Jennifer T. Loud

Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer

CONTEXT Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear. OBJECTIVE To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. DESIGN, SETTING, AND PARTICIPANTS A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n = 909) or BRCA2 (n = 304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998). MAIN OUTCOME MEASURE Five-year overall mortality. RESULTS The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P < .001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P < .001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P < .001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P < .001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity = .003). CONCLUSION Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis.

Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study.

Fanconi anaemia (FA), dyskeratosis congenita (DC), Diamond‐Blackfan anaemia (DBA), and Shwachman‐Diamond syndrome (SDS) comprise major inherited bone marrow failure syndromes (IBMFS). Adverse events include severe bone marrow failure (BMF), myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and solid tumours (ST). The natural history of FA is well characterised; hazard rates in the other syndromes have not yet been quantified. An open cohort was established at the National Cancer Institute (NCI) in 2002. Patients enrolled prior to December, 2007 were followed up to December, 2008. Diagnoses were confirmed with standard tests. Age‐associated risks of adverse events were calculated. Most patients in each syndrome survived to young adulthood. Patients with FA had earlier onset of cancers, need for stem cell transplant, and death; followed by DC; DBA and SDS were mildest. While FA and DC patients had markedly increased risks of cancer, AML and MDS, there were no cases of leukaemia in DBA or SDS patients. The NCI cohort provides the first direct quantitative comparison of timing and magnitude of cancer risk in the IBMFS. The findings demonstrate that both FA and DC are major cancer susceptibility syndromes. The IBMFS, historically considered paediatric disorders, have important management implications for physicians treating adult patients.

Meta-analysis identifies four new loci associated with testicular germ cell tumor

We conducted a meta-analysis to identify new susceptibility loci for testicular germ cell tumor (TGCT). In the discovery phase, we analyzed 931 affected individuals and 1,975 controls from 3 genome-wide association studies (GWAS). We conducted replication in 6 independent sample sets comprising 3,211 affected individuals and 7,591 controls. In the combined analysis, risk of TGCT was significantly associated with markers at four previously unreported loci: 4q22.2 in HPGDS (per-allele odds ratio (OR) = 1.19, 95% confidence interval (CI) = 1.12–1.26; P = 1.11 × 10−8), 7p22.3 in MAD1L1 (OR = 1.21, 95% CI = 1.14–1.29; P = 5.59 × 10−9), 16q22.3 in RFWD3 (OR = 1.26, 95% CI = 1.18–1.34; P = 5.15 × 10−12) and 17q22 (rs9905704: OR = 1.27, 95% CI = 1.18–1.33; P = 4.32 × 10−13 and rs7221274: OR = 1.20, 95% CI = 1.12–1.28; P = 4.04 × 10−9), a locus that includes TEX14, RAD51C and PPM1E. These new TGCT susceptibility loci contain biologically plausible genes encoding proteins important for male germ cell development, chromosomal segregation and the DNA damage response.

Characteristics of Health Information Gatherers, Disseminators, and Blockers Within Families at Risk of Hereditary Cancer: Implications for Family Health Communication Interventions

OBJECTIVES Given the importance of the dissemination of accurate family history to assess disease risk, we characterized the gatherers, disseminators, and blockers of health information within families at high genetic risk of cancer. METHODS A total of 5466 personal network members of 183 female participants of the Breast Imaging Study from 124 families with known mutations in the BRCA1/2 genes (associated with high risk of breast, ovarian, and other types of cancer) were identified by using the Colored Eco-Genetic Relationship Map (CEGRM). Hierarchical nonlinear models were fitted to characterize information gatherers, disseminators, and blockers. RESULTS Gatherers of information were more often female (P<.001), parents (P<.001), and emotional support providers (P<.001). Disseminators were more likely female first- and second-degree relatives (both P<.001), family members in the older or same generation as the participant (P<.001), those with a cancer history (P<.001), and providers of emotional (P<.001) or tangible support (P<.001). Blockers tended to be spouses or partners (P<.001) and male, first-degree relatives (P<.001). CONCLUSIONS Our results provide insight into which family members may, within a family-based intervention, effectively gather family risk information, disseminate information, and encourage discussions regarding shared family risk.

