A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Peer reviewedPublisher PD

Transcriptomic analysis of milk somatic cells in mastitis resistant and susceptible sheep upon challenge with Staphylococcus epidermidis and Staphylococcus aureus

<p>Abstract</p> <p>Background</p> <p>The existence of a genetic basis for host responses to bacterial intramammary infections has been widely documented, but the underlying mechanisms and the genes are still largely unknown. Previously, two divergent lines of sheep selected for high/low milk somatic cell scores have been shown to be respectively susceptible and resistant to intramammary infections by <it>Staphylococcus spp</it>. Transcriptional profiling with an 15K ovine-specific microarray of the milk somatic cells of susceptible and resistant sheep infected successively by <it>S. epidermidis </it>and <it>S. aureus </it>was performed in order to enhance our understanding of the molecular and cellular events associated with mastitis resistance.</p> <p>Results</p> <p>The bacteriological titre was lower in the resistant than in the susceptible animals in the 48 hours following inoculation, although milk somatic cell concentration was similar. Gene expression was analysed in milk somatic cells, mainly represented by neutrophils, collected 12 hours post-challenge. A high number of differentially expressed genes between the two challenges indicated that more T cells are recruited upon inoculation by <it>S. aureus </it>than <it>S. epidermidis</it>. A total of 52 genes were significantly differentially expressed between the resistant and susceptible animals. Further Gene Ontology analysis indicated that differentially expressed genes were associated with immune and inflammatory responses, leukocyte adhesion, cell migration, and signal transduction. Close biological relationships could be established between most genes using gene network analysis. Furthermore, gene expression suggests that the cell turn-over, as a consequence of apoptosis/granulopoiesis, may be enhanced in the resistant line when compared to the susceptible line.</p> <p>Conclusions</p> <p>Gene profiling in resistant and susceptible lines has provided good candidates for mapping the biological pathways and genes underlying genetically determined resistance and susceptibility towards <it>Staphylococcus </it>infections, and opens new fields for further investigation.</p

Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs

Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk

In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene

Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP &lt; 0.15). RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P &lt; 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis.

Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10-8 and 4.42 × 10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations