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1. Meta-analysis of genome-wide association studies identifies multiple lung cancer susceptibility loci in never-smoking Asian women.

Author

Wang Z, Seow WJ, Shiraishi K, Hsiung CA, Matsuo K, Liu J, Chen K, Yamji T, Yang Y, Chang IS, Wu C, Hong YC, Burdett L, Wyatt K, Chung CC, Li SA, Yeager M, Hutchinson A, Hu W, Caporaso N, Landi MT, Chatterjee N, Song M, Fraumeni JF Jr, Kohno T, Yokota J, Kunitoh H, Ashikawa K, Momozawa Y, Daigo Y, Mitsudomi T, Yatabe Y, Hida T, Hu Z, Dai J, Ma H, Jin G, Song B, Wang Z, Cheng S, Yin Z, Li X, Ren Y, Guan P, Chang J, Tan W, Chen CJ, Chang GC, Tsai YH, Su WC, Chen KY, Huang MS, Chen YM, Zheng H, Li H, Cui P, Guo H, Xu P, Liu L, Iwasaki M, Shimazu T, Tsugane S, Zhu J, Jiang G, Fei K, Park JY, Kim YH, Sung JS, Park KH, Kim YT, Jung YJ, Kang CH, Park IK, Kim HN, Jeon HS, Choi JE, Choi YY, Kim JH, Oh IJ, Kim YC, Sung SW, Kim JS, Yoon HI, Kweon SS, Shin MH, Seow A, Chen Y, Lim WY, Liu J, Wong MP, Lee VH, Bassig BA, Tucker M, Berndt SI, Chow WH, Ji BT, Wang J, Xu J, Sihoe AD, Ho JC, Chan JK, Wang JC, Lu D, Zhao X, Zhao Z, Wu J, Chen H, Jin L, Wei F, Wu G, An SJ, Zhang XC, Su J, Wu YL, Gao YT, Xiang YB, He X, Li J, Zheng W, Shu XO, Cai Q, Klein R, Pao W, Lawrence C, Hosgood HD 3rd, Hsiao CF, Chien LH, Chen YH, Chen CH, Wang WC, Chen CY, Wang CL, Yu CJ, Chen HL, Su YC, Tsai FY, Chen YS, Li YJ, Yang TY, Lin CC, Yang PC, Wu T, Lin D, Zhou B, Yu J, Shen H, Kubo M, Chanock SJ, Rothman N, and Lan Q

Subjects
Adult, Alleles, Asian People, Case-Control Studies, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 6, Chromosomes, Human, Pair 9, Female, Genome-Wide Association Study, Humans, Lung Neoplasms diagnosis, Lung Neoplasms pathology, Odds Ratio, Smoking, Genetic Loci, Genetic Predisposition to Disease, Lung Neoplasms genetics, Polymorphism, Single Nucleotide
Abstract

Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk. To further discover new susceptibility loci, we imputed data from four GWAS of Asian non-smoking female lung cancer (6877 cases and 6277 controls) using the 1000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5878 cases and 7046 controls) for possible replication. In our meta-analysis, three new loci achieved genome-wide significance, marked by single nucleotide polymorphism (SNP) rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 × 10(-13)), rs72658409 at 9p21.3 (per-allele OR = 0.77; P = 1.41 × 10(-10)) and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 × 10(-9)). These findings identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia and merit follow-up to understand their biological underpinnings., (Published by Oxford University Press 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Published
2016
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2. Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types.

