The 12p13.33/RAD52 Locus and Genetic Susceptibility to Squamous Cell Cancers of Upper Aerodigestive Tract

Manon Delahaye-Sourdeix; Javier Oliver; Maria N Timofeeva; Valérie Gaborieau; Mattias Johansson; Amélie Chabrier; Magdalena B Wozniak; Darren R Brenner; Maxime P Vallée; Devasena Anantharaman; Pagona Lagiou; Ivana Holcátová; Lorenzo Richiardi; Kristina Kjaerheim; Antonio Agudo; Xavier Castellsagué; Tatiana MacFarlane; Luigi Barzan; Cristina Canova; Nalin S Thakker; David I Conway; Ariana Znaor; Claire M Healy; Wolfgang Ahrens; David Zaridze; Neonilia Szeszenia-Dabrowska; Jolanta Lissowska; Eleonora Fabianova; Ioan Nicolae Mates; Vladimir Bencko; Lenka Foretova; Vladimir Janout; Maria Paula Curado; Sergio Koifman; Ana Menezes; Victor Wünsch-Filho; José Eluf-Neto; Paolo Boffetta; Leticia Fernández Garrote; Diego Serraino; Marcin Lener; Ewa Jaworowska; Jan Lubiński; Stefania Boccia; Thangarajan Rajkumar; Tanuja A Samant; Manoj B Mahimkar; Keitaro Matsuo; Silvia Franceschi; Graham Byrnes; Paul Brennan; James D McKay

doi:10.1371/journal.pone.0117639

The 12p13.33/RAD52 Locus and Genetic Susceptibility to Squamous Cell Cancers of Upper Aerodigestive Tract

Manon Delahaye-Sourdeix, Javier Oliver, Maria N Timofeeva, Valérie Gaborieau, Mattias Johansson, Amélie Chabrier, Magdalena B Wozniak, Darren R Brenner, Maxime P Vallée, Devasena Anantharaman, Pagona Lagiou, Ivana Holcátová, Lorenzo Richiardi, Kristina Kjaerheim, Antonio Agudo, Xavier Castellsagué, Tatiana MacFarlane, Luigi Barzan, Cristina Canova, Nalin S ThakkerDavid I Conway, Ariana Znaor, Claire M Healy, Wolfgang Ahrens, David Zaridze, Neonilia Szeszenia-Dabrowska, Jolanta Lissowska, Eleonora Fabianova, Ioan Nicolae Mates, Vladimir Bencko, Lenka Foretova, Vladimir Janout, Maria Paula Curado, Sergio Koifman, Ana Menezes, Victor Wünsch-Filho, José Eluf-Neto, Paolo Boffetta, Leticia Fernández Garrote, Diego Serraino, Marcin Lener, Ewa Jaworowska, Jan Lubiński, Stefania Boccia, Thangarajan Rajkumar, Tanuja A Samant, Manoj B Mahimkar, Keitaro Matsuo, Silvia Franceschi, Graham Byrnes, Paul Brennan, James D McKay

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Abstract

Genetic variants located within the 12p13.33/RAD52 locus have been associated with lung squamous cell carcinoma (LUSC). Here, within 5,947 UADT cancers and 7,789 controls from 9 different studies, we found rs10849605, a common intronic variant in RAD52, to be also associated with upper aerodigestive tract (UADT) squamous cell carcinoma cases (OR = 1.09, 95% CI: 1.04-1.15, p = 6x10-4). We additionally identified rs10849605 as a RAD52 cis-eQTL inUADT(p = 1x10-3) and LUSC (p = 9x10-4) tumours, with the UADT/LUSC risk allele correlated with increased RAD52 expression levels. The 12p13.33 locus, encompassing rs10849605/RAD52, was identified as a significant somatic focal copy number amplification in UADT(n = 374, q-value = 0.075) and LUSC (n = 464, q-value = 0.007) tumors and correlated with higher RAD52 tumor expression levels (p = 6x10-48 and p = 3x10-29 in UADT and LUSC, respectively). In combination, these results implicate increased RAD52 expression in both genetic susceptibility and tumorigenesis of UADT and LUSC tumors.

Original language	English
Article number	e0117639
Number of pages	12
Journal	PloS ONE
Volume	10
Issue number	3
Early online date	20 Mar 2015
DOIs	https://doi.org/10.1371/journal.pone.0117639
Publication status	Published - 20 Mar 2015

Bibliographical note

Acknowledgments:
The authors thank all of the participants who took part in this research and the funders and support and technical staff who made this study possible. We also acknowledge and thank The Cancer Genome Atlas initiative whose data contributed heavily to this study.

