer and used to offer screening based on estimated risk.Setting-A family cancer clinic was set up as part of the North East Thames Regional Genetic Service for relatives ofpatients who had developed colorectal cancer before the age of 45 and members of families in which multiple cancer had occurred.Patients-Self referrals as well as patients referred by general and hospital practitioners.Intervention-Relatives with a lifetime risk of 1 in 10 or greater (high risk group) were offered screening five yearly by colonoscopy, and those whose risk was between 1 in 10 and 1 in 17 were offered yearly screening for faecal occult blood. Women with family histories compatible with Lynch type II cancer family syndrome were offered screening for breast and pelvic tumours.Results-In four years 715 patients were seen. Acceptance of screening was 90% (644 patients). Of 151 patients screened for faecal occult blood, two were found to have polyps. This screening test was unsatisfactory for the high risk group, having a negative predictive value of 78% in 59 patients tested. Regular screening by colonoscopy was offered to 382 high risk patients; 62 patients with polyps and five with colonic cancer were found. One hundred and ten pedigrees were identified with the Lynch type II cancer family syndrome, and four of 35 women screened were found to have breast cancer. Of 14 relatives aged over 65 with a 1 in 2 risk of site specific colonic cancer or Lynch type II cancer family syndrome, seven were found to have polyps, one of whom had carcinoma in situ.Conclusions-Family history can be used to identify those at risk of colonic cancer and to target appropriate screening. Colonoscopy detected a high number of premalignant colonic polyps, but faecal occult blood testing was unsatisfactory for those at high risk of colorectal cancer. IntroductionThe lifetime risk of death from colorectal cancer in England and Wales is approximately 1 in 50 and increases rapidly from age 50. Unfortunately, the results of treatment are disappointing with an acknowledged survival rate of 50% in patients undergoing surgery with a view to cure. In 1974 Morson pointed
Hereditary non-polyposis colorectal cancer (HNPCC) is a clinical syndrome characterised by an inherited predisposition to early onset colorectal and uterine cancers and an increased incidence of other cancers. It is caused by germline defects in the human mismatch repair genes. Defects in two of the known mismatch repair genes (namely hMSH2 and hMLH1) account for over 90% of mutations found in HNPCC families. In this study we have identified 14 families that fulfilled the clinical criteria for HNPCC and screened the hMSH2 and hMLH1 genes for germline mutations using single-strand conformational polymorphism (SSCP) analysis and DNA sequencing. Seven mutations were identified. Of these, there were five frameshifts, one missense mutation and a further novel mutation that involved separate transition and transversion changes in successive amino acid residues. Three of the mutations were in hMSH2 and four in hMLH1. The identification of germ-line mutations in an HNPCC family enables targeted surveillance and the possibility of early curative intervention. SSCP is a simple and effective method for identifying most mutations in the human mismatch repair genes using DNA from fresh, frozen or archival material.
To estimate the relative risks of cancer in first-degree relatives of index patients, 130 pedigrees of dominantly inherited Lynch type II cancer family syndrome have been analysed. The risk of death from all causes was significantly increased in women over 45 years of age and the overall liability to cancer in women was greater than for men. A sevenfold increase in risk of colon cancer was found in both sexes. In female relatives the risk of breast cancer was increased fivefold and lifetime risk of breast cancer was 1 in 3.7. A screening programme based on estimated risks could be offered to first-degree relatives of index patients with Lynch type II cancer family syndrome.
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