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• W1598750330 abstract "Multiple myeloma (MM) is an incurable plasma cell malignancy accounting for 2% of cancer-related deaths worldwide. Ethnic and population variation as well as some evidence of familial clustering indicates a genetic component to myeloma aetiology (Landgren & Weiss, 2009). The 8q24 locus has been identified as a hotspot of susceptibility in various cancers (Easton et al, 2007; Gudmundsson et al, 2007; Haiman et al, 2007; Tomlinson et al, 2007). This locus harbours multiple variants, which map to five cancer-specific regions that are localized to a 600 kb area (Ghoussaini et al, 2008). This region is referred to as a gene desert as there are no known genes located within, however it may contain regulatory elements that exert their influence through long range interactions with the cancer-related genes FAM84B and MYC that are located in centromeric and telomeric positions. MYC alterations are well documented in myeloma pathology and are linked with an aggressive disease course (Anguiano et al, 2009). We hypothesized that germline variation at the 8q24 locus may affect the risk of acquiring MM. In order to test this hypothesis, we genotyped six single nucleotide polymorphisms (SNPs) in a study of 424 cases and 429 controls. Subjects were recruited from the Epilymph study and the Irish myeloma study. The Epilymph study is a European multi-centre study on the epidemiology of lymphoid neoplasms and was conducted in compliance with the Helsinki declaration. The present study includes participants from France, Germany and Spain and consists of 224 cases and 227 controls. Controls were age (±5 years) and sex-matched to the cases and recruited from the same study sites. The Irish myeloma study is a prospective study on the incidence of MM in Ireland. Controls were age (±5 years) and sex-matched and recruited from the Trinity Biobank, which provided DNA extracted from the blood of healthy donors. The Irish study consisted of 200 cases and 202 controls. Informed consent was obtained from study participants and studies were approved by the ethics committees of participating centres. All participants were of European ancestry. Further details are available in Data SI and Table SI. The following variants were selected for genotyping: rs13254738, rs16901979, rs13281615, rs6983267, rs7000448, rs1447295, which best represent cancer-specific regions at the 8q24 locus (Fig 1). Linkage Disequilibrium across the 8q24 locus as visualized by Haploview (v4·2) depicting the five cancer associated regions and the SNPs that have emerged as top ranking risk variants in these regions. DNA was isolated using the DNA blood Minikit (Qiagen, Crawley, UK) and quantified by spectrofluorometry. Genotyping was carried out using TaqMan® assays on the Applied Biosystems 7900HT System (Foster City, CA, USA). Duplicates of 10% of the samples were interspersed throughout the plates. Statistical analysis was carried out using genepop and plink. Hardy–Weinberg Equilibrium (HWE) was assessed in controls by the HWE exact test. Matching in study design was used to control for confounders such as age and sex. Data from the study centres were pooled to determine a relationship between variants and MM risk. Allelic and genotype frequencies were compared in cases and controls by chi-square tests. The homozygous wild-type genotype was used as the reference group for comparing with the heterozygote and homozygote variants (dominant model). The wild type homozygotes and heterozygote variants were combined and used as a referent for comparing with homozygote variants (recessive model). Cochran-Mantel-Haenszel (CMH) test was applied to carry out stratified analysis by study centre and the Breslow–Day test was employed to determine the degree of heterogeneity of association across study sites. Bonferroni correction and False Discovery Rate were applied to correct for multiple testing. We also had access to genotype data (affymetrix v.6) for 1000 Irish blood donors for SNPs rs16901979 and rs6983267. We performed additional analysis by combining the supplementary control data with our original genotype data. This is the first study to report an analysis of genetic variants at the 8q24 locus and the risk of developing MM. Average allele call rate for individual SNPs was 98·6%. Genotype frequencies in controls were in accordance with HWE. For SNP rs16901979, the risk allele A emerged significant in the overall study population, after application of the CMH test (Table IP‡ = 0·03). Genotype analysis also suggested a trend for association in both genotypic and recessive models (Table II). The association between the homozygous genotype AA and MM susceptibility appears primarily due to the Irish Myeloma study, in which 14 cases had the AA genotype whereas only one control from the Epilymph study had the AA genotype (Table SII). The significant associations for SNP rs16901979 did not hold after correcting for multiple testing in the primary analysis. Nonetheless, when the supplementary analysis was carried out by combining the additional control data, the association for rs16901979 emerged highly significant (P = 1·5 × 10−7). For SNP rs6983267, the risk allele G emerged significantly associated with MM (P = 0·02) after supplementary analysis. However we also observed a high frequency of risk allele G in the Irish and the French control populations (Tables SIII and SIV). This is most likely due to stochastic variance in allele frequencies across different sub-populations. Both SNPs rs16901979 and rs6983267 are well-established cancer risk variants. SNP rs16901979 is an established risk variant for prostate cancer and upper aero-digestive tract cancers (Park et al, 2008), and SNP rs6983267 is associated with a range of cancers (Wokolorczyk et al, 2008). It is intriguing to note the high frequency of these variants considering that the 8q24 locus is relatively gene-poor. SNPs rs16901979 and rs6983267 have been recently identified in enhancer elements and might be involved in long range regulation of MYC, which is located 624 kb telomeric to the 8q24 locus. Another possibility could be that these variants are in high linkage with yet to be characterized true causal SNPs. A recent genome-wide scan in chronic lymphocytic leukaemia has identified a risk variant rs2456449 at the 8q24 locus, which is in high linkage with rs16901979 (D′ = 1). These findings suggest that the 8q24 locus may be involved in the aetiology of B cell malignancies through a common regulatory mechanism. Our results suggest an underlying trend for association between variants at the 8q24 locus and MM. However, these findings should be subjected to replication in independent study populations for testing the robustness of findings. This study was supported in parts by grants from the Health Research Board Ireland and the Haematology Association of Ireland. We are also grateful to Dr Joe McPartlin Trinity Biobank and the Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine and Trinity College Dublin for making available the additional control genotype data. We are grateful to all study participants for their invaluable contribution. Data S1. Details of Epilymph study. Table SI. Details of study participants. Table SII. Allele frequencies for SNPs tested in the study and association results for individual study centre. Table SIII. Genotype frequencies for SNPs tested in the study and association results for individual study centre. Table SIV. Results of Supplementary analysis. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W1598750330 date "2011-07-19" @default.
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• W1598750330 title "Genetic variation at the 8q24 locus confers risk to multiple myeloma" @default.
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