[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.
OBJECTIVE:To identify mutation-specific cancer risks for carriers of BRCA1/2.
DESIGN, SETTING, AND PARTICIPANTS:Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.
EXPOSURES:Mutations of BRCA1 or BRCA2.
MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks.
RESULTS:Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.
CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.
JAMA The Journal of the American Medical Association 04/2015; 313(13):1347-61. DOI:10.1001/jama.2014.5985 · 30.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10-4 (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.
PMID: 25830658 [PubMed - in process]
PLoS ONE 04/2015; 10(4). DOI:10.1371/journal.pone.0120020 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Multiple endocrine neoplasia 1 (MEN1) is a cancer syndrome resulting from mutations of the MEN1 gene. The syndrome is characterized by neoplasia of the parathyroid and pituitary glands, and malignant tumors of the endocrine pancreas. Other manifestations include benign lipomas, angiofibromas, and carcinoid tumors commonly originating in the colon, thymus, and lung. This is the first report of MEN1 syndrome manifesting as bilateral granulosa cell ovarian tumors, and which is associated with a rare intronic mutation of the MEN1 gene.
A 41-year-old woman presented with abdominal pain, increasing abdominal girth, and dysmenorrhea. Ultrasound demonstrated enlarged ovaries and uterine fibroids. After an exploratory laparotomy, she subsequently underwent bilateral salpingo-oophorectomy with hysterectomy where the pathology revealed bilateral cystic granulosa cell tumors of the ovaries. Additional workup including computed tomography imaging discovered a thymic mass, which the pathology showed was malignant, along with a pancreatic mass suspicious for a neuroendocrine tumor. Hyperparathyroidism was also discovered and was found to be secondary to a parathyroid adenoma. Genetic testing revealed an exceedingly rare mutation in the MEN1 gene (c.654 + 1 G>A).
Mutations of the menin gene leading to MEN1 syndrome are classically nonsense or missense mutations producing a dysfunctional protein product. Recently, researchers described a novel mutation of MEN1 (c.654 + 1 G>A) in a male proband meeting the criteria for clinical MEN1 syndrome. Functional analysis performed on the stable mutant protein showed selective disruption of the transforming growth factor beta signaling pathway, yet it maintained its wild-type ability to inhibit nuclear factor kappa B and to suppress JunD transcriptional activity.
To our knowledge, this is the first report of MEN1 syndrome associated with bilateral granulosa cell malignancy. We postulate that this presentation may be due to the novel menin gene mutation recently described.
The Application of Clinical Genetics 02/2015; 8:69-73. DOI:10.2147/TACG.S72223
[Show abstract][Hide abstract] ABSTRACT: Loss-of-function mutations in PALB2 are associated with an increased risk of breast cancer, with recent data showing that female breast cancer risks for PALB2 mutation carriers are comparable in magnitude to those for BRCA2 mutation carriers. This study applied targeted massively parallel sequencing to characterize the mutation spectrum of PALB2 in probands attending breast cancer genetics clinics in the USA. The coding regions and proximal intron-exon junctions of PALB2 were screened in probands not known to carry a mutation in BRCA1 or BCRA2 from 1,250 families enrolled through familial cancer clinics by the Breast Cancer Family Registry. Mutation screening was performed using Hi-Plex, an amplicon-based targeted massively parallel sequencing platform. Screening of PALB2 was successful in 1,240/1,250 probands and identified nine women with protein-truncating mutations (three nonsense mutations and five frameshift mutations). Four of the 33 missense variants were predicted to be deleterious to protein function by in silico analysis using two different programs. Analysis of tumors from carriers of truncating mutations revealed that the majority were high histological grade, invasive ductal carcinomas. Young onset was apparent in most families, with 19 breast cancers under 50 years of age, including eight under the age of 40 years. Our data demonstrate the utility of Hi-Plex in the context of high-throughput testing for rare genetic mutations and provide additional timely information about the nature and prevalence of PALB2 mutations, to enhance risk assessment and risk management of women at high risk of cancer attending clinical genetic services.
Breast Cancer Research and Treatment 01/2015; 149(2). DOI:10.1007/s10549-014-3260-8 · 4.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction
More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers.
We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement.
The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10−6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement.
Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0492-9) contains supplementary material, which is available to authorized users.
Breast Cancer Research 12/2014; 16(6). DOI:10.1186/s13058-014-0492-9 · 5.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The existing knowledge on the survivorship experiences of Chinese American breast cancer survivors (CABCS) has arisen largely from aggregated data across multiethnic or multicancer studies that have focused on quality of life. Little is known about Chinese American perspectives and preferences for survivorship care.