Author

Sampson JN, Wheeler WA, Yeager M, Panagiotou O, Wang Z, Berndt SI, Lan Q, Abnet CC, Amundadottir LT, Figueroa JD, Landi MT, Mirabello L, Savage SA, Taylor PR, De Vivo I, McGlynn KA, Purdue MP, Rajaraman P, Adami HO, Ahlbom A, Albanes D, Amary MF, An SJ, Andersson U, Andriole G Jr, Andrulis IL, Angelucci E, Ansell SM, Arici C, Armstrong BK, Arslan AA, Austin MA, Baris D, Barkauskas DA, Bassig BA, Becker N, Benavente Y, Benhamou S, Berg C, Van Den Berg D, Bernstein L, Bertrand KA, Birmann BM, Black A, Boeing H, Boffetta P, Boutron-Ruault MC, Bracci PM, Brinton L, Brooks-Wilson AR, Bueno-de-Mesquita HB, Burdett L, Buring J, Butler MA, Cai Q, Cancel-Tassin G, Canzian F, Carrato A, Carreon T, Carta A, Chan JK, Chang ET, Chang GC, Chang IS, Chang J, Chang-Claude J, Chen CJ, Chen CY, Chen C, Chen CH, Chen C, Chen H, Chen K, Chen KY, Chen KC, Chen Y, Chen YH, Chen YS, Chen YM, Chien LH, Chirlaque MD, Choi JE, Choi YY, Chow WH, Chung CC, Clavel J, Clavel-Chapelon F, Cocco P, Colt JS, Comperat E, Conde L, Connors JM, Conti D, Cortessis VK, Cotterchio M, Cozen W, Crouch S, Crous-Bou M, Cussenot O, Davis FG, Ding T, Diver WR, Dorronsoro M, Dossus L, Duell EJ, Ennas MG, Erickson RL, Feychting M, Flanagan AM, Foretova L, Fraumeni JF Jr, Freedman ND, Beane Freeman LE, Fuchs C, Gago-Dominguez M, Gallinger S, Gao YT, Gapstur SM, Garcia-Closas M, García-Closas R, Gascoyne RD, Gastier-Foster J, Gaudet MM, Gaziano JM, Giffen C, Giles GG, Giovannucci E, Glimelius B, Goggins M, Gokgoz N, Goldstein AM, Gorlick R, Gross M, Grubb R 3rd, Gu J, Guan P, Gunter M, Guo H, Habermann TM, Haiman CA, Halai D, Hallmans G, Hassan M, Hattinger C, He Q, He X, Helzlsouer K, Henderson B, Henriksson R, Hjalgrim H, Hoffman-Bolton J, Hohensee C, Holford TR, Holly EA, Hong YC, Hoover RN, Horn-Ross PL, Hosain GM, Hosgood HD 3rd, Hsiao CF, Hu N, Hu W, Hu Z, Huang MS, Huerta JM, Hung JY, Hutchinson A, Inskip PD, Jackson RD, Jacobs EJ, Jenab M, Jeon HS, Ji BT, Jin G, Jin L, Johansen C, Johnson A, Jung YJ, Kaaks R, Kamineni A, Kane E, Kang CH, Karagas MR, Kelly RS, Khaw KT, Kim C, Kim HN, Kim JH, Kim JS, Kim YH, Kim YT, Kim YC, Kitahara CM, Klein AP, Klein RJ, Kogevinas M, Kohno