A Prospective Study of Risk-Reducing Salpingo-oophorectomy and Longitudinal CA-125 Screening among Women at Increased Genetic Risk of Ovarian Cancer: Design and Baseline Characteristics: A Gynecologic Oncology Group Study

Background: Women who are genetically predisposed to ovarian cancer are at very high risk of developing this disease. Although risk-reducing salpingo-oophorectomy (RRSO) and various screening regimens are currently recommended to reduce ovarian cancer risk, the optimal management strategy has not been established nor have multiple additional issues been adequately addressed. We developed a collaboration among the Clinical Genetics Branch (National Cancer Institutes Intramural Research Program), the Gynecologic Oncology Group (GOG), and the Cancer Genetics Network to address these issues. Methods: This is a prospective, international, two-cohort, nonrandomized study of women at genetic risk of ovarian cancer, who chose either to undergo RRSO or screening, at study enrollment. Primary study objectives include quantifying and comparing ovarian and breast cancer incidence in the two study groups, assessing feasibility and selected performance characteristics of a novel ovarian cancer screening strategy (the Risk of Ovarian Cancer Algorithm), evaluating various aspects of quality of life and nononcologic morbidity related to various interventions in at-risk women, and creating a biospecimen repository for subsequent translational research. Results: Study accrual is complete as of November 2006; 2,605 participants enrolled: 1,030 (40%) into the surgical cohort and 1,575 (60%) into the screening cohort. Five years of prospective follow-up ends in November 2011. Verification of BRCA mutation carrier status is under way, either through patient-provided reports from clinical genetic testing done before enrollment or through research-based genetic testing being conducted as part of the protocol. Patient eligibility is currently under evaluation and baseline, surgical, pathology, and outcome data are still being collected. The study design and selected baseline characteristics of cohort members are summarized. Conclusion: This National Cancer Institute intramural/extramural collaboration will provide invaluable prospectively collected observational data on women at high familial ovarian cancer risk, including substantial numbers of women carrying BRCA1/2 mutations. These data will aid in elucidating the effect of RRSO on breast/ovarian cancer risk and the effects of two management strategies, on quality of life and other issues that may influence patient care, as well as providing preliminary estimates of test specificity and positive predictive value of a novel ovarian cancer screening strategy. (Cancer Epidemiol Biomarkers Prev 2008;17(3):594–604)

Sisters in hereditary breast and ovarian cancer families: communal coping, social integration, and psychological well-being

Objective: We investigated the association between psychological distress and indices of social integration and communal coping among sisters from hereditary breast and ovarian cancer (HBOC) families.

Germline Mutation in BRCA1 or BRCA2 and Ten-Year Survival for Women Diagnosed with Epithelial Ovarian Cancer

Purpose: To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis. Experimental Design: We used unpublished survival time data for 2,242 patients from two case–control studies and extended survival time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analyzed using Fine and Gray model. Results: The combined 10-year overall survival rate was 30% [95% confidence interval (CI), 28%–31%] for non-carriers, 25% (95% CI, 22%–28%) for BRCA1 carriers, and 35% (95% CI, 30%–41%) for BRCA2 carriers. The HR for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the HR was 0.42 at time zero and increased over time (predicted to become greater than 1 at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors and to ovarian cancer–specific mortality. Conclusions: BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers. Clin Cancer Res; 21(3); 652–7. ©2014 AACR.

BRCA mutation-negative women from hereditary breast and ovarian cancer families: a qualitative study of the BRCA-negative experience

Background  When women from families with a known BRCA1 or BRCA2 mutation test negative for the family mutation, it is assumed that they will transition their personal cancer risk perception from high to average risk. However, there are scant data regarding the experience of mutation‐negative women after genetic testing disclosure, particularly related to the shift of risk perception from assumed mutation‐positive to actual mutation‐negative. This study was designed to explore cancer risk perception and the experience of being a mutation‐negative woman within a known BRCA1/2 mutation‐positive family.

Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23

Genome-wide association studies (GWASs) have identified multiple common genetic variants associated with an increased risk of testicular germ cell tumors (TGCTs). A previous GWAS reported a possible TGCT susceptibility locus on chromosome 1q23 in the UCK2 gene, but failed to reach genome-wide significance following replication. We interrogated this region by conducting a meta-analysis of two independent GWASs including a total of 940 TGCT cases and 1559 controls for 122 single-nucleotide polymorphisms (SNPs) on chromosome 1q23 and followed up the most significant SNPs in an additional 2202 TGCT cases and 2386 controls from four case-control studies. We observed genome-wide significant associations for several UCK2 markers, the most significant of which was for rs3790665 (PCombined = 6.0 × 10(-9)). Additional support is provided from an independent familial study of TGCT where a significant over-transmission for rs3790665 with TGCT risk was observed (PFBAT = 2.3 × 10(-3)). Here, we provide substantial evidence for the association between UCK2 genetic variation and TGCT risk.

Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort.

Li‐Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome characterized by a very high lifetime cancer risk and an early age at diagnosis of a wide cancer spectrum. Precise estimates for the risk of first and subsequent cancers are lacking.