To examine the experiences of CABCS to better understand their information and communication needs and their preferences for survivorship care plans (SCPs).
16 CABCS, aged 37-72 years, were recruited through community-based organizations in the Northeast United States to participate in one-on-one telephone interviews about their breast cancer survivorship experience. The semistructured interviews were conducted in Mandarin, Cantonese, or English. Two investigators transcribed and translated the audio recordings into English and analyzed the interview transcripts using established methods of qualitative content analysis.
Three main themes were identified through analysis of interview transcripts: the need for evidence-based and culturally and linguistically appropriate health information; the role of language or communication barriers and culture in accessing care and communicating with providers; and preferences for SCP elements and format.
The sample may not be representative of the entire population of CABCS.
The findings provide insight into the information and communication needs and SCP preferences of CABCS. Understanding the cultural nuances that underlie these needs and preferences is critical for improving CABCS's quality of life after treatment for cancer. SCPs that incorporate Chinese-language resources and address the unique cultural needs of this population should be developed and they should include information about diet and nutrition as well as traditional Chinese medicine.
[Show abstract][Hide abstract] ABSTRACT: Genomic tests are increasingly complex, less expensive, and more widely available with the advent of next-generation sequencing (NGS). We assessed knowledge and perceptions among genetic counselors pertaining to NGS genomic testing via an online survey. Associations between selected characteristics and perceptions were examined. Recent education on NGS testing was common, but practical experience limited. Perceived understanding of clinical NGS was modest, specifically concerning tumor testing. Greater perceived understanding of clinical NGS testing correlated with more time spent in cancer-related counseling, exposure to NGS testing, and NGS-focused education. Substantial disagreement about the role of counseling for tumor-based testing was seen. Finally, a majority of counselors agreed with the need for more education about clinical NGS testing, supporting this approach to optimizing implementation.
[Show abstract][Hide abstract] ABSTRACT: Purpose:To analyse the effect of germline mutations in BRCA1 and BRCA2 on mortality in ovarian cancer patients up to ten 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 analysed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analysed using Fine and Gray model. Results: The combined 10-year overall survival was 30% (95% CI, 28%-31%) for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The hazard ratio for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the hazard ratio was 0.42 at time zero and increased over time (predicted to become greater than one 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.
Clinical Cancer Research 11/2014; 21(3). DOI:10.1158/1078-0432.CCR-14-2497 · 8.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dissemination of genetic testing for disease susceptibility, one application of "personalized medicine", holds the potential to empower patients and providers through informed risk reduction and prevention recommendations. Genetic testing has become a standard practice in cancer prevention for high-risk populations. Heightened consumer awareness of "cancer genes" and genes for other diseases (eg, cardiovascular and Alzheimer's disease), as well as the burgeoning availability of increasingly complex genomic tests (ie, multi-gene, whole-exome and -genome sequencing), has escalated interest in and demand for genetic risk assessment and the specialists who provide it. Increasing demand is expected to surpass access to genetic specialists. Thus, there is urgent need to develop effective and efficient models of delivery of genetic information that comparably balance the risks and benefits to the current standard of in-person communication.
[Show abstract][Hide abstract] ABSTRACT: Inherited mutations in BRCA1 or BRCA2 (BRCA1/2) confer very high risk of breast and ovarian cancers. Genetic testing and counseling can reduce risk and death from these cancers if appropriate preventive strategies are applied, including risk-reducing salpingo-oophorectomy (RRSO) or risk-reducing mastectomy (RRM). However, some women who might benefit from these interventions do not take full advantage of them. We evaluated RRSO and RRM use in a prospective cohort of 1,499 women with inherited BRCA1/2 mutations from 20 centers who enrolled in the study without prior cancer or RRSO or RRM and were followed forward for the occurrence of these events. We estimated the age-specific usage of RRSO/RRM in this cohort using Kaplan-Meier analyses. Use of RRSO was 45 % for BRCA1 and 34 % for BRCA2 by age 40, and 86 % for BRCA1 and 71 % for BRCA2 by age 50. RRM usage was estimated to be 46 % by age 70 in both BRCA1 and BRCA2 carriers. BRCA1 mutation carriers underwent RRSO more frequently than BRCA2 mutation carriers overall, but the uptake of RRSO in BRCA2 was similar after mutation testing and in women born since 1960. RRM uptake was similar for both BRCA1 and BRCA2. Childbearing influenced the use of RRSO and RRM in both BRCA1 and BRCA2. Uptake of RRSO is high, but some women are still diagnosed with ovarian cancer before undergoing RRSO. This suggests that research is needed to understand the optimal timing of RRSO to maximize risk reduction and limit potential adverse consequences of RRSO.