T, Kolonel LN, Kooperberg C, Kricker A, Krogh V, Kunitoh H, Kurtz RC, Kweon SS, LaCroix A, Lawrence C, Lecanda F, Lee VH, Li D, Li H, Li J, Li YJ, Li Y, Liao LM, Liebow M, Lightfoot T, Lim WY, Lin CC, Lin D, Lindstrom S, Linet MS, Link BK, Liu C, Liu J, Liu L, Ljungberg B, Lloreta J, Di Lollo S, Lu D, Lund E, Malats N, Mannisto S, Le Marchand L, Marina N, Masala G, Mastrangelo G, Matsuo K, Maynadie M, McKay J, McKean-Cowdin R, Melbye M, Melin BS, Michaud DS, Mitsudomi T, Monnereau A, Montalvan R, Moore LE, Mortensen LM, Nieters A, North KE, Novak AJ, Oberg AL, Offit K, Oh IJ, Olson SH, Palli D, Pao W, Park IK, Park JY, Park KH, Patiño-Garcia A, Pavanello S, Peeters PH, Perng RP, Peters U, Petersen GM, Picci P, Pike MC, Porru S, Prescott J, Prokunina-Olsson L, Qian B, Qiao YL, Rais M, Riboli E, Riby J, Risch HA, Rizzato C, Rodabough R, Roman E, Roupret M, Ruder AM, Sanjose Sd, Scelo G, Schned A, Schumacher F, Schwartz K, Schwenn M, Scotlandi K, Seow A, Serra C, Serra M, Sesso HD, Setiawan VW, Severi G, Severson RK, Shanafelt TD, Shen H, Shen W, Shin MH, Shiraishi K, Shu XO, Siddiq A, Sierrasesúmaga L, Sihoe AD, Skibola CF, Smith A, Smith MT, Southey MC, Spinelli JJ, Staines A, Stampfer M, Stern MC, Stevens VL, Stolzenberg-Solomon RS, Su J, Su WC, Sund M, Sung JS, Sung SW, Tan W, Tang W, Tardón A, Thomas D, Thompson CA, Tinker LF, Tirabosco R, Tjønneland A, Travis RC, Trichopoulos D, Tsai FY, Tsai YH, Tucker M, Turner J, Vajdic CM, Vermeulen RC, Villano DJ, Vineis P, Virtamo J, Visvanathan K, Wactawski-Wende J, Wang C, Wang CL, Wang JC, Wang J, Wei F, Weiderpass E, Weiner GJ, Weinstein S, Wentzensen N, White E, Witzig TE, Wolpin BM, Wong MP, Wu C, Wu G, Wu J, Wu T, Wu W, Wu X, Wu YL, Wunder JS, Xiang YB, Xu J, Xu P, Yang PC, Yang TY, Ye Y, Yin Z, Yokota J, Yoon HI, Yu CJ, Yu H, Yu K, Yuan JM, Zelenetz A, Zeleniuch-Jacquotte A, Zhang XC, Zhang Y, Zhao X, Zhao Z, Zheng H, Zheng T, Zheng W, Zhou B, Zhu M, Zucca M, Boca SM, Cerhan JR, Ferri GM, Hartge P, Hsiung CA, Magnani C, Miligi L, Morton LM, Smedby KE, Teras LR, Vijai J, Wang SS, Brennan P, Caporaso NE, Hunter DJ, Kraft P, Rothman N, Silverman DT, Slager SL, Chanock SJ, and Chatterjee N

