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>

Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium

Milne, Roger L.,Burwinkel, Barbara,Michailidou, Kyriaki,Arias-Perez, Jose-Ignacio,Zamora, M. Pilar,Mené,ndez-Rodrí,guez, Primitiva,Hardisson, David,Mendiola, Marta,Gonzá,lez-Neira, A IRL Press 2014 Human molecular genetics Vol.23 No.22

<P>Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: <I>ATXN7-</I>K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04–1.10, <I>P</I> = 2.9 × 10<SUP>−6</SUP>], <I>AKAP9-</I>M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03–1.07, <I>P</I> = 1.7 × 10<SUP>−6</SUP>) and <I>NEK10-</I>L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07–1.12, <I>P</I> = 5.1 × 10<SUP>−17</SUP>). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for <I>ATXN7-</I>K264R, OR = 1.07 (95% CI = 1.05–1.10, <I>P</I> = 1.0 × 10<SUP>−8</SUP>); for <I>AKAP9-</I>M463I, OR = 1.05 (95% CI = 1.04–1.07, <I>P</I> = 2.0 × 10<SUP>−10</SUP>). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.</P>

Risk of Estrogen Receptor-Positive and -Negative Breast Cancer and Single-Nucleotide Polymorphism 2q35-rs13387042

Milne, Roger L.,Bení,tez, Javier,Nevanlinna, Heli,Heikkinen, Tuomas,Aittomä,ki, Kristiina,Blomqvist, Carl,Arias, José,Ignacio,Zamora, M. Pilar,Burwinkel, Barbara,Bartram, Claus R.,Mein Oxford University Press 2009 Journal of the National Cancer Institute Vol.101 No.14

<P>BACKGROUND: A recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)-positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium. METHODS: 2q35-rs13387042 SNP was genotyped for 31 510 women with invasive breast cancer, 1101 women with ductal carcinoma in situ, and 35 969 female control subjects from 25 studies. Odds ratios (ORs) were estimated by logistic regression, adjusted for study. Heterogeneity in odds ratios by each of age, ethnicity, and study was assessed by fitting interaction terms. Heterogeneity by each of invasiveness, family history, bilaterality, and hormone receptor status was assessed by subclassifying case patients and applying polytomous logistic regression. All statistical tests were two-sided. RESULTS: We found strong evidence of association between rs13387042 and breast cancer in white women of European origin (per-allele OR = 1.12, 95% confidence interval [CI] = 1.09 to 1.15; P(trend) = 1.0 x 10(-19)). The odds ratio was lower than that previously reported (P = .02) and did not vary by age or ethnicity (all P > or = .2). However, it was higher when the analysis was restricted to case patients who were selected for a strong family history (P = .02). An association was observed for both ER-positive (OR = 1.14, 95% CI = 1.10 to 1.17; P = 10(-15)) and ER-negative disease (OR = 1.10, 95% CI = 1.04 to 1.15; P = .0003) and both progesterone receptor (PR)-positive (OR = 1.15, 95% CI = 1.11 to 1.19; P = 5 x 10(-14)) and PR-negative disease (OR = 1.10, 95% CI = 1.06 to 1.15; P = .00002). CONCLUSION: The rs13387042 is associated with both ER-positive and ER-negative breast cancer in European women.</P>

Five polymorphisms and breast cancer risk: results from the Breast Cancer Association Consortium.

Gaudet, Mia M,Milne, Roger L,Cox, Angela,Camp, Nicola J,Goode, Ellen L,Humphreys, Manjeet K,Dunning, Alison M,Morrison, Jonathan,Giles, Graham G,Severi, Gianluca,Baglietto, Laura,English, Dallas R,Cou American Association for Cancer Research 2009 Cancer Epidemiology, Biomarkers & Prevention Vol.18 No.5

<P>Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97-1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95-1.06), 5.0%; CASP10 1.02 (0.98-1.07), 6.5%; PGR 1.02 (0.99-1.06), 15.3%; and BID 0.98 (0.86-1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent.</P>

Joint associations of a polygenic risk score and environmental risk factors for breast cancer in the Breast Cancer Association Consortium

Rudolph, Anja,Song, Minsun,Brook, Mark N,Milne, Roger L,Mavaddat, Nasim,Michailidou, Kyriaki,Bolla, Manjeet K,Wang, Qin,Dennis, Joe,Wilcox, Amber N,Hopper, John L,Southey, Melissa C,Keeman, Renske,Fas Oxford University Press 2018 International journal of epidemiology Vol.47 No.2

<P>Conclusions: The combined effects of the 77-SNP PRS and environmental risk factors for breast cancer are generally well described by a multiplicative model. Larger studies are required to confirm possible departures from the multiplicative model for individual risk factors, and assess models specific for ER-negative disease.</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>