Breast Cancer Research and Treatment 10/2014; 148(2). DOI:10.1007/s10549-014-3134-0 · 4.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:Multiplex genetic testing, including both moderate- and high-penetrance genes for cancer susceptibility, is associated with greater uncertainty than traditional testing, presenting challenges to informed consent and genetic counseling. We sought to develop a new model for informed consent and genetic counseling for four ongoing studies. Methods:Drawing from professional guidelines, literature, conceptual frameworks, and clinical experience, a multidisciplinary group developed a tiered-binned genetic counseling approach proposed to facilitate informed consent and improve outcomes of cancer susceptibility multiplex testing.Results:In this model, tier 1 "indispensable" information is presented to all patients. More specific tier 2 information is provided to support variable informational needs among diverse patient populations. Clinically relevant information is "binned" into groups to minimize information overload, support informed decision making, and facilitate adaptive responses to testing. Seven essential elements of informed consent are provided to address the unique limitations, risks, and uncertainties of multiplex testing.Conclusion:A tiered-binned model for informed consent and genetic counseling has the potential to address the challenges of multiplex testing for cancer susceptibility and to support informed decision making and adaptive responses to testing. Future prospective studies including patient-reported outcomes are needed to inform how to best incorporate multiplex testing for cancer susceptibility into clinical practice.Genet Med advance online publication 09 October 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.134.
Genetics in medicine: official journal of the American College of Medical Genetics 10/2014; 17(6). DOI:10.1038/gim.2014.134 · 6.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The heterogeneity among multiple ductal carcinoma in situ (DCIS) lesions within the same patient also diagnosed with invasive ductal carcinoma (IDC) has not been well evaluated, leaving research implications of intra-individual DCIS heterogeneity yet to be explored. In this study formalin-fixed paraffin embedded sections from 36 patients concurrently diagnosed with DCIS and IDC were evaluated by immunohistochemistry. Ten DCIS lesions from each patient were then randomly selected and scored. Our results showed that expression of PR, HER2, Ki-67, and p16 varied significantly within DCIS lesions from a single patient (P<0.05 for PR; P<1×10-8 for HER2, Ki-67 and p16). In addition, seventy-two percent of the individuals had heterogeneous expression of at least 2/6 markers. Importantly, by evaluating the expression of promising DCIS risk biomarkers (Ki-67, p53 and p16) among different DCIS subgroups classified by comparing DCIS molecular subtypes with those of adjacent normal terminal duct lobular units (TDLU) and IDC, our results suggest the existence of a highly-aggressive DCIS subgroup, which had the same molecular subtype as the adjacent IDC but not the same subtype as the adjacent normal TDLU. By using a systematic approach, our results clearly demonstrate that intra-individual heterogeneity in DCIS is very common in patients concurrently diagnosed with IDC. Our novel findings of a DCIS subpopulation with aggressive characteristics will provide a new paradigm for mechanistic studies of breast tumor progression and also have broad implications for prevention research as heterogeneous pre-invasive lesions are present in many other cancer types.
PLoS ONE 06/2014; 9(6):e100488. DOI:10.1371/journal.pone.0100488 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose: Researchers must monitor the safety of research participants, particularly in studies involving children and adolescents. Yet, there is limited guidance for the development and implementation of oversight committees for psychosocial, behavioral intervention, and observational studies. Methods: We implemented a model for an Event Monitoring Committee (EMC) in three related studies recruiting 6- to 19-year-old girls from families with and without breast cancer. Results: The EMC model can be valuable for investigators and local institutional review boards when additional oversight is desired. Recommendations are provided and intended to be broadly applicable to a wide range of research activities designed to improve the health of children, adolescents, and families. EMC goals, membership, and procedures for monitoring and assessing risks and benefits should be defined but should also be flexible and tailored to the study design and population. The EMC model also provides an independent comprehensive, study-wide oversight mechanism for multicenter psychosocial, behavioral intervention, and observational studies. Conclusions: An EMC provides an alternative oversight approach where additional independent assessment and oversight of study-related risks are desired, particularly in the setting of vulnerable populations, children and adolescents, or where risks nontraditional to the medical field (i.e., social, emotional, or cultural) are possible.
Journal of Adolescent Health 05/2014; 55(3). DOI:10.1016/j.jadohealth.2014.03.007 · 2.75 Impact Factor