Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21

There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, $\textit{cis}$-acting variants represent an important source of phenotypic variation. Consequently, $\textit{cis}$-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, $\textit{P}$ = 5.6x10$^{-6}$). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, $\textit{HELQ}$, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, $\textit{MRPS18C}$ encoding the Mitochondrial Ribosomal Protein S18C and $\textit{FAM175A (ABRAXAS)}$, encoding a $\textit{BRCA1}$ BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with $\textit{HELQ }$ ($\textit{P}$ = 8.28x10$^{-14}$), $\textit{MRPS18C}$ ($\textit{P}$ = 1.94x10$^{-27}$) and $\textit{FAM175A }$ ($\textit{P}$ = 3.83x10$^{-3}$), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.Information regarding funding can be found in the published article or the publisher's website. Funders include Cancer Research UK and the National Institute for Health Research

CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer.

Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10(-11)). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.Fine-mapping analysis was supported by NHMRC project grant [ID#1031333] to ABS, DFE and AMD. ABS, PW, GWM, and DRN are supported by the NHMRC Fellowship scheme. AMD is supported by the Joseph Mitchell Trust. IT is supported by Cancer Research UK and the Oxford Comprehensive Biomedical Research Centre. Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no 223175 [HEALTH-F2-2009-223175] [COGS], Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565], the National Institutes of Health [CA128978] and Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative], the Department of Defence [W81XWH-10-1-0341], the Canadian Institutes of Health Research [CIHR] for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. ANECS recruitment was supported by project grants from the NHMRC [ID#339435], The Cancer Council Queensland [ID#4196615] and Cancer Council Tasmania [ID#403031 and ID#457636]. SEARCH recruitment was funded by a programme grant from Cancer Research UK [C490/A10124]. Stage 1 and stage 2 case genotyping was supported by the NHMRC [ID#552402, ID#1031333]. This study 647 makes use of data generated by the Wellcome Trust Case-Control Consortium (WTCCC). A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02 - funding for this project was provided by the Wellcome Trust under award 085475. NSECG was supported by the EU FP7 CHIBCHA grant and Wellcome Trust Centre for Human Genetics Grant 090532/Z/09Z, and CORGI by Cancer Research UK. Recruitment of the QIMR Berghofer controls was supported by the NHMRC. The University of Newcastle, the Gladys M Brawn Senior Research Fellowship scheme, The Vincent Fairfax Family Foundation, the Hunter Medical Research Institute and the Hunter Area Pathology Service all contributed towards the costs of establishing the Hunter Community Study. The Bavarian Endometrial Cancer Study (BECS) was partly funded by the ELAN fund of the University of Erlangen. The Leuven Endometrium Study (LES) was supported by the Verelst Foundation for endometrial cancer. The Mayo Endometrial Cancer Study (MECS) and Mayo controls (MAY) were supported by grants from the National Cancer Institute of United States Public Health Service [R01 CA122443, P30 CA15083, P50 CA136393, and GAME-ON the NCI Cancer Post-GWAS Initiative U19 CA148112], the Fred C and Katherine B Andersen Foundation, the Mayo Foundation, and the Ovarian Cancer Research Fund with support of the Smith family, in memory of Kathryn Sladek Smith. MoMaTEC received financial support from a Helse Vest Grant, the University of Bergen, Melzer Foundation, The Norwegian Cancer Society (Harald Andersens legat), The Research Council of Norway and Haukeland University Hospital. 672 The Newcastle Endometrial Cancer Study (NECS) acknowledges contributions from the University of Newcastle, The NBN Children’s Cancer Research Group, Ms Jennie Thomas and the Hunter Medical Research Institute. RENDOCAS was supported through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet [numbers: 20110222, 20110483, 20110141 and DF 07015], The Swedish Labor Market Insurance [number 100069] and The Swedish Cancer Society [number 11 0439]. The Cancer Hormone Replacement Epidemiology in Sweden Study (CAHRES, formerly called The Singapore and Swedish Breast/Endometrial Cancer Study; SASBAC) was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institutes of Health and the Susan G. Komen Breast Cancer Foundation. The Breast Cancer Association Consortium (BCAC) is funded by Cancer Research UK [C1287/A10118, C1287/A12014]. The Ovarian Cancer Association Consortium (OCAC) is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith [PPD/RPCI.07], and the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge. Additional funding for individual control groups is detailed in the Supplementary Information. EPIC-Norfolk was funded by research programme grant funding from Cancer Research UK and the Medical Research Council with additional support from the Stroke Association, British Heart Foundation, Department of Health, Research into Ageing and Academy of Medical Sciences. The SIBS study was supported by program grant C1287/A10118 and project grants from Cancer Research 697 UK (grant numbers C1287/8459).This is the author accepted manuscript. The final version is available from Bioscientifica via http://dx.doi.org/10.1530/ERC-15-038

Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

© 2015 Nature America, Inc. All rights reserved.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 id

CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer

Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10(-11)). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.status: publishe

Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21.

There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas

Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array.

Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the ‘iCOGS’ genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84−0.87; P=1.7 × 10^−43) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology

Newly discovered breast cancer susceptibility loci in 3p24 and 17q23.2

Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage1. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08–1.13, P = 4.1 times 10-23) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92–0.97, P = 1.4 times 10-8). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17