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Meta-Analysis
. 2021 Mar 5;17(3):e1009254.
doi: 10.1371/journal.pgen.1009254. eCollection 2021 Mar.

Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers

Corina Lesseur  1   2 , Aida Ferreiro-Iglesias  1 , James D McKay  3 , Yohan Bossé  4 , Mattias Johansson  1 , Valerie Gaborieau  1 , Maria Teresa Landi  5 , David C Christiani  6 , Neil C Caporaso  5 , Stig E Bojesen  7 , Christopher I Amos  8 , Sanjay Shete  9 , Geoffrey Liu  10 , Gadi Rennert  11 , Demetrius Albanes  5 , Melinda C Aldrich  12 , Adonina Tardon  13 , Chu Chen  14 , Liloglou Triantafillos  15 , John K Field  15 , Marion Dawn Teare  16 , Lambertus A Kiemeney  17 , Brenda Diergaarde  18   19   20 , Robert L Ferris  20 , Shanbeh Zienolddiny  21 , Stephen Lam  22 , Andrew F Olshan  23 , Mark C Weissler  24 , Martin Lacko  25 , Angela Risch  26   27   28 , Heike Bickeböller  29 , Andy R Ness  30   31 , Steve Thomas  31 , Loic Le Marchand  32 , Matthew B Schabath  33 , Victor Wünsch-Filho  34 , Eloiza H Tajara  35 , Angeline S Andrew  36 , Gary M Clifford  37 , Philip Lazarus  38 , Kjell Grankvist  39 , Mikael Johansson  40 , Susanne Arnold  41 , Olle Melander  42   43 , Hans Brunnström  44 , Stefania Boccia  45   46 , Gabriella Cadoni  47   48 , Wim Timens  49   50 , Ma'en Obeidat  51 , Xiangjun Xiao  8 , Richard S Houlston  52 , Rayjean J Hung  53 , Paul Brennan  1
Affiliations
Meta-Analysis

Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers

Corina Lesseur et al. PLoS Genet. .

Abstract

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes rel to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.

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Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests. Dr. Ferris has the following financial disclosures: Aduro Biotech, Inc (consulting); Astra-Zeneca/MedImmune (clinical trial, research funding); Bristol-Myers Squibb (advisory board, clinical trial, research funding); EMD Serono (advisory board); MacroGenics, Inc (advisory board); Merck (advisory board, clinical trial); Novasenta (consulting, stock, research funding); Numab Therapeutics AG (advisory board); Pfizer (advisory board); Sanofi (consultant); Tesaro (research funding) and Zymeworks, Inc (consultant). All other authors have no conflicts to disclose.

Figures

Fig 1
Fig 1. Manhattan plot of aerodigestive SqCC genome-wide association fixed-effects meta-analysis results.
The y-axis corresponds to −log10 P-values, and x-axis to genomic positions. Horizontal red dashed line (P = 5x10−8) and black dashed line (P = 5x10−7). Highlighted in red are the newly identified pleotropic aerodigestive SqCC loci (P<5x10-8), in blue new loci at P<5x10-7 and in purple previously identified pleotropic loci (at least 2 cancer sites). Loci labeled in black are loci that reached P<5x10-7 but were not pleiotropic associated only in single-cancer analyses.
Fig 2
Fig 2. Forest plots of ORs for new aerodigestive SqCC-related loci.
a) rs56321285 at 2q33.1 (TMEM23). Subset refers to subset based meta-analyses (ASSET). b) rs12133735 at 1q32.1 (near MDM4).
Fig 3
Fig 3. Forest plots of ORs for new aerodigestive SqCC-related loci.
a) rs13181561 at 5q31.2 (TMEM173); b) rs61494113 at 19p13.1 (ABHD8). Subset refers to subset based meta-analyses (ASSET).
See this image and copyright information in PMC

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