Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

Milne, Roger L,Kuchenbaecker, Karoline B,Michailidou, Kyriaki,Beesley, Jonathan,Kar, Siddhartha,Lindströ,m, Sara,Hui, Shirley,Lemaç,on, Audrey,Soucy, Penny,Dennis, Joe,Jiang, Xia,Rostamianfa Nature Pub. Co 2017 Nature genetics Vol.49 No.12

<P>Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease(1). We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 x 10(-8) with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.</P>

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Phelan, Catherine M,Kuchenbaecker, Karoline B,Tyrer, Jonathan P,Kar, Siddhartha P,Lawrenson, Kate,Winham, Stacey J,Dennis, Joe,Pirie, Ailith,Riggan, Marjorie J,Chornokur, Ganna,Earp, Madalene A,Lyra J Nature Pub. Co 2017 Nature genetics Vol.49 No.5

<P>To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.</P>

Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

Lecarpentier, Julie,Silvestri, Valentina,Kuchenbaecker, Karoline B. American Society of Clinical Oncology 2017 Journal of clinical oncology Vol.35 No.20

<P>PurposeBRCA1/2 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 investigatedfor the first time to our knowledgeassociations 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 MethodsWe 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.ResultsIn 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 x 10(-6)). 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 x 10(-9)). 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.ConclusionPRSs 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.</P>

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Zeng, Chenjie,Guo, Xingyi,Long, Jirong,Kuchenbaecker, Karoline B.,Droit, Arnaud,Michailidou, Kyriaki,Ghoussaini, Maya,Kar, Siddhartha,Freeman, Adam,Hopper, John L.,Milne, Roger L.,Bolla, Manjeet K.,Wa BioMed Central 2016 Breast cancer research Vol.18 No.-

<P><B>Background</B></P><P>Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.</P><P><B>Method</B></P><P>We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 <I>BRCA1</I> mutation carriers in the Consortium of Investigators of Modifiers of <I>BRCA1/2</I> (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.</P><P><B>Results</B></P><P>Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; <I>P</I> = 3 × 10<SUP>-9</SUP>), rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, <I>P</I> = 2 × 10<SUP>-5</SUP>), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; <I>P</I> = 2 × 10<SUP>-4</SUP>) identified in the general populations, and rs113824616 (<I>P</I> = 7 × 10<SUP>-5</SUP>) identified in the meta-analysis of BCAC ER-negative cases and <I>BRCA1</I> mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at <I>P</I> < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that <I>PTHLH</I> was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of <I>PTHLH</I> and its nearby gene <I>CCDC91</I> at <I>P</I> < 0.05.</P><P><B>Conclusion</B></P><P>This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1186/s13058-016-0718-0) contains supplementary material, which is available to authorized users.</P>

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

Dunning, Alison M,Michailidou, Kyriaki,Kuchenbaecker, Karoline B,Thompson, Deborah,French, Juliet D,Beesley, Jonathan,Healey, Catherine S,Kar, Siddhartha,Pooley, Karen A,Lopez-Knowles, Elena,Dicks, Ed Springer Science and Business Media LLC 2016 Nature genetics Vol.48 No.4

<P>We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor a) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER+ or ER-) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER-tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.</P>