Screening RAD51C nucleotide alterations in patients with a family history of breast and ovarian cancer.

It has been reported that one biallelic missense mutation in the RAD51C gene was found in a Fanconi anemia-like disorder and six monoallelic pathogenic mutations were identified in 480 BRCA1/2 negative breast and ovarian cancer pedigrees but not in 620 pedigrees with breast cancer only. Additionally, the RAD51C gene was reported to be involved in gene fusion events in the MCF-7 breast cancer cell line. We performed complete sequencing and fusion gene breakpoint screening to detect deleterious mutations and chromosomal structure change in the RAD51C gene. Ninety-two hereditary gynecological cancer patients with a family history of breast and ovarian cancer but not carrying BRCA1/2 mutations were studied. In addition, 46 breast cancer cell lines were screened for the gene fusion events. Ten DNA sequence variants but no deleterious mutations were identified. We did not observe the occurrence of the known gene fusion either. We were unable to confirm the contribution of the RAD51C gene to hereditary breast and ovarian cancer (HBOC) in this relatively small cohort. Nonetheless, larger studies in diverse populations to fully investigate the mutation spectrum of the RAD51C gene are needed.

Parent opinions regarding the genetic testing of minors for BRCA1/2.

PURPOSE: Although not currently recommended, genetic testing of minors for adult hereditary cancer syndromes, along with risks and benefits, is still being debated. Thus, we evaluated parent opinions regarding BRCA1/2 testing of minors, in general, and hypothetically, for parents' own minor child. METHODS: Semistructured interviews were conducted to assess parent opinions regarding BRCA1/2 testing in minors, along with parent rationale for and factors associated with these opinions. RESULTS: In total, 246 parents at two academic cancer risk assessment programs who underwent BRCA1/2 testing completed the interview (60% response rate). In response to a dichotomous question, 37% of parents supported testing minors. Responses to an open-ended query suggest that 47% support testing minors in some or all circumstances. Parent negative BRCA1/2 test result (P = .02), parent male sex (P = .03), and minority race (P = .01) were independently associated with support of testing minors. In response to a dichotomous question, 44% of parents reported hypothetical interest in testing their own minor offspring. Responses to an open-ended query suggest that 55% would consider, hypothetically, testing their child in some or all circumstances. Parent negative test result (P = .01), less than a college education (P < .01), and older mean offspring age (P = .05) were associated with interest in testing one's own child. CONCLUSION: Parents' opinions regarding BRCA1/2 testing of minors are divided. Given the lack of evidence supporting either the permission or restriction of BRCA1/2 testing in minors, further evaluation of the risks and benefits of providing genetic risk information and genetic testing to minors for adult-onset disease is needed to inform clinical practice and guidelines.

Prediction of BRCA Mutations Using the BRCAPRO Model in Clinic-Based African American, Hispanic, and Other Minority Families in the United States.

PURPOSE: BRCAPRO, a BRCA mutation carrier prediction model, was developed on the basis of studies in individuals of Ashkenazi Jewish and European ancestry. We evaluated the performance of the BRCAPRO model among clinic-based minority families. We also assessed the clinical utility of mutation status of probands (the first individual tested in a family) in the recommendation of BRCA mutation testing for other at-risk family members. PATIENTS AND METHODS: A total of 292 minority families with at least one member who was tested for BRCA mutations were identified through the Breast Cancer Family Registry and the University of Chicago. Using the BRCAPRO model, the predicted likelihood of carrying BRCA mutations was generated. Area under the receiver operating characteristic curves (AUCs) were calculated. RESULTS: There were 104 African American, 130 Hispanic, 37 Asian-American, and 21 other minority families. The AUC was 0.748 (95% CI, 0.672 to 0.823) for all minorities combined. There was a statistically nonsignificant trend for BRCAPRO to perform better in Hispanic families than in other minority families. After taking into account the mutation status of probands, BRCAPRO performance in additional tested family members was improved: the AUC increased from 0.760 to 0.902. CONCLUSION: The findings support the use of BRCAPRO in pretest BRCA mutation prediction among minority families in clinical settings, but there is room for improvement in ethnic groups other than Hispanics. Knowledge of the mutation status of the proband provides additional predictive value, which may guide genetic counselors in recommending BRCA testing of additional relatives when a proband has tested negative.

Translational integrity and continuity: personalized biomedical data integration.

Translational research data are generated in multiple research domains from the bedside to experimental laboratories. These data are typically stored in heterogeneous databases, held by segregated research domains, and described with inconsistent terminologies. Such inconsistency and fragmentation of data significantly impedes the efficiency of tracking and analyzing human-centered records. To address this problem, we have developed a data repository and management system named TraM (http://tram.uchicago.edu), based on a domain ontology integrated entity relationship model. The TraM system has the flexibility to recruit dynamically evolving domain concepts and the ability to support data integration for a broad range of translational research. The web-based application interfaces of TraM allow curators to improve data quality and provide robust and user-friendly cross-domain query functions. In its current stage, TraM relies on a semi-automated mechanism to standardize and restructure source data for data integration and thus does not support real-time data application.