Impact of gynecological screening in Lynch syndrome carriers with an MSH2 mutation.

Lifetime risk of developing endometrial cancer in Lynch syndrome carriers is very high and females are also at an increased risk of developing ovarian cancer. The aim of the study was to determine the impact of gynecological screening in MSH2 mutation carriers. Gynecological cancer incidence and overall survival was compared in female mutation carriers who received gynecological screening (cases) and in matched controls. Controls were randomly selected from non-screened mutation carriers who were alive and disease-free at the age the case entered the screening program. Median age to diagnosis of gynecological cancer was 54 years in the screened group compared to 56 years in controls (p = 0.50). Stage I or II cancer was diagnosed in 92% of screened patients compared to 71% in the control group (p = 0.17). Two of three deaths in the screened group were the result of ovarian cancer. Mean survival in the screened group was 79 years compared to 69 years in the control group (p = 0.11), likely associated with concomitant colonoscopy screening. Gynecological screening did not result in earlier gynecologic cancer detection and despite screening two young women died from ovarian cancer suggesting that prophylactic hysterectomy with bilateral salpingo-oophorectomy be considered in female mutation carriers who have completed childbearing.

Impact of colonoscopic screening in male and female Lynch syndrome carriers with an MSH2 mutation.

The lifetime risk of developing colorectal cancer (CRC) in Lynch syndrome (LS) carriers is very high. To determine the impact of colonoscopic screening in 54 male and 98 female MSH2 mutation carriers, outcomes were compared with 94 males and 76 females who were not screened. CRC incidence and survival in the screened group were compared to that expected, derived from the non-screened group. To correct for survivor bias, controls were matched for age at entry into screening and also for gender. In males, median age to CRC was 58 years, whereas expected was 47 years (p = 0.000), and median survival was 66 years vs 62 years (p = 0.034). In screened females, median age to CRC was 79 years compared to 57 years in the non-screened group (p = 0.000), and median survival was 80 years compared with expected of 63 years (p = 0.001). Twenty percent of males and 7% of females developed an interval CRC within 2 years of previous colonoscopy. Although colonoscopic screening was associated with decreased CRC risk and better survival, CRCs continued to occur. CRC development may be further reduced by decreasing the screening interval to 1 year and improving quality of colonoscopy.

The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease.

BACKGROUND AND AIMS: Colorectal cancer (CRC) is the second most frequent cancer in developed countries. Newfoundland has the highest incidence of CRC in Canada and the highest rate of familial CRC yet reported in the world. To determine the impact of mutations in known CRC susceptibility genes and the contribution of the known pathways to the development of hereditary CRC, an incident cohort of 750 patients with CRC (708 different families) from the Newfoundland population was studied. METHODS: Microsatellite instability (MSI) testing was performed on tumours, together with immunohistochemistry analysis for mismatch repair (MMR) genes. Where indicated, DNA sequencing and multiplex ligation-dependent probe amplifications of MMR genes and APC was undertaken. DNA from all patients was screened for MUTYH mutations. The presence of the BRAF variant, p.V600E, and of MLH1 promoter methylation was also tested in tumours. RESULTS: 4.6% of patients fulfilled the Amsterdam criteria (AC), and an additional 44.6% fulfilled the revised Bethesda criteria. MSI-high (MSI-H) was observed in 10.7% (n=78) of 732 tumours. In 3.6% (n=27) of patients, CRC was attributed to 12 different inherited mutations in six known CRC-related genes associated with chromosomal instability or MSI pathways. Seven patients (0.9%) carried a mutation in APC or biallelic mutations in MUTYH. Of 20 patients (2.7%) with mutations in MMR genes, 14 (70%) had one of two MSH2 founder mutations. 17 of 28 (61%) AC families did not have a genetic cause identified, of which 15 kindreds fulfilled the criteria for familial CRC type X (FCCTX). CONCLUSIONS: Founder mutations accounted for only 2.1% of cases and this was insufficient to explain the high rate of familial CRC. Many of the families classified as FCCTX may have highly penetrant mutations segregating in a Mendelian-like manner. These families will be important for identifying additional CRC susceptibility loci.

Health-related quality of life in a cohort of adult patients with mild hemophilia A.

OBJECTIVES: To compare the health-related quality of life among adult males affected with mild hemophilia A due to the same mutation (Val2016ala) to that of unaffected age and sex matched controls from the same general population. METHODS: The Short-Form 36 (SF-36) and Health Assessment Questionnaire (HAQ) were used to measure health-related quality of life and physical function. Other measures included bleeding history, a measure of joint damage, body mass index, age, and viral infection status. Cross-sectional data were collected through research clinics and a retrospective chart audit over a two-year period. RESULTS AND CONCLUSIONS: The study included 47 affected males and 33 controls. The affected males had a higher level of co-morbidity, prior bleeding, and existing joint damage than controls. With the exception of the social function and health transition scales, mean scores for each of the SF-36 domains were worse among affected males. Mean differences were more than a clinically important five points in five of eight domains, with the general health scale showing more than a 10-point difference. Despite the degree of difference noted, only two of the differences were statistically significant (general health and role emotional scales) because of the small sample size and considerable individual variation in SF-36 scale scores. Multiple regression analyses suggested existing joint damage and presence of heart disease as the strongest associates of lower physical health-related quality of life. Joint damage in turn was partly related to prior hemarthroses. Compared to the Canadian population, affected males had lower scores in six out of eight SF-36 domains as well as the physical component summary score. There were no significant differences found in the HAQ scores between the two groups. So-called mild hemophilia A was associated with a negative effect on physical health-related quality of life, contributed to by joint damage as a result of prior bleeding.