The predicted truncation from a cancer-associated variant of the MSH2 initiation codon alters activity of the MSH2-MSH6 mismatch repair complex.

Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes. MMR recognizes and repairs DNA mismatches and small insertion/deletion loops. Carriers of MMR gene variants have a high risk of developing colorectal, endometrial, ovarian, and other extracolonic carcinomas. We report on an ovarian cancer patient who carries a germline MSH2 c.1A>C variant which alters the translation initiation codon. Mutations affecting the MSH2 start codon have been described previously for LS-related malignancies. However, the patients often lack a clear family history indicative of LS and their tumors often fail to display microsatellite instability, a hallmark feature of LS. Therefore, the pathogenicity of start codon variants remains undefined. Loss of the MSH2 start codon has been predicted to result in a truncated protein translated from a downstream in-frame AUG that would lack the first 25 amino acids. We therefore purified recombinant MSH2(NΔ25)-MSH6 and MSH2(NΔ25)-MSH3 to examine their DNA lesion recognition and adenosine nucleotide processing functions in vitro. We found that the MSH2(NΔ25) mutant confers distinct biochemical defects on MSH2-MSH6, but does not have a significant effect on MSH2-MSH3. We confirmed that expression of the MSH2 c.1A>C cDNA results in the production of multiple protein products in human cells that may include the truncated and full-length forms of MSH2. An in vivo MMR assay revealed a slight reduction in MMR efficiency in these cells. These data suggest that mutation of the MSH2 initiation codon, while not a strong, high-risk disease allele, may have a moderate impact on disease phenotype.

Attitudes toward direct-to-consumer advertisements and online genetic testing among high-risk women participating in a hereditary cancer clinic.

Genetic testing for the breast cancer genes 1/2 (BRCA 1/2) has helped women determine their risk of developing breast and ovarian cancer. As interest in genetic testing has grown, companies have created strategies to disseminate information about testing, including direct-to-consumer advertising (DTCA) and online genetic testing. This study examined attitudes toward DTCA and online testing for BRCA among 84 women at a high-risk clinic as well as additional factors that may be associated with these attitudes, such as personal and familial cancer history, cancer worry and risk perception, and history with genetic testing/counseling. Results showed that the majority of the women held favorable attitudes toward DTCA for BRCA testing but did not support online testing. Factors such as familial ovarian cancer, cancer worry, and satisfaction with genetic counseling/testing were associated with positive attitudes toward DTCA, whereas personal breast cancer history was related to negative attitudes. The findings suggest that women may view DTCA as informational but rely on physicians for help in their decision to undergo testing, and also suggest that cancer history may affect women's acceptance of DTCA and genetic testing.

Genetic issues in patients with breast cancer.

Screening for genetic abnormalities is a relatively complex task requiring detailed training and knowledge. Analysis of a person's genetic makeup has implications not only for that individual but also for their progenitors, offspring, siblings, and spouses. There are potential insurance, employment, and other risks regarding disclosure of this information. With proper training, surgeons or nurses with advanced skills can be qualified to conduct this type of initial analysis. Geneticists may be the ideal professionals to counsel patients. In this article, we explore these and other issues. The goal is to provide the surgeon with the information needed to identify patients at risk for carrying identifiable mutations that might lead to the development of breast cancer.

Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer.

CONTEXT: Hereditary diffuse gastric cancer is caused by germline mutations in the epithelial cadherin (CDH1) gene and is characterized by an increased risk for diffuse gastric cancer and lobular breast cancer. OBJECTIVE: To determine whether recurring germline CDH1 mutations occurred due to independent mutational events or common ancestry. DESIGN, SETTING, AND PATIENTS: Thirty-eight families diagnosed clinically with hereditary diffuse gastric cancer were accrued between November 2004 and January 2006 and were analyzed for CDH1 mutations as part of an ongoing study at the British Columbia Cancer Agency. Twenty-six families had at least 2 gastric cancer cases with 1 case of diffuse gastric cancer in a person younger than 50 years; 12 families had either a single case of diffuse gastric cancer diagnosed in a person younger than 35 years or multiple cases of diffuse gastric cancer diagnosed in persons older than 50 years. MAIN OUTCOME MEASURES: Classification of family members as carriers or noncarriers of CDH1 mutations. Haplotype analysis to assess recurring mutations for common ancestry was performed on 7 families from this study and 7 previously reported families with the same mutations. RESULTS: Thirteen mutations (6 novel) were identified in 15 of the 38 families (40% detection rate). The 1137G>A splicing mutation and the 1901C>T (A634V) missense/splicing mutation occurred on common haplotypes in 2 families but on different haplotypes in a third family. The 2195G>A (R732Q) missense/splicing mutation occurred in 2 families on different haplotypes. The 2064-2065delTG mutation occurred on a common haplotype in 2 families. Two families from this study plus 2 additional families carrying the novel 2398delC mutation shared a common haplotype, suggesting a founder effect. All 4 families originate from the southeast coast of Newfoundland. Due to concentrations of lobular breast cancer cases, 2 branches of this family had been diagnosed as having hereditary breast cancer and were tested for BRCA mutations. Within these 4 families, the cumulative risk by age 75 years in mutation carriers for clinically detected gastric cancer was 40% (95% confidence interval [CI], 12%-91%) for males and 63% (95% CI, 19%-99%) for females and the risk for breast cancer in female mutation carriers was 52% (95% CI, 29%-94%). CONCLUSIONS: Recurrent CDH1 mutations in families with hereditary diffuse gastric cancer are due to both independent mutational events and common ancestry. The presence of a founder mutation from Newfoundland is strongly supported.