Funding:
Funding for study coordination, genotyping of replication studies and statistical analysis was provided by the US National Institutes of Health (R01 CA092039 05/05S1) and the National Institute of Dental and Craniofacial Research (1R03DE020116). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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The 12p13.33/RAD52 Locus and Genetic Susceptibility to Squamous Cell Cancers of Upper Aerodigestive Tract
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Delahaye-Sourdeix, M., Oliver, J., Timofeeva, M. N., Gaborieau, V., Johansson, M., Chabrier, A., Wozniak, M. B., Brenner, D. R., Vallée, M. P., Anantharaman, D., Lagiou, P., Holcátová, I., Richiardi, L., Kjaerheim, K., Agudo, A., Castellsagué, X., MacFarlane, T., Barzan, L., Canova, C., ... McKay, J. D. (2015). The 12p13.33/RAD52 Locus and Genetic Susceptibility to Squamous Cell Cancers of Upper Aerodigestive Tract. PloS ONE, 10(3), Article e0117639. https://doi.org/10.1371/journal.pone.0117639

Delahaye-Sourdeix, M, Oliver, J, Timofeeva, MN, Gaborieau, V, Johansson, M, Chabrier, A, Wozniak, MB, Brenner, DR, Vallée, MP, Anantharaman, D, Lagiou, P, Holcátová, I, Richiardi, L, Kjaerheim, K, Agudo, A, Castellsagué, X, MacFarlane, T, Barzan, L, Canova, C, Thakker, NS, Conway, DI, Znaor, A, Healy, CM, Ahrens, W, Zaridze, D, Szeszenia-Dabrowska, N, Lissowska, J, Fabianova, E, Mates, IN, Bencko, V, Foretova, L, Janout, V, Curado, MP, Koifman, S, Menezes, A, Wünsch-Filho, V, Eluf-Neto, J, Boffetta, P, Garrote, LF, Serraino, D, Lener, M, Jaworowska, E, Lubiński, J, Boccia, S, Rajkumar, T, Samant, TA, Mahimkar, MB, Matsuo, K, Franceschi, S, Byrnes, G, Brennan, P & McKay, JD 2015, 'The 12p13.33/RAD52 Locus and Genetic Susceptibility to Squamous Cell Cancers of Upper Aerodigestive Tract', PloS ONE, vol. 10, no. 3, e0117639. https://doi.org/10.1371/journal.pone.0117639

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title = "The 12p13.33/RAD52 Locus and Genetic Susceptibility to Squamous Cell Cancers of Upper Aerodigestive Tract",

abstract = "Genetic variants located within the 12p13.33/RAD52 locus have been associated with lung squamous cell carcinoma (LUSC). Here, within 5,947 UADT cancers and 7,789 controls from 9 different studies, we found rs10849605, a common intronic variant in RAD52, to be also associated with upper aerodigestive tract (UADT) squamous cell carcinoma cases (OR = 1.09, 95% CI: 1.04-1.15, p = 6x10-4). We additionally identified rs10849605 as a RAD52 cis-eQTL inUADT(p = 1x10-3) and LUSC (p = 9x10-4) tumours, with the UADT/LUSC risk allele correlated with increased RAD52 expression levels. The 12p13.33 locus, encompassing rs10849605/RAD52, was identified as a significant somatic focal copy number amplification in UADT(n = 374, q-value = 0.075) and LUSC (n = 464, q-value = 0.007) tumors and correlated with higher RAD52 tumor expression levels (p = 6x10-48 and p = 3x10-29 in UADT and LUSC, respectively). In combination, these results implicate increased RAD52 expression in both genetic susceptibility and tumorigenesis of UADT and LUSC tumors.",

author = "Manon Delahaye-Sourdeix and Javier Oliver and Timofeeva, {Maria N} and Val{\'e}rie Gaborieau and Mattias Johansson and Am{\'e}lie Chabrier and Wozniak, {Magdalena B} and Brenner, {Darren R} and Vall{\'e}e, {Maxime P} and Devasena Anantharaman and Pagona Lagiou and Ivana Holc{\'a}tov{\'a} and Lorenzo Richiardi and Kristina Kjaerheim and Antonio Agudo and Xavier Castellsagu{\'e} and Tatiana MacFarlane and Luigi Barzan and Cristina Canova and Thakker, {Nalin S} and Conway, {David I} and Ariana Znaor and Healy, {Claire M} and Wolfgang Ahrens and David Zaridze and Neonilia Szeszenia-Dabrowska and Jolanta Lissowska and Eleonora Fabianova and Mates, {Ioan Nicolae} and Vladimir Bencko and Lenka Foretova and Vladimir Janout and Curado, {Maria Paula} and Sergio Koifman and Ana Menezes and Victor W{\"u}nsch-Filho and Jos{\'e} Eluf-Neto and Paolo Boffetta and Garrote, {Leticia Fern{\'a}ndez} and Diego Serraino and Marcin Lener and Ewa Jaworowska and Jan Lubi{\'n}ski and Stefania Boccia and Thangarajan Rajkumar and Samant, {Tanuja A} and Mahimkar, {Manoj B} and Keitaro Matsuo and Silvia Franceschi and Graham Byrnes and Paul Brennan and McKay, {James D}",

note = "Acknowledgments: The authors thank all of the participants who took part in this research and the funders and support and technical staff who made this study possible. We also acknowledge and thank The Cancer Genome Atlas initiative whose data contributed heavily to this study. Funding: Funding for study coordination, genotyping of replication studies and statistical analysis was provided by the US National Institutes of Health (R01 CA092039 05/05S1) and the National Institute of Dental and Craniofacial Research (1R03DE020116). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.",

