Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3

Abstract

PurposeCis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways.MethodsUsing data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ∼320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2.ResultsWe identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10−6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance.ConclusionWe identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

Higher order genomic organization and regulatory compartmentalization for cell cycle control at the G1/S‐phase transition

“…This question has been the focus of studies on subnuclear organization (Cremer & Cremer, ; Zaidi et al, ). Emerging evidence using genome‐wide high‐resolution chromosome conformation capture (Hi‐C) technologies indicates that non‐random higher‐order organization of genes into structural domains supports regulatory activities involving non‐contiguous sequences that influence transcription (Barutcu et al, ; Belton et al, ; Ching, Ahmed, Boutros, Penn, & Bazett‐Jones, ; Dekker, Marti‐Renom, & Mirny, ; Hamdi et al, ; Lieberman‐Aiden et al, ; Martin et al, ; Matheson & Kaufman, ; Mifsud et al, ; Rowley & Corces, ; Tjong et al, ; Wang et al, ).…”

Can chimerism explain breast/ovarian cancers in BRCA non-carriers from BRCA-positive families?

“…Penetrance of g BRCA mutations vary in families and populations. Some SNPs have been reported to modify cancer risk in g BRCA mutation carriers [ 76 – 77 ]. It is possible that the same SNPs that increase cancer risk in g BRCA carriers can increase the cancer risk in their non-carrier relatives and thus, account for the phenomenon of BRCA phenocopies.…”

Functional Analysis of Promoter Variants in Genes Involved in Sex Steroid Action, DNA Repair and Cell Cycle Control

“…Moreover, two recent studies performed by our group led to the identification of two new loci, 4q21 and 11q22.3 that show evidence of association with overall breast cancer risk and with the modification of breast cancer risk in BRCA1 mutation carriers, respectively. In both studies, the associated variants are non-coding variants associated with differential allelic expression [18,19]. In addition, in vitro studies suggest that a high percentage of rSNPs lie within the core and proximal gene promoter regions, and 90% of the validated functional cis -regulatory polymorphisms have been shown to lie within the 2-kb proximal promoter [20].…”