Subjects
Adult, Aged, Asian People genetics, Asian People statistics & numerical data, Bone Neoplasms genetics, Female, Humans, Kidney Neoplasms genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Lung Neoplasms etiology, Lung Neoplasms genetics, Lymphoma, Large B-Cell, Diffuse genetics, Male, Middle Aged, Neoplasms etiology, Osteosarcoma genetics, Polymorphism, Single Nucleotide, Smoking adverse effects, Testicular Neoplasms genetics, Tissue Array Analysis, Urinary Bladder Neoplasms etiology, Urinary Bladder Neoplasms genetics, White People genetics, White People statistics & numerical data, Genetic Predisposition to Disease, Genome-Wide Association Study, Neoplasms genetics
Abstract

Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites., Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers., Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures., Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation., (Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Published
2015
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3. Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: a report from the female lung cancer consortium in Asia.

Author

Machiela MJ, Hsiung CA, Shu XO, Seow WJ, Wang Z, Matsuo K, Hong YC, Seow A, Wu C, Hosgood HD 3rd, Chen K, Wang JC, Wen W, Cawthon R, Chatterjee N, Hu W, Caporaso NE, Park JY, Chen CJ, Kim YH, Kim YT, Landi MT, Shen H, Lawrence C, Burdett L, Yeager M, Chang IS, Mitsudomi T, Kim HN, Chang GC, Bassig BA, Tucker M, Wei F, Yin Z, An SJ, Qian B, Lee VH, Lu D, Liu J, Jeon HS, Hsiao CF, Sung JS, Kim JH, Gao YT, Tsai YH, Jung YJ, Guo H, Hu Z, Hutchinson A, Wang WC, Klein RJ, Chung CC, Oh IJ, Chen KY, Berndt SI, Wu W, Chang J, Zhang XC, Huang MS, Zheng H, Wang J, Zhao X, Li Y, Choi JE, Su WC, Park KH, Sung SW, Chen YM, Liu L, Kang CH, Hu L, Chen CH, Pao W, Kim YC, Yang TY, Xu J, Guan P, Tan W, Su J, Wang CL, Li H, Sihoe AD, Zhao Z, Chen Y, Choi YY, Hung JY, Kim JS, Yoon HI, Cai Q, Lin CC, Park IK, Xu P, Dong J, Kim C, He Q, Perng RP, Kohno T, Kweon SS, Chen CY, Vermeulen RC, Wu J, Lim WY, Chen KC, Chow WH, Ji BT, Chan JK, Chu M, Li YJ, Yokota J, Li J, Chen H, Xiang YB, Yu CJ, Kunitoh H, Wu G, Jin L, Lo YL, Shiraishi K, Chen YH, Lin HC, Wu T, Wong MP, Wu YL, Yang PC, Zhou B, Shin MH, Fraumeni JF Jr, Zheng W, Lin D, Chanock SJ, Rothman N, and Lan Q

Subjects
Adult, Aged, Asian People genetics, China, Female, Genetic Predisposition to Disease ethnology, Genome-Wide Association Study statistics & numerical data, Hong Kong, Humans, Japan, Lung Neoplasms ethnology, Middle Aged, Odds Ratio, Prospective Studies, Republic of Korea, Risk Factors, Singapore, Smoking, Taiwan, Telomere Homeostasis genetics, Genetic Predisposition to Disease genetics, Lung Neoplasms genetics, Polymorphism, Single Nucleotide, Telomere genetics
Abstract

Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10(-14) ) even after removing rs2736100 (p value = 4.81 × 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk., (Published 2014. This article is a US Government work and, as such, is in the public domain of the United States of America.)

Published
2015
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4. Lack of association of C-Met-N375S sequence variant with lung cancer susceptibility and prognosis.

Author

Shieh JM, Tang YA, Yang TH, Chen CY, Hsu HS, Tan YH, Salgia R, and Wang YC

Subjects
Base Sequence, Case-Control Studies, DNA Primers, Female, Humans, Lung Neoplasms pathology, Male, Polymerase Chain Reaction, Prognosis, Carcinoma, Non-Small-Cell Lung genetics, Genetic Predisposition to Disease, Lung Neoplasms genetics, Proto-Oncogene Proteins c-met genetics
Abstract

Background: Previously, we identified a sequence variant (N375S) of c-Met gene, however, its association with lung cancer risk and prognosis remain undefined., Patients and Methods: We investigated the genotype distribution of the c-Met-N375S sequence variant in 206 lung cancer patients and 207 non-cancer controls in the Taiwanese population by DNA sequencing., Results: Lung cancer patients with variant A/G and G/G genotypes showed 1.08-fold increased cancer risk when compared to patients with the wild-type A/A genotype (95% CI, 0.60-1.91). There were no significant differences in postoperative survival between c-Met-N375S and wild-type patients. In the cell model, the c-Met-N375S cells showed a decrease in cell death upon treatment with MET inhibitor SU11274 compared to wild-type cells., Conclusion: Our data suggest that the c-Met-N375S sequence variant may not play a significant role in cancer susceptibility and the prognosis of lung cancer patients. The correlation with chemoresponse of c-Met-N375S is worth further investigation in patients receiving MET therapy.

Published
2013
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5. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia.

