Program in Molecular and Genetic Epidemiology

Boston, MA, United States

Program in Molecular and Genetic Epidemiology

Boston, MA, United States

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Chung C.C.,Laboratory of Translational Genomics | Chung C.C.,U.S. National Institutes of Health | Ciampa J.,U.S. National Institutes of Health | Yeager M.,U.S. National Institutes of Health | And 53 more authors.
Human Molecular Genetics | Year: 2011

Genome-wide association studies have identified prostate cancer susceptibility alleles on chromosome 11q13. As part of the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, the region flanking the most significant marker, rs10896449, was fine mapped in 10 272 cases and 9123 controls of European origin (10 studies) using 120 common single nucleotide polymorphisms (SNPs) selected by a two-staged tagging strategy using HapMap SNPs. Single-locus analysis identified 18 SNPs below genome-wide significance (P < 10-8) with rs10896449 the most significant (P = 7.94 × 10-19). Multi-locus models that included significant SNPs sequentially identified a second association at rs12793759 [odds ratio (OR) = 1.14, P = 4.76 × 10-5, adjusted P = 0.004] that is independent of rs10896449 and remained significant after adjustment for multiple testing within the region. rs10896438, a proxy of previously reported rs12418451 (r2= 0.96), independent of both rs10896449 and rs12793759 was detected (OR = 1.07, P = 5.92 × 10-3, adjusted P = 0.054). Our observation of a recombination hotspot that separates rs10896438 from rs10896449 and rs12793759, and low linkage disequilibrium (rs10896449-rs12793759, r2= 0.17; r2=10896449-rs10896438, r2= 0.10; rs12793759- rs10896438, r2= 0.12) corroborate our finding of three independent signals. By analysis of tagged SNPs across ~123 kb using next generation sequencing of 63 controls of European origin, 1000 Genome and HapMap data, we observed multiple surrogates for the three independent signals marked by rs10896449 (n = 31), rs10896438 (n = 24) and rs12793759 (n = 8). Our results indicate that a complex architec- ture underlying the common variants contributing to prostate cancer risk at 11q13. We estimate that at least 63 common variants should be considered in future studies designed to investigate the biological basis of the multiple association signals. © The Author 2011. Published by Oxford University Press. All rights reserved.


Al Olama A.A.,Center for Cancer Genetic Epidemiology | Kote-Jarai Z.,The Institute of Cancer Research | Schumacher F.R.,University of Southern California | Wiklund F.,Karolinska Institutet | And 163 more authors.
Human Molecular Genetics | Year: 2013

Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significantSNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10-8]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis. © The Author 2012. Published by Oxford University Press. All rights reserved.


PubMed | Karolinska Institutet, Brown University, International Agency for Research on Cancer IARC WHO, Complex Traits Genetics Team and. and 130 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2014

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 10(-39); Region 3: rs2853677, P = 3.30 10(-36) and PConditional = 2.36 10(-8); Region 4: rs2736098, P = 3.87 10(-12) and PConditional = 5.19 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 10(-6); and Region 6: rs10069690, P = 7.49 10(-15) and PConditional = 5.35 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 10(-18) and PConditional = 7.06 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

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