Interpretation of genetic test results for hereditary nonpolyposis colorectal cancer: implications for clinical predisposition testing.

CONTEXT: Genetic testing for cancer predisposition is evolving from purely research applications to affecting clinical management. OBJECTIVE: To determine how often genetic test results for hereditary nonpolyposis colorectal cancer (HNPCC) can be definitively interpreted and used to guide clinical management. DESIGN: Case-series study conducted in 1996 to 1998 in which a complete sequence analysis of hMSH2 and hMLH1 coding sequence and flanking intronic regions was performed. Mutations were categorized as protein truncating and missense. In the case of missense alterations, additional analyses were performed in an effort to assess pathogenicity. SETTING AND PARTICIPANTS: Families were identified by self-referral or health care provider referral to a cancer genetics program. Participants and kindreds were classified into 1 of 4 categories: (1) Amsterdam criteria for HNPCC, (2) modified Amsterdam criteria for HNPCC, (3) young age at onset, or (4) HNPCC-variant. In addition, each proband was classified according to the Bethesda guidelines for identification of individuals with HNPCC. MAIN OUTCOME MEASURE: Alterations of hMSH2 and hMLH1 genes. RESULTS: Twenty-seven alterations of hMSH2 and hMLH1 were found in 24 of 70 families (34.3%). Of these, deleterious mutations that could be used with confidence in clinical management were identified in 25.7% (18/70) of families. The rates of definitive results for families fulfilling Amsterdam criteria, modified Amsterdam criteria, young age at onset, HNPCC-variant, and Bethesda guidelines were 27 (39.3%), 13 (18.2%), 12 (16.7%), 11 (15.8%), and 21 (30.4%), respectively. The prevalence of missense mutations, genetic heterogeneity of the syndrome, and limited availability of validated functional assays present a challenge in the interpretation of genetic test results of HNPCC families. CONCLUSIONS: The identification of pathogenic mutations in a significant subset of families for whom the results may have marked clinical importance makes genetic testing an important option for HNPCC and HNPCC-like kindreds. However, for the majority of individuals in whom sequence analysis of hMSH2 and hMLH1 does not give a definitive result, intensive follow-up is still warranted.     

Selective use of maternal serum testing.

Maternal serum testing is used to screen for both trisomy 21 (T21) and structural fetal abnormalities such as neural tube defects (NTDs). Second line diagnostic testing for T21 is usually by amniocentesis but for NTDs it is simply a detailed scan. It is possible that a proportion of women unnecessarily reject both parts of the screening test because they would not wish to undergo invasive testing and yet would accept a detailed ultrasound scan. This is particularly important in maternity units, such as ours, which cannot yet offer detailed fetal anomaly scans routinely. A retrospective case-note review of 231 consecutive new bookings over a 4-month period identified 61 women who chose initially not to have serum measurement of AFP/hCG (double test). Of the 61 women, 23 had rejected serum testing because they would not agree to amniocentesis and 29 because they would not agree to termination of pregnancy. All 61 women were offered serum screening for structural anomalies alone and 21 (34%) then chose to have AFP measurement. Maternal serum screening is not a single test and clinicians working in units with a limited antenatal ultrasound service should consider offering AFP measurement alone to women who decline comprehensive testing.     

Prevalence of a positive family history of type 2 diabetes in women with polycystic ovarian disease.

The known association between insulin resistance and polycystic ovarian disease (PCOD) has been studied by determination of the prevalence of a positive family history of diabetes in a consecutive series of oligomenorrheic women with polycystic ovaries and eumenorrheic women with normal ovaries who served as controls. A significantly greater proportion of the families of the patients with PCOD had at least one member affected by type 2 diabetes (39.1% of the PCOD group and 7.6% of the controls; p < 0.001). Both obese (54.8%) and non-obese women (24.2%) with PCOD had an increased prevalence of type 2 diabetes within their families. Paternal and maternal family members affected were in similar proportions, there being no evidence of preferential transmission through the female line in this study. The increased prevalence of type 2 diabetes in the families of women with polycystic ovaries is further evidence for the association between PCOD and insulin resistance, and provides a possible explanation for the familial nature of the ovarian disorder.