Author

Lan Q, Hsiung CA, Matsuo K, Hong YC, Seow A, Wang Z, Hosgood HD 3rd, Chen K, Wang JC, Chatterjee N, Hu W, Wong MP, Zheng W, Caporaso N, Park JY, Chen CJ, Kim YH, Kim YT, Landi MT, Shen H, Lawrence C, Burdett L, Yeager M, Yuenger J, Jacobs KB, Chang IS, Mitsudomi T, Kim HN, Chang GC, Bassig BA, Tucker M, Wei F, Yin Z, Wu C, An SJ, Qian B, Lee VH, Lu D, Liu J, Jeon HS, Hsiao CF, Sung JS, Kim JH, Gao YT, Tsai YH, Jung YJ, Guo H, Hu Z, Hutchinson A, Wang WC, Klein R, Chung CC, Oh IJ, Chen KY, Berndt SI, He X, Wu W, Chang J, Zhang XC, Huang MS, Zheng H, Wang J, Zhao X, Li Y, Choi JE, Su WC, Park KH, Sung SW, Shu XO, Chen YM, Liu L, Kang CH, Hu L, Chen CH, Pao W, Kim YC, Yang TY, Xu J, Guan P, Tan W, Su J, Wang CL, Li H, Sihoe AD, Zhao Z, Chen Y, Choi YY, Hung JY, Kim JS, Yoon HI, Cai Q, Lin CC, Park IK, Xu P, Dong J, Kim C, He Q, Perng RP, Kohno T, Kweon SS, Chen CY, Vermeulen R, Wu J, Lim WY, Chen KC, Chow WH, Ji BT, Chan JK, Chu M, Li YJ, Yokota J, Li J, Chen H, Xiang YB, Yu CJ, Kunitoh H, Wu G, Jin L, Lo YL, Shiraishi K, Chen YH, Lin HC, Wu T, Wu YL, Yang PC, Zhou B, Shin MH, Fraumeni JF Jr, Lin D, Chanock SJ, and Rothman N

Subjects
Adenocarcinoma of Lung, Adult, Aged, Asian People genetics, Chromosomes, Human, Pair 10 genetics, Chromosomes, Human, Pair 15 genetics, Chromosomes, Human, Pair 17, Chromosomes, Human, Pair 5 genetics, Chromosomes, Human, Pair 6 genetics, Female, Humans, Middle Aged, Polymorphism, Single Nucleotide, Smoking, Adenocarcinoma genetics, Carcinoma, Squamous Cell genetics, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Lung Neoplasms genetics
Abstract

To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10(-6)) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10(-18)), 6q22.2 (rs9387478, P = 4.14 × 10(-10)) and 6p21.32 (rs2395185, P = 9.51 × 10(-9)). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.

Published
2012
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6. The APE1 Asp/Asp genotype and the combination of APE1 Asp/Asp and hOGG1-Cys variants are associated with increased p53 mutation in non-small cell lung cancer.

Author

Lin CH, Chen PM, Cheng YW, Chen CY, Yuan CJ, and Lee H

Subjects
Adult, Aged, Aged, 80 and over, Female, Genotype, Humans, Male, Middle Aged, Mutation, Taiwan, Carcinoma, Non-Small-Cell Lung genetics, DNA Glycosylases genetics, DNA-(Apurinic or Apyrimidinic Site) Lyase genetics, Genetic Predisposition to Disease, Lung Neoplasms genetics, Peptide Fragments genetics, Polymorphism, Genetic, Tumor Suppressor Protein p53 genetics
Abstract

