[Show abstract][Hide abstract] ABSTRACT: Breast density and single-nucleotide polymorphisms (SNPs) have both been associated with breast cancer risk. To determine the extent to which these two breast cancer risk factors are associated, we investigate the association between a panel of validated SNPs related to breast cancer and quantitative measures of mammographic density in a cohort of Caucasian and African-American women.
In this IRB-approved, HIPAA-compliant study, we analyzed a screening population of 639 women (250 African American and 389 Caucasian) who were tested with a validated panel assay of 12 SNPs previously associated to breast cancer risk. Each woman underwent digital mammography as part of routine screening and all were interpreted as negative. Both absolute and percent estimates of area and volumetric density were quantified on a per-woman basis using validated software. Associations between the number of risk alleles in each SNP and the density measures were assessed through a race-stratified linear regression analysis, adjusted for age, BMI, and Gail lifetime risk.
The majority of SNPs were not found to be associated with any measure of breast density. SNP rs3817198 (in LSP1) was significantly associated with both absolute area (p = 0.004) and volumetric (p = 0.019) breast density in Caucasian women. In African-American women, SNPs rs3803662 (in TNRC9/TOX3) and rs4973768 (in NEK10) were significantly associated with absolute (p = 0.042) and percent (p = 0.028) volume density respectively.
The majority of SNPs investigated in our study were not found to be significantly associated with breast density, even when accounting for age, BMI, and Gail risk, suggesting that these two different risk factors contain potentially independent information regarding a woman's risk to develop breast cancer. Additionally, the few statistically significant associations between breast density and SNPs were different for Caucasian versus African American women. Larger prospective studies are warranted to validate our findings and determine potential implications for breast cancer risk assessment.
BMC Cancer 12/2015; 15(1):1159. DOI:10.1186/s12885-015-1159-3 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers.
Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided.
The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed.
Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.
Journal of the National Cancer Institute 11/2015; 108(2). DOI:10.1093/jnci/djv315 · 12.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary outcome:
Area under curve (AUC) for urinary estrogen. Secondary measures: urinary progesterone, quantitative digitized breast dynamic contrast-enhanced magnetic resonance imaging background parenchymal enhancement. Mean age 34 years, mean BMI 26.8 kg/m(2). A linear dose-response relationship was observed such that every 100 min of exercise is associated with 3.6 % lower follicular phase estrogen AUC (linear trend test, p = 0.03). No changes in luteal phase estrogen or progesterone levels. There was also a dose-response effect noted: for every 100 min of exercise, there was a 9.7 % decrease in background parenchymal enhancement as measured by imaging (linear trend test, p = 0.009). Linear dose-response effect observed to reduce follicular phase estrogen exposure measured via urine and hormone sensitive breast tissue as measured by imaging. Future research should explore maintenance of effects and extent to which findings are repeatable in lower risk women. Given the high benefit to risk ratio, clinicians can inform young women at increased risk that exercise may blunt estrogen exposure while considering whether to try other preventive therapies.
Breast Cancer Research and Treatment 10/2015; 154(2). DOI:10.1007/s10549-015-3604-z · 3.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Studies report conflicting evidence regarding the existence of a DCIS-associated premalignant pathway in BRCA mutation carriers. We aimed to examine the prevalence, phenotype, and expression of oncodrivers in pure DCIS (pDCIS) and invasive breast cancer with concurrent DCIS (IBC + DCIS) in mutation carriers.
A cohort of BRCA1 and BRCA2 mutation carriers >18 years old who underwent surgery for breast cancer at an academic hospital (1992-2011) and had pathology available for review were included for study. Invasive breast cancer (IBC) and DCIS were stained for ER, PR, HER1, HER2, and HER3, and C-MET. DCIS prevalence was evaluated. Correlation of IBC and DCIS phenotypes was evaluated in patients with IBC + DCIS. DCIS and IBC expression of tumor markers were examined by BRCA mutation.
We identified 114 breast tumors. Of all BRCA1-associated tumors, 21.1 % were pDCIS and 63.4 % were IBC + DCIS. Of all BRCA2-associated tumors, 23.3 % were pDCIS and 60.5 % were IBC + DCIS. In BRCA1 and BRCA2 mutation carriers with IBC + DCIS, there was a significant correlation in ER, PR, and HER3 expression between the DCIS and IBC components. Most BRCA1-associated DCIS did not express ER, PR or HER2, while most BRCA2-associated DCIS did express ER and PR. BRCA1- as well as BRCA2-associated DCIS had expression of HER3 and C-MET.
The majority of BRCA-associated tumors had DCIS present. Concordance of DCIS and IBC phenotypes was high, arguing for the existence of a DCIS-associated premalignant pathway. Oncodrivers HER3 and C-MET were expressed in the DCIS of mutation carriers, suggesting an opportunity for prevention strategies.
