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

Corina Lesseur; Aida Ferreiro-Iglesias; James D McKay; Yohan Bossé; Mattias Johansson; Valerie Gaborieau; Maria Teresa Landi; David C Christiani; Neil C Caporaso; Stig E Bojesen; Christopher I Amos; Sanjay Shete; Geoffrey Liu; Gadi Rennert; Demetrius Albanes; Melinda C Aldrich; Adonina Tardon; Chu Chen; Liloglou Triantafillos; John K Field; Marion Dawn Teare; Lambertus A Kiemeney; Brenda Diergaarde; Robert L Ferris; Shanbeh Zienolddiny; Stephen Lam; Andrew F Olshan; Mark C Weissler; Martin Lacko; Angela Risch; Heike Bickeböller; Andy R Ness; Steve Thomas; Loic Le Marchand; Matthew B Schabath; Victor Wünsch-Filho; Eloiza H Tajara; Angeline S Andrew; Gary M Clifford; Philip Lazarus; Kjell Grankvist; Mikael Johansson; Susanne Arnold; Olle Melander; Hans Brunnström; Stefania Boccia; Gabriella Cadoni; Wim Timens; Ma'en Obeidat; Xiangjun Xiao; Richard S Houlston; Rayjean J Hung; Paul Brennan

doi:10.1371/journal.pgen.1009254

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

Corina Lesseur, Aida Ferreiro-Iglesias, James D McKay, Yohan Bossé, Mattias Johansson, Valerie Gaborieau, Maria Teresa Landi, David C Christiani, Neil C Caporaso, Stig E Bojesen, Christopher I Amos, Sanjay Shete, Geoffrey Liu, Gadi Rennert, Demetrius Albanes, Melinda C Aldrich, Adonina Tardon, Chu Chen, Liloglou Triantafillos, John K FieldMarion Dawn Teare, Lambertus A Kiemeney, Brenda Diergaarde, Robert L Ferris, Shanbeh Zienolddiny, Stephen Lam, Andrew F Olshan, Mark C Weissler, Martin Lacko, Angela Risch, Heike Bickeböller, Andy R Ness, Steve Thomas, Loic Le Marchand, Matthew B Schabath, Victor Wünsch-Filho, Eloiza H Tajara, Angeline S Andrew, Gary M Clifford, Philip Lazarus, Kjell Grankvist, Mikael Johansson, Susanne Arnold, Olle Melander, Hans Brunnström, Stefania Boccia, Gabriella Cadoni, Wim Timens, Ma'en Obeidat, Xiangjun Xiao, Richard S Houlston, Rayjean J Hung, Paul Brennan

Klinisk Biokemisk afd.

19 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	e1009254
Tidsskrift	P L o S Genetics
Vol/bind	17
Udgave nummer	3
Sider (fra-til)	e1009254
ISSN	1553-7390
DOI	https://doi.org/10.1371/journal.pgen.1009254
Status	Udgivet - mar. 2021

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10.1371/journal.pgen.1009254

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Lesseur, C., Ferreiro-Iglesias, A., McKay, J. D., Bossé, Y., Johansson, M., Gaborieau, V., Landi, M. T., Christiani, D. C., Caporaso, N. C., Bojesen, S. E., Amos, C. I., Shete, S., Liu, G., Rennert, G., Albanes, D., Aldrich, M. C., Tardon, A., Chen, C., Triantafillos, L., ... Brennan, P. (2021). Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers. P L o S Genetics, 17(3), e1009254. Artikel e1009254. https://doi.org/10.1371/journal.pgen.1009254

Lesseur, C, Ferreiro-Iglesias, A, McKay, JD, Bossé, Y, Johansson, M, Gaborieau, V, Landi, MT, Christiani, DC, Caporaso, NC, Bojesen, SE, Amos, CI, Shete, S, Liu, G, Rennert, G, Albanes, D, Aldrich, MC, Tardon, A, Chen, C, Triantafillos, L, Field, JK, Teare, MD, Kiemeney, LA, Diergaarde, B, Ferris, RL, Zienolddiny, S, Lam, S, Olshan, AF, Weissler, MC, Lacko, M, Risch, A, Bickeböller, H, Ness, AR, Thomas, S, Le Marchand, L, Schabath, MB, Wünsch-Filho, V, Tajara, EH, Andrew, AS, Clifford, GM, Lazarus, P, Grankvist, K, Johansson, M, Arnold, S, Melander, O, Brunnström, H, Boccia, S, Cadoni, G, Timens, W, Obeidat, M, Xiao, X, Houlston, RS, Hung, RJ & Brennan, P 2021, 'Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers', P L o S Genetics, bind 17, nr. 3, e1009254, s. e1009254. https://doi.org/10.1371/journal.pgen.1009254