Background: The hOGG1 Ser326Cys polymorphism is associated with lung cancer risk, but there are limited data regarding an association between the APE1 Asp148Glu polymorphism and lung cancer. Biological evidence shows that the hOGG1-Cys allele results in less DNA repair activity; however, this is not associated with p53 mutation in lung cancer. Therefore, we investigated whether an interaction between hOGG1 and APE1 is associated with the frequency of p53 mutation in lung cancer., Methods: We studied 217 Taiwanese adults with primary lung cancer. DNA polymorphisms of hOGG1 and APE1 were determined by polymerase chain reaction (PCR)-based restriction fragment length polymorphism. Mutations in p53 exons 5-8 were detected by direct sequencing. Multiple logistic regression was used to estimate odds ratios (ORs) and 95% CIs for the risk of p53 mutation associated with polymorphisms of hOGG1 and APE1 in lung cancer., Results: As expected, no association between hOGG1 polymorphism and p53 mutation was observed in this population. However, a higher risk of p53 mutation was found in participants with the APE1 Asp/Asp genotype than in those with the APE1-Glu allele (OR, 2.15; 95% CI, 1.19-3.87; P = 0.011). The risk of p53 mutation was also higher in participants with APE1 Asp/Asp plus hOGG1-Cys than in those with APE1-Glu plus hOGG1 Ser/Ser (OR, 3.72; 95% CI, 1.33-10.40; P = 0.012)., Conclusions: These results suggest that the APE1 Asp/Asp genotype and the combination of the APE1 Asp/Asp and hOGG1-Cys variants are associated with increased risk of p53 mutation in non-small cell lung cancer.

Published
2012
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7. The 5p15.33 locus is associated with risk of lung adenocarcinoma in never-smoking females in Asia.

Author

Hsiung CA, Lan Q, Hong YC, Chen CJ, Hosgood HD, Chang IS, Chatterjee N, Brennan P, Wu C, Zheng W, Chang GC, Wu T, Park JY, Hsiao CF, Kim YH, Shen H, Seow A, Yeager M, Tsai YH, Kim YT, Chow WH, Guo H, Wang WC, Sung SW, Hu Z, Chen KY, Kim JH, Chen Y, Huang L, Lee KM, Lo YL, Gao YT, Kim JH, Liu L, Huang MS, Jung TH, Jin G, Caporaso N, Yu D, Kim CH, Su WC, Shu XO, Xu P, Kim IS, Chen YM, Ma H, Shen M, Cha SI, Tan W, Chang CH, Sung JS, Zhang M, Yang TY, Park KH, Yuenger J, Wang CL, Ryu JS, Xiang Y, Deng Q, Hutchinson A, Kim JS, Cai Q, Landi MT, Yu CJ, Park JY, Tucker M, Hung JY, Lin CC, Perng RP, Boffetta P, Chen CY, Chen KC, Yang SY, Hu CY, Chang CK, Fraumeni JF Jr, Chanock S, Yang PC, Rothman N, and Lin D

Subjects
Adenocarcinoma ethnology, Adult, Aged, Asian People genetics, Case-Control Studies, Female, Genome-Wide Association Study, Humans, Lung Neoplasms ethnology, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Adenocarcinoma genetics, Chromosomes, Human, Pair 5 genetics, Genetic Predisposition to Disease, Lung Neoplasms genetics
Abstract

Genome-wide association studies of lung cancer reported in populations of European background have identified three regions on chromosomes 5p15.33, 6p21.33, and 15q25 that have achieved genome-wide significance with p-values of 10(-7) or lower. These studies have been performed primarily in cigarette smokers, raising the possibility that the observed associations could be related to tobacco use, lung carcinogenesis, or both. Since most women in Asia do not smoke, we conducted a genome-wide association study of lung adenocarcinoma in never-smoking females (584 cases, 585 controls) among Han Chinese in Taiwan and found that the most significant association was for rs2736100 on chromosome 5p15.33 (p = 1.30 x 10(-11)). This finding was independently replicated in seven studies from East Asia totaling 1,164 lung adenocarcinomas and 1,736 controls (p = 5.38 x 10(-11)). A pooled analysis achieved genome-wide significance for rs2736100. This SNP marker localizes to the CLPTM1L-TERT locus on chromosome 5p15.33 (p = 2.60 x 10(-20), allelic risk = 1.54, 95% Confidence Interval (CI) 1.41-1.68). Risks for heterozygote and homozygote carriers of the minor allele were 1.62 (95% CI; 1.40-1.87), and 2.35 (95% CI: 1.95-2.83), respectively. In summary, our results show that genetic variation in the CLPTM1L-TERT locus of chromosome 5p15.33 is directly associated with the risk of lung cancer, most notably adenocarcinoma., Competing Interests: The authors have declared that no competing interests exist.

