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Association analysis identifies 65 new breast cancer risk loci
Michailidou, Kyriaki,Lindströ,m, Sara,Dennis, Joe,Beesley, Jonathan,Hui, Shirley,Kar, Siddhartha,Lemaç,on, Audrey,Soucy, Penny,Glubb, Dylan,Rostamianfar, Asha,Bolla, Manjeet K.,Wang, Qin,Tyr Macmillan Publishers Limited, part of Springer Nat 2017 Nature Vol.551 No.7678
<P>Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry(1). We identified 65 new loci that are associated with overall breast cancer risk at P < 5 x 10(-8). The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.</P>
Michailidou, Kyriaki,Beesley, Jonathan,Lindstrom, Sara,Canisius, Sander,Dennis, Joe,Lush, Michael J,Maranian, Mel J,Bolla, Manjeet K,Wang, Qin,Shah, Mitul,Perkins, Barbara J,Czene, Kamila,Eriksson, Mi Nature Publishing Group, a division of Macmillan P 2015 Nature genetics Vol.47 No.4
Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10<SUP>−8</SUP>. Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.
Genome-wide association analysis identifies three new breast cancer susceptibility loci
Ghoussaini, Maya,Fletcher, Olivia,Michailidou, Kyriaki,Turnbull, Clare,Schmidt, Marjanka K,Dicks, Ed,Dennis, Joe,Wang, Qin,Humphreys, Manjeet K,Luccarini, Craig,Baynes, Caroline,Conroy, Don,Maranian, Nature Publishing Group, a division of Macmillan P 2012 Nature genetics Vol.44 No.3
Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ??% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ??0,000 cases and ??8,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 ? 10<SUP>??35</SUP>), 12q24 (rs1292011; P = 4.3 ? 10<SUP>??19</SUP>) and 21q21 (rs2823093; P = 1.1 ? 10<SUP>??12</SUP>). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.
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>
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>
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>
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>
Zheng, Wei,Zhang, Ben,Cai, Qiuyin,Sung, Hyuna,Michailidou, Kyriaki,Shi, Jiajun,Choi, Ji-Yeob,Long, Jirong,Dennis, Joe,Humphreys, Manjeet K.,Wang, Qin,Lu, Wei,Gao, Yu-Tang,Li, Chun,Cai, Hui,Park, Sue K Oxford University Press 2013 Human Molecular Genetics Vol.22 No.12
<P>In a consortium including 23 637 breast cancer patients and 25 579 controls of East Asian ancestry, we investigated 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci recently identified by genome-wide association studies (GWASs) conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at <I>P</I> < 0.05 in a direction consistent with that reported previously. Twenty-one of them remained statistically significant after adjusting for multiple comparisons with the Bonferroni-corrected significance level of <0.0015. Eight of the 70 SNPs showed a significantly different association with breast cancer risk by estrogen receptor (ER) status at <I>P</I> < 0.05. With the exception of rs2046210 at 6q25.1, the seven other SNPs showed a stronger association with ER-positive than ER-negative cancer. This study replicated all five genetic risk variants initially identified in Asians and provided evidence for associations of breast cancer risk in the East Asian population with nearly half of the genetic risk variants initially reported in GWASs conducted in European descendants. Taken together, these common genetic risk variants explain ∼10% of excess familial risk of breast cancer in Asian populations.</P>
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>
Lin, Wei-Yu,Camp, Nicola J,Ghoussaini, Maya,Beesley, Jonathan,Michailidou, Kyriaki,Hopper, John L,Apicella, Carmel,Southey, Melissa C,Stone, Jennifer,Schmidt, Marjanka K,Broeks, Annegien,Van't Veer, L IRL Press 2015 Human molecular genetics Vol.24 No.1
<P>Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 ?? 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 ?? 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 ?? 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.</P>