Journal of Translational Medicine 10/2015; 13(1):335. DOI:10.1186/s12967-015-0698-3 · 3.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The American Society of Clinical Oncology (ASCO) has long affirmed that the recognition and management of individuals with an inherited susceptibility to cancer are core elements of oncology care. ASCO released its first statement on genetic testing in 1996 and updated that statement in 2003 and 2010 in response to developments in the field. In 2014, the Cancer Prevention and Ethics Committees of ASCO commissioned another update to reflect the impact of advances in this area on oncology practice. In particular, there was an interest in addressing the opportunities and challenges arising from the application of massively parallel sequencing-also known as next-generation sequencing-to cancer susceptibility testing. This technology introduces a new level of complexity into the practice of cancer risk assessment and management, requiring renewed effort on the part of ASCO to ensure that those providing care to patients with cancer receive the necessary education to use this new technology in the most effective, beneficial manner. The purpose of this statement is to explore the challenges of new and emerging technologies in cancer genetics and provide recommendations to ensure their optimal deployment in oncology practice. Specifically, the statement makes recommendations in the following areas: germline implications of somatic mutation profiling, multigene panel testing for cancer susceptibility, quality assurance in genetic testing, education of oncology professionals, and access to cancer genetic services.
[Show abstract][Hide abstract] ABSTRACT: Advances in sequencing technology have made multigene testing, or "panel testing," a practical option when looking for genetic variants that may be associated with a risk of breast cancer. In June 2013, the U.S. Supreme Court(1) invalidated specific claims made by Myriad Genetics with respect to the patenting of the genomic DNA sequence of BRCA1 and BRCA2. Other companies immediately began to offer panel tests for breast cancer genes that included BRCA1 and BRCA2. The subsequent flourishing of gene-panel testing services (Table 1, and Table S1 in the Supplementary Appendix, available with the full text of this article at . . .
New England Journal of Medicine 05/2015; 372(23). DOI:10.1056/NEJMsr1501341 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We present a fully-automated method for deriving quantitative measures of background parenchymal enhancement (BPE) from breast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and perform a preliminary evaluation of these measures to assess the effect of risk-reducing salpingo-oophorectomy (RRSO) in a cohort of BReast CAncer susceptibility gene 1/2 (BRCA1/2) mutation carriers.
Breast DCE-MRI data from 50 BRCA1/2 carriers were retrospectively analyzed under the Health Insurance Portability and Accountability Act (HIPAA) and institutional review board approval. Both the absolute (| |) and relative ( %) measures of BPE and fibroglandular tissue (FGT) were computed from the MRI scans acquired before and after RRSO. These pre- and post-RRSO measures were compared using paired Student's t-test. The area under the curve (AUC) of the receiver operating characteristic (ROC) were used to evaluate the performance of relative changes in the BPE and FGT measures in predicting breast cancer developed among these women after the RRSO surgery.
For the 44 women who did not develop breast cancer after RRSO, absolute volume of BPE and FGT has a significant decrease (p < 0.05) post-RRSO, while for the 6 women who developed breast cancer there are no significant changes in these measures. Higher values in all BPE and FGT measures are also observed post-RRSO for the women who developed breast cancer, compared to women who did not. Relative changes in BPE % are most predictive of women who develop breast cancer after RRSO (p < 0.05), while combining BPE % and |FGT| yields an AUC of 0.80, higher than BPE % (AUC = 0.78) or |FGT| (AUC = 0.66) alone (both p > 0.02).
Quantitative measures of BPE and FGT are different before and after RRSO, and their relative changes are associated with prediction of developing breast cancer, potentially indicative of women who are more susceptible to develop breast cancer after RRSO in BRCA1/2 mutation carriers.
Breast cancer research: BCR 05/2015; 17(1):67. DOI:10.1186/s13058-015-0577-0 · 5.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370.
Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers).
We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations.
rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
[Show abstract][Hide abstract] ABSTRACT: Individuals carrying pathogenic mutations in BRCA1/2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals from different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. Here we test the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.
We genotyped 22214 (11421 affected, 10793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched for affected or unaffected individuals.
We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers than the rest of clade T, (Hazard Ratio (HR) = 0.55 (95% Confidence Interval (CI) 0.34-0.88, p-value = 0.01). Compared with the most frequent haplogroup in the general population i.e. H and T clade, the T1a1 haplogroup has an HR = 0.62 (95% CI = 0.40-0.95, p-value = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.
This study illustrates how original approaches like the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.
Breast cancer research: BCR 04/2015; 17(1):61. DOI:10.1186/s13058-015-0567-2 · 5.49 Impact Factor