Abstract
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 CLPTM1Lgene(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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 6616-6633 |
| Number of pages | 18 |
| Journal | Human molecular genetics |
| Volume | 23 |
| Issue number | 24 |
| DOIs | |
| State | Published - Nov 15 2014 |
Bibliographical note
Funding Information:This work was supported by the Intramural Research Program and by contract number HHSN261200800001E of the US National Institutes of Health (NIH), National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. Additional funding acknowledgements are listed in Supplementary Material. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