Published
2010
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8. Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types

Author

Sampson, Joshua N, Wheeler, William A, Yeager, Meredith, Panagiotou, Orestis, Wang, Zhaoming, Berndt, Sonja I, Lan, Qing, Abnet, Christian C, Amundadottir, Laufey T, Figueroa, Jonine D, Landi, Maria Teresa, Mirabello, Lisa, Savage, Sharon A, Taylor, Philip R, De Vivo, Immaculata, McGlynn, Katherine A, Purdue, Mark P, Rajaraman, Preetha, Adami, Hans-Olov, Ahlbom, Anders, Albanes, Demetrius, Amary, Maria Fernanda, An, She-Juan, Andersson, Ulrika, Andriole, Gerald, Andrulis, Irene L, Angelucci, Emanuele, Ansell, Stephen M, Arici, Cecilia, Armstrong, Bruce K, Arslan, Alan A, Austin, Melissa A, Baris, Dalsu, Barkauskas, Donald A, Bassig, Bryan A, Becker, Nikolaus, Benavente, Yolanda, Benhamou, Simone, Berg, Christine, Van Den Berg, David, Bernstein, Leslie, Bertrand, Kimberly A, Birmann, Brenda M, Black, Amanda, Boeing, Heiner, Boffetta, Paolo, Boutron-Ruault, Marie-Christine, Bracci, Paige M, Brinton, Louise, Brooks-Wilson, Angela R, Bueno-de-Mesquita, H Bas, Burdett, Laurie, Buring, Julie, Butler, Mary Ann, Cai, Qiuyin, Cancel-Tassin, Geraldine, Canzian, Federico, Carrato, Alfredo, Carreon, Tania, Carta, Angela, Chan, John KC, Chang, Ellen T, Chang, Gee-Chen, Chang, I-Shou, Chang, Jiang, Chang-Claude, Jenny, Chen, Chien-Jen, Chen, Chih-Yi, Chen, Chu, Chen, Chung-Hsing, Chen, Constance, Chen, Hongyan, Chen, Kexin, Chen, Kuan-Yu, Chen, Kun-Chieh, Chen, Ying, Chen, Ying-Hsiang, Chen, Yi-Song, Chen, Yuh-Min, Chien, Li-Hsin, Chirlaque, María-Dolores, Choi, Jin Eun, Choi, Yi Young, Chow, Wong-Ho, Chung, Charles C, Clavel, Jacqueline, Clavel-Chapelon, Françoise, Cocco, Pierluigi, Colt, Joanne S, Comperat, Eva, Conde, Lucia, Connors, Joseph M, Conti, David, Cortessis, Victoria K, Cotterchio, Michelle, Cozen, Wendy, Crouch, Simon, Crous-Bou, Marta, Cussenot, Olivier, and Davis, Faith G

Subjects
Tobacco, Clinical Research, Urologic Diseases, Lung, Genetics, Rare Diseases, Lung Cancer, Human Genome, Hematology, Cancer, Tobacco Smoke and Health, Prevention, Lymphoma, Adult, Aged, Asian People, Bone Neoplasms, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kidney Neoplasms, Leukemia, Lymphocytic, Chronic, B-Cell, Lung Neoplasms, Lymphoma, Large B-Cell, Diffuse, Male, Middle Aged, Neoplasms, Osteosarcoma, Polymorphism, Single Nucleotide, Smoking, Testicular Neoplasms, Tissue Array Analysis, Urinary Bladder Neoplasms, White People, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

