Rapidly emerging technologies make it possible for consumers to acquire information that is intended to explain their inherited susceptibility to disease and facilitate tailored healthcare services ...through direct-to-consumer (DTC) marketing of personal genetic (PG) and personal genomic (PGM) testing. However, the health benefits and risks associated with these technologies are largely unknown. Consumers will turn to their healthcare providers, including nurse practitioners, to interpret test results and seek guidance on how to use these test results for medical decision-making. Nurse practitioners will need to constantly update their practice skills in response to advances in genomic technology that create new expectations among patients and lead to substantial changes in healthcare delivery.
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.
Methods We employed a qualitative descriptive design and convened a sample of 13 women who contributed in‐depth, semi‐structured telephone interviews (audio‐recorded and transcribed verbatim) and performed qualitative content analysis with NVivo 2.0 software.
Results Six major content areas emerged from interview data: (i) rationale for initial involvement in the breast imaging study, (ii) rationale for continued participation, (iii) experience of living in a multiple‐case family, (iv) risk perception: the personal meaning of mutation‐negative status, (v) opinions regarding cancer aetiology and (vi) communication patterns between mutation‐negative and mutation‐positive family members.
Conclusions Living in a hereditary breast and ovarian cancer family is a complex experience that affects cognitive, emotional and social functioning. Our findings indicate that mutation‐negative women may have unmet psychosocial needs that must be addressed by health‐care professionals, particularly in the primary‐care setting following genetic disclosure of a potentially reassuring result regarding their lack of the very high cancer risks associated with BRCA1/2 mutations.
Ductal lavage (DL) has been proposed as a minimally-invasive, well-tolerated tool for obtaining breast epithelial cells for cytological evaluation of breast cancer risk. We report DL tolerability in ...BRCA1/2 mutation-positive and -negative women from an IRB-approved research study.
165 BRCA1/2 mutation-positive, 26 mutation-negative and 3 mutation unknown women underwent mammography, breast MRI and DL. Psychological well-being and perceptions of pain were obtained before and after DL, and compared with pain experienced during other screening procedures.
The average anticipated and experienced discomfort rating for DL, 47 and 48 (0-100), were significantly higher (p < 0.01) than the anticipated and experienced discomfort of mammogram (38 and 34), MRI (36 and 25) or nipple aspiration (42 and 27). Women with greater pre-existing emotional distress experienced more DL-related discomfort than they anticipated. Women reporting DL-related pain as worse than expected were nearly three times more likely to refuse subsequent DL than those reporting it as the same or better than expected. Twenty-five percent of participants refused repeat DL at first annual follow-up.
DL was anticipated to be and experienced as more uncomfortable than other procedures used in breast cancer screening. Higher underlying psychological distress was associated with decreased DL tolerability.
BRCA1/2-positive women who learn their mutation status early in the life-course face unique challenges related to navigating the tasks of young adulthood. Using qualitative methods and grounded ...theory, the authors analyzed in-depth interviews with 11 women aged 26 to 35 who learned their mutation status before marriage. Their narratives illustrate the complexity of relationship formation, and highlight the potential for relationship-bonding and intimacy-building in the course of sharing mutation information. Disclosing BRCA mutation status to dating partners is often preceded by feelings of fear and anxiety, yet many participants reported that doing so has positive effects on relationships. Partners' abilities to respond with interest, empathy, and affection are associated with increased future intimacy, consistent with generally accepted principles within the family/couple systems field. Individual cancer risk perception and familial cancer experiences may affect the disclosure experience, which can be understood via Attachment Theory. Our findings provide clinical insight, identify new areas for research, and suggest ways to assist this unique population in their adjustment to being BRCA mutation-positive.
Testicular germ cell tumors (TGCT) exhibit striking familial aggregation that remains incompletely explained. To improve the phenotypic definition of familial TGCT (FTGCT), we studied an ...international cohort of multiple‐case TGCT families to determine whether first‐degree relatives of FTGCT cases are at increased risk of other types of cancer. We identified 1041 first‐degree relatives of TGCT cases in 66 multiple‐case TGCT families from Norway and 64 from the United States (combined follow‐up of 31,556 person‐years). We collected data on all cancers (except nonmelanoma skin cancers) reported by the family informant in these relatives, and we attempted to verify all reported cancer diagnoses through medical or cancer registry records. We calculated observed‐to‐expected (O/E) standardized incidence ratios, together with 95% confidence intervals (CI), for invasive cancers other than TGCT. We found no increase in risk of cancer overall (Norway O/E = 0.8; 95% CI: 0.6–1.1 and United States O/E = 0.9; 95% CI: 0.7–1.3). Site‐specific analyses pooled across the two countries revealed a leukemia excess (O/E = 6.5; 95% CI: 3.0–12.3), deficit of female breast cancer (O/E = 0.0; 95% CI: 0.0–0.6) and increased risk of soft tissue sarcoma (O/E = 7.2; 95% CI: 2.0–18.4); in all instances, these results were based on small case numbers and statistically significant only in Norway. While limited by sample size and potential issues relating to completeness of cancer reporting, this study in multiple‐case TGCT families does not support the hypothesis that cancers other than testis cancer contribute to the FTGCT phenotype.
We identified 1041 first‐degree relatives of testicular germ cell tumor (TGCT) case in 66 multiple‐case TGCT families from Norway and 64 families from the United States (combined follow‐up of 31,556 person‐years. We calculated observed‐to‐expected standardized incidence rations, together with 95% confidence intervals, for invasive cancers other than TGCT occurring in these individuals. We found no risk of cancer overall, suggesting that familial TGCT may be a site‐specific syndrome.
Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype
. To identify novel loci, we performed a genome-wide association study including 133,384 breast ...cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10
), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. ...Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates.
We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor ER-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS.
The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval CI = 1.23 to 1.31, P = 8.2×10 -53 ). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2×10 -20 ). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS.
BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.
The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The ...Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease‐associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population‐specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad‐based oncogenetic testing in some populations.
The prevalence and spectrum of germline mutations in BPCA1/2 have been reported in single populations, with the majority of reports focused on Caucasians in, Europe and North America. This study comprehensively describes the characteristics of worldwide disease‐associated BPCA1/2 mutations. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. Knowledge of the population‐specific mutational spectrum in BPCA1/2 could inform efficient strategies' or genetic testing and may justify a more broad‐based oncogenetic testing in some populations.
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.
To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns.
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).
Five-year overall mortality.
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).
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.
Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first ...time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10
). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10
). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.
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