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Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2
Orr, Nick,Dudbridge, Frank,Dryden, Nicola,Maguire, Sarah,Novo, Daniela,Perrakis, Eleni,Johnson, Nichola,Ghoussaini, Maya,Hopper, John L.,Southey, Melissa C.,Apicella, Carmel,Stone, Jennifer,Schmidt, M IRL Press 2015 Human molecular genetics Vol.24 No.10
<P>We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88–0.92]; <I>P</I>-value = 1.58 × 10<SUP>−25</SUP>). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08–1.17]; <I>P</I>-value = 7.89 × 10<SUP>−09</SUP>) and rs13294895 (OR = 1.09 [1.06–1.12]; <I>P</I>-value = 2.97 × 10<SUP>−11</SUP>). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06–1.18]; <I>P</I>-value = 2.77 × 10<SUP>−05</SUP>). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. <I>In vitro</I> analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the <I>KLF4</I> gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.</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>
11q13 is a susceptibility locus for hormone receptor positive breast cancer
Lambrechts, Diether,Truong, Therese,Justenhoven, Christina,Humphreys, Manjeet K.,Wang, Jean,Hopper, John L.,Dite, Gillian S.,Apicella, Carmel,Southey, Melissa C.,Schmidt, Marjanka K.,Broeks, Annegien Wiley (John WileySons) 2012 Human mutation Vol.33 No.7
Johnson, Nichola,Dudbridge, Frank,Orr, Nick,Gibson, Lorna,Jones, Michael E,Schoemaker, Minouk J,Folkerd, Elizabeth J,Haynes, Ben P,Hopper, John L,Southey, Melissa C,Dite, Gillian S,Apicella, Carmel,Sc BioMed Central 2014 Breast cancer research Vol.16 No.3
<P><B>Introduction</B></P><P>We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the <I>CYP3A</I> locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years.</P><P><B>Methods</B></P><P>We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics.</P><P><B>Results</B></P><P>We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; <I>P</I> = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; <I>P</I> = 0.004), respectively (<I>P</I><SUB>trend</SUB> = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (<I>P</I><SUB>trend</SUB> = 0.005) but not cases (<I>P</I><SUB>trend</SUB> = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (<I>P</I><SUB>het</SUB> = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (OR<SUB>het</SUB> = 0.84, 95% CI 0.75, 0.94; OR<SUB>hom</SUB> = 0.81, 95% CI 0.51, 1.30; <I>P</I><SUB>trend</SUB> = 0.002) but not for those who had their menarche age ≤11 years (OR<SUB>het</SUB> = 1.06, 95% CI 0.95, 1.19, OR<SUB>hom</SUB> = 1.07, 95% CI 0.67, 1.72; <I>P</I><SUB>trend</SUB> = 0.29).</P><P><B>Conclusions</B></P><P>To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.</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>