BackgroundStudies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.MethodsBetween 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.ResultsGWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.ConclusionOur results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

Published
2015

9. Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33

Author

Wang, Zhaoming, Zhu, Bin, Zhang, Mingfeng, Parikh, Hemang, Jia, Jinping, Chung, Charles C, Sampson, Joshua N, Hoskins, Jason W, Hutchinson, Amy, Burdette, Laurie, Ibrahim, Abdisamad, Hautman, Christopher, Raj, Preethi S, Abnet, Christian C, Adjei, Andrew A, Ahlbom, Anders, Albanes, Demetrius, Allen, Naomi E, Ambrosone, Christine B, Aldrich, Melinda, Amiano, Pilar, Amos, Christopher, Andersson, Ulrika, Andriole, Gerald, Andrulis, Irene L, Arici, Cecilia, Arslan, Alan A, Austin, Melissa A, Baris, Dalsu, Barkauskas, Donald A, Bassig, Bryan A, Beane Freeman, Laura E, Berg, Christine D, Berndt, Sonja I, Bertazzi, Pier Alberto, Biritwum, Richard B, Black, Amanda, Blot, William, Boeing, Heiner, Boffetta, Paolo, Bolton, Kelly, Boutron-Ruault, Marie-Christine, Bracci, Paige M, Brennan, Paul, Brinton, Louise A, Brotzman, Michelle, Bueno-de-Mesquita, H Bas, Buring, Julie E, Butler, Mary Ann, Cai, Qiuyin, Cancel-Tassin, Geraldine, Canzian, Federico, Cao, Guangwen, Caporaso, Neil E, Carrato, Alfredo, Carreon, Tania, Carta, Angela, Chang, Gee-Chen, Chang, I-Shou, Chang-Claude, Jenny, Che, Xu, Chen, Chien-Jen, Chen, Chih-Yi, Chen, Chung-Hsing, Chen, Constance, Chen, Kuan-Yu, Chen, Yuh-Min, Chokkalingam, Anand P, Chu, Lisa W, Clavel-Chapelon, Francoise, Colditz, Graham A, Colt, Joanne S, Conti, David, Cook, Michael B, Cortessis, Victoria K, Crawford, E David, Cussenot, Olivier, Davis, Faith G, De Vivo, Immaculata, Deng, Xiang, Ding, Ti, Dinney, Colin P, Di Stefano, Anna Luisa, Diver, W Ryan, Duell, Eric J, Elena, Joanne W, Fan, Jin-Hu, Feigelson, Heather Spencer, Feychting, Maria, Figueroa, Jonine D, Flanagan, Adrienne M, Fraumeni, Joseph F, Freedman, Neal D, Fridley, Brooke L, Fuchs, Charles S, Gago-Dominguez, Manuela, Gallinger, Steven, Gao, Yu-Tang, Gapstur, Susan M, and Garcia-Closas, Montserrat

Subjects
Biological Sciences, Genetics, Cancer, Clinical Research, Human Genome, Prevention, Aetiology, 2.1 Biological and endogenous factors, Alleles, Chromosomes, Human, Pair 5, Computational Biology, DNA Methylation, Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Membrane Proteins, Neoplasm Proteins, Neoplasms, Odds Ratio, Polymorphism, Single Nucleotide, Risk, Telomerase, Medical and Health Sciences, Genetics & Heredity
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 CLPTM1L gene (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.

Published
2014

10. Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population

Author

Shi, Jianxin, Shiraishi, Kouya, Choi, Jiyeon, Matsuo, Keitaro, Chen, Tzu-Yu, Dai, Juncheng, Hung, Rayjean J, Chen, Kexin, Shu, Xiao-Ou, Kim, Young Tae, Landi, Maria Teresa, Lin, Dongxin, Zheng, Wei, Yin, Zhihua, Zhou, