Protein-altering germline mutations implicate novel genes related to lung cancer development

Ji, X.; Mukherjee, S.; Landi, M.T.; Bosse, Y.; Joubert, P.; Zhu, D.; Gorlov, I.; Xiao, X.; Han, Y.; Gorlova, O.; Hung, R.J.; Brhane, Y.; Carreras-Torres, R.; Christiani, D.C.; Caporaso, N.; Johansson, M.; Liu, G.; Bojesen, S.E.; Le Marchand, L.; Albanes, D.; Bickeboller, H.; Aldrich, M.C.; Bush, W.S.; Tardon, A.; Rennert, G.; Chen, C.; Byun, J.; Dragnev, K.H.; Field, J.K.; Kiemeney, L.F.; Lazarus, P.; Zienolddiny, S.; Lam, S.; Schabath, M.B.; Andrew, A.S.; Bertazzi, P.A.; Pesatori, A.C.; Diao, N.; Su, L.; Song, L.; Zhang, R.; Leighl, N.; Johansen, J.S.; Mellemgaard, A.; Saliba, W.; Haiman, C.; Wilkens, L.; Fernandez-Somoano, A.; Fernandez-Tardon, G.; Heijden, E.H.F.M.; Kim, J.H.; Davies, M.P.A.; Marcus, M.W.; Brunnstrom, H.; Manjer, J.; Melander, O.; Muller, D.C.; Overvad, K.; Trichopoulou, A.; Tumino, R.; Goodman, G.E.; Cox, A.; Taylor, F.; Woll, P.; Wichmann, E.; Muley, T.; Risch, A.; Rosenberger, A.; Grankvist, K.; Johansson, M.; Shepherd, F.; Tsao, M.-.; Arnold, S.M.; Haura, E.B.; Bolca, C.; Holcatova, I.; Janout, V.; Kontic, M.; Lissowska, J.; Mukeria, A.; Ognjanovic, S.; Orlowski, T.M.; Scelo, G.; Swiatkowska, B.; Zaridze, D.; Bakke, P.; Skaug, V.; Butler, L.M.; Offit, K.; Srinivasan, P.; Bandlamudi, C.; Hellmann, M.D.; Solit, D.B.; Robson, M.E.; Rudin, C.M.; Stadler, Z.K.; Taylor, B.S.; Berger, M.F.; Houlston, R.; Mclaughlin, J.; Stevens, V.; Nickle, D.C.; Obeidat, M.; Timens, W.; Artigas, M.S.; Shete, S.; Brenner, H.; Chanock, S.; Brennan, P.; Mckay, J.D.; Amos, C.I.

doi:10.1038/s41467-020-15905-6

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10−15) and replication (adjusted OR = 2.93, P = 2.22 × 10−3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10−22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.

Protein-altering germline mutations implicate novel genes related to lung cancer development / X. Ji, S. Mukherjee, M.T. Landi, Y. Bosse, P. Joubert, D. Zhu, I. Gorlov, X. Xiao, Y. Han, O. Gorlova, R.J. Hung, Y. Brhane, R. Carreras-Torres, D.C. Christiani, N. Caporaso, M. Johansson, G. Liu, S.E. Bojesen, L. Le Marchand, D. Albanes, H. Bickeboller, M.C. Aldrich, W.S. Bush, A. Tardon, G. Rennert, C. Chen, J. Byun, K.H. Dragnev, J.K. Field, L.F. Kiemeney, P. Lazarus, S. Zienolddiny, S. Lam, M.B. Schabath, A.S. Andrew, P.A. Bertazzi, A.C. Pesatori, N. Diao, L. Su, L. Song, R. Zhang, N. Leighl, J.S. Johansen, A. Mellemgaard, W. Saliba, C. Haiman, L. Wilkens, A. Fernandez-Somoano, G. Fernandez-Tardon, E.H.F.M. Heijden, J.H. Kim, M.P.A. Davies, M.W. Marcus, H. Brunnstrom, J. Manjer, O. Melander, D.C. Muller, K. Overvad, A. Trichopoulou, R. Tumino, G.E. Goodman, A. Cox, F. Taylor, P. Woll, E. Wichmann, T. Muley, A. Risch, A. Rosenberger, K. Grankvist, M. Johansson, F. Shepherd, M.-. Tsao, S.M. Arnold, E.B. Haura, C. Bolca, I. Holcatova, V. Janout, M. Kontic, J. Lissowska, A. Mukeria, S. Ognjanovic, T.M. Orlowski, G. Scelo, B. Swiatkowska, D. Zaridze, P. Bakke, V. Skaug, L.M. Butler, K. Offit, P. Srinivasan, C. Bandlamudi, M.D. Hellmann, D.B. Solit, M.E. Robson, C.M. Rudin, Z.K. Stadler, B.S. Taylor, M.F. Berger, R. Houlston, J. McLaughlin, V. Stevens, D.C. Nickle, M. Obeidat, W. Timens, M.S. Artigas, S. Shete, H. Brenner, S. Chanock, P. Brennan, J.D. McKay, C.I. Amos. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 11:1(2020 Dec 01). [10.1038/s41467-020-15905-6]

Protein-altering germline mutations implicate novel genes related to lung cancer development

Ji X.;Mukherjee S.;Landi M. T.;Bosse Y.;Joubert P.;Zhu D.;Gorlov I.;Xiao X.;Han Y.;Gorlova O.;Hung R. J.;Brhane Y.;Carreras-Torres R.;Christiani D. C.;Caporaso N.;Johansson M.;Liu G.;Bojesen S. E.;Le Marchand L.;Albanes D.;Bickeboller H.;Aldrich M. C.;Bush W. S.;Tardon A.;Rennert G.;Chen C.;Byun J.;Dragnev K. H.;Field J. K.;Kiemeney L. F.;Lazarus P.;Zienolddiny S.;Lam S.;Schabath M. B.;Andrew A. S.;P.A. Bertazzi;A.C. Pesatori;Diao N.;Su L.;Song L.;Zhang R.;Leighl N.;Johansen J. S.;Mellemgaard A.;Saliba W.;Haiman C.;Wilkens L.;Fernandez-Somoano A.;Fernandez-Tardon G.;Heijden E. H. F. M.;Kim J. H.;Davies M. P. A.;Marcus M. W.;Brunnstrom H.;Manjer J.;Melander O.;Muller D. C.;Overvad K.;Trichopoulou A.;Tumino R.;Goodman G. E.;Cox A.;Taylor F.;Woll P.;Wichmann E.;Muley T.;Risch A.;Rosenberger A.;Grankvist K.;Johansson M.;Shepherd F.;Tsao M. -S.;Arnold S. M.;Haura E. B.;Bolca C.;Holcatova I.;Janout V.;Kontic M.;Lissowska J.;Mukeria A.;Ognjanovic S.;Orlowski T. M.;Scelo G.;Swiatkowska B.;Zaridze D.;Bakke P.;Skaug V.;Butler L. M.;Offit K.;Srinivasan P.;Bandlamudi C.;Hellmann M. D.;Solit D. B.;Robson M. E.;Rudin C. M.;Stadler Z. K.;Taylor B. S.;Berger M. F.;Houlston R.;McLaughlin J.;Stevens V.;Nickle D. C.;Obeidat M.;Timens W.;Artigas M. S.;Shete S.;Brenner H.;Chanock S.;Brennan P.;McKay J. D.;Amos C. I.

2020

Abstract

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10−15) and replication (adjusted OR = 2.93, P = 2.22 × 10−3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10−22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.

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	Parole chiave
	
			Adenocarcinoma; Aged; Alleles; Ataxia Telangiectasia Mutated Proteins; Databases, Genetic; European Continental Ancestry Group; Female; Genetic Predisposition to Disease; Genotyping Techniques; Germ-Line Mutation; Heterozygote; Humans; Jews; Lung Neoplasms; Male; Middle Aged; Mutation, Missense; Odds Ratio; Oligonucleotide Array Sequence Analysis; Pedigree; RNA-Seq; Risk Factors
		
	Settori scientifico-disciplinari dell'articolo
	
			Settore MED/44 - Medicina del Lavoro
		
	Data di pubblicazione
	
			1-dic-2020
		
	Data ahead of print o data di stampa
	
			11-mag-2020
		
	Rivista in ANCE
	
			NATURE COMMUNICATIONS
		
	DOI
	
			https://dx.doi.org/10.1038/s41467-020-15905-6
		
	Tipologia
	
			Article (author)
		
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			01 - Articolo su periodico

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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/801623

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