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title = "Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers",

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.",

keywords = "Alleles, Biomarkers, Tumor, Carcinoma, Squamous Cell/genetics, Digestive System Neoplasms/genetics, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Odds Ratio, Signal Transduction",

author = "Corina Lesseur and Aida Ferreiro-Iglesias and McKay, {James D} and Yohan Boss{\'e} and Mattias Johansson and Valerie Gaborieau and Landi, {Maria Teresa} and Christiani, {David C} and Caporaso, {Neil C} and Bojesen, {Stig E} and Amos, {Christopher I} and Sanjay Shete and Geoffrey Liu and Gadi Rennert and Demetrius Albanes and Aldrich, {Melinda C} and Adonina Tardon and Chu Chen and Liloglou Triantafillos and Field, {John K} and Teare, {Marion Dawn} and Kiemeney, {Lambertus A} and Brenda Diergaarde and Ferris, {Robert L} and Shanbeh Zienolddiny and Stephen Lam and Olshan, {Andrew F} and Weissler, {Mark C} and Martin Lacko and Angela Risch and Heike Bickeb{\"o}ller and Ness, {Andy R} and Steve Thomas and {Le Marchand}, Loic and Schabath, {Matthew B} and Victor W{\"u}nsch-Filho and Tajara, {Eloiza H} and Andrew, {Angeline S} and Clifford, {Gary M} and Philip Lazarus and Kjell Grankvist and Mikael Johansson and Susanne Arnold and Olle Melander and Hans Brunnstr{\"o}m and Stefania Boccia and Gabriella Cadoni and Wim Timens and Ma'en Obeidat and Xiangjun Xiao and Houlston, {Richard S} and Hung, {Rayjean J} and Paul Brennan",

year = "2021",

month = mar,

doi = "10.1371/journal.pgen.1009254",

language = "English",

volume = "17",

pages = "e1009254",

journal = "P L o S Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "3",

}

TY - JOUR

T1 - Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers

AU - Lesseur, Corina

AU - Ferreiro-Iglesias, Aida

AU - McKay, James D

AU - Bossé, Yohan

AU - Johansson, Mattias

AU - Gaborieau, Valerie

AU - Landi, Maria Teresa

AU - Christiani, David C

AU - Caporaso, Neil C

AU - Bojesen, Stig E

AU - Amos, Christopher I

AU - Shete, Sanjay

AU - Liu, Geoffrey

AU - Rennert, Gadi

AU - Albanes, Demetrius

AU - Aldrich, Melinda C

AU - Tardon, Adonina

AU - Chen, Chu

AU - Triantafillos, Liloglou

AU - Field, John K

AU - Teare, Marion Dawn

AU - Kiemeney, Lambertus A

AU - Diergaarde, Brenda

AU - Ferris, Robert L

AU - Zienolddiny, Shanbeh

AU - Lam, Stephen

AU - Olshan, Andrew F

AU - Weissler, Mark C

AU - Lacko, Martin

AU - Risch, Angela

AU - Bickeböller, Heike

AU - Ness, Andy R

AU - Thomas, Steve

AU - Le Marchand, Loic

AU - Schabath, Matthew B

AU - Wünsch-Filho, Victor

AU - Tajara, Eloiza H

AU - Andrew, Angeline S

AU - Clifford, Gary M

AU - Lazarus, Philip

AU - Grankvist, Kjell

AU - Johansson, Mikael

AU - Arnold, Susanne

AU - Melander, Olle

AU - Brunnström, Hans

AU - Boccia, Stefania

AU - Cadoni, Gabriella

AU - Timens, Wim

AU - Obeidat, Ma'en

AU - Xiao, Xiangjun

AU - Houlston, Richard S

AU - Hung, Rayjean J

AU - Brennan, Paul

PY - 2021/3

Y1 - 2021/3

N2 - 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.

AB - 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.

KW - Alleles

KW - Biomarkers, Tumor

KW - Carcinoma, Squamous Cell/genetics

KW - Digestive System Neoplasms/genetics

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Odds Ratio

KW - Signal Transduction

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U2 - 10.1371/journal.pgen.1009254

DO - 10.1371/journal.pgen.1009254

M3 - Journal article

C2 - 33667223

SN - 1553-7390

VL - 17

SP - e1009254

JO - P L o S Genetics

JF - P L o S Genetics

IS - 3

M1 - e1009254

ER -

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

Abstract

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