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AU - Delahaye-Sourdeix, Manon

AU - Oliver, Javier

AU - Timofeeva, Maria N

AU - Gaborieau, Valérie

AU - Johansson, Mattias

AU - Chabrier, Amélie

AU - Wozniak, Magdalena B

AU - Brenner, Darren R

AU - Vallée, Maxime P

AU - Anantharaman, Devasena

AU - Lagiou, Pagona

AU - Holcátová, Ivana

AU - Richiardi, Lorenzo

AU - Kjaerheim, Kristina

AU - Agudo, Antonio

AU - Castellsagué, Xavier

AU - MacFarlane, Tatiana

AU - Barzan, Luigi

AU - Canova, Cristina

AU - Thakker, Nalin S

AU - Conway, David I

AU - Znaor, Ariana

AU - Healy, Claire M

AU - Ahrens, Wolfgang

AU - Zaridze, David

AU - Szeszenia-Dabrowska, Neonilia

AU - Lissowska, Jolanta

AU - Fabianova, Eleonora

AU - Mates, Ioan Nicolae

AU - Bencko, Vladimir

AU - Foretova, Lenka

AU - Janout, Vladimir

AU - Curado, Maria Paula

AU - Koifman, Sergio

AU - Menezes, Ana

AU - Wünsch-Filho, Victor

AU - Eluf-Neto, José

AU - Boffetta, Paolo

AU - Garrote, Leticia Fernández

AU - Serraino, Diego

AU - Lener, Marcin

AU - Jaworowska, Ewa

AU - Lubiński, Jan

AU - Boccia, Stefania

AU - Rajkumar, Thangarajan

AU - Samant, Tanuja A

AU - Mahimkar, Manoj B

AU - Matsuo, Keitaro

AU - Franceschi, Silvia

AU - Byrnes, Graham

AU - Brennan, Paul

AU - McKay, James D

N1 - Acknowledgments: The authors thank all of the participants who took part in this research and the funders and support and technical staff who made this study possible. We also acknowledge and thank The Cancer Genome Atlas initiative whose data contributed heavily to this study. Funding: Funding for study coordination, genotyping of replication studies and statistical analysis was provided by the US National Institutes of Health (R01 CA092039 05/05S1) and the National Institute of Dental and Craniofacial Research (1R03DE020116). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PY - 2015/3/20

Y1 - 2015/3/20

N2 - Genetic variants located within the 12p13.33/RAD52 locus have been associated with lung squamous cell carcinoma (LUSC). Here, within 5,947 UADT cancers and 7,789 controls from 9 different studies, we found rs10849605, a common intronic variant in RAD52, to be also associated with upper aerodigestive tract (UADT) squamous cell carcinoma cases (OR = 1.09, 95% CI: 1.04-1.15, p = 6x10-4). We additionally identified rs10849605 as a RAD52 cis-eQTL inUADT(p = 1x10-3) and LUSC (p = 9x10-4) tumours, with the UADT/LUSC risk allele correlated with increased RAD52 expression levels. The 12p13.33 locus, encompassing rs10849605/RAD52, was identified as a significant somatic focal copy number amplification in UADT(n = 374, q-value = 0.075) and LUSC (n = 464, q-value = 0.007) tumors and correlated with higher RAD52 tumor expression levels (p = 6x10-48 and p = 3x10-29 in UADT and LUSC, respectively). In combination, these results implicate increased RAD52 expression in both genetic susceptibility and tumorigenesis of UADT and LUSC tumors.

AB - Genetic variants located within the 12p13.33/RAD52 locus have been associated with lung squamous cell carcinoma (LUSC). Here, within 5,947 UADT cancers and 7,789 controls from 9 different studies, we found rs10849605, a common intronic variant in RAD52, to be also associated with upper aerodigestive tract (UADT) squamous cell carcinoma cases (OR = 1.09, 95% CI: 1.04-1.15, p = 6x10-4). We additionally identified rs10849605 as a RAD52 cis-eQTL inUADT(p = 1x10-3) and LUSC (p = 9x10-4) tumours, with the UADT/LUSC risk allele correlated with increased RAD52 expression levels. The 12p13.33 locus, encompassing rs10849605/RAD52, was identified as a significant somatic focal copy number amplification in UADT(n = 374, q-value = 0.075) and LUSC (n = 464, q-value = 0.007) tumors and correlated with higher RAD52 tumor expression levels (p = 6x10-48 and p = 3x10-29 in UADT and LUSC, respectively). In combination, these results implicate increased RAD52 expression in both genetic susceptibility and tumorigenesis of UADT and LUSC tumors.

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M1 - e0117639

ER -

The 12p13.33/RAD52 Locus and Genetic Susceptibility to Squamous Cell Cancers of Upper Aerodigestive Tract

Abstract

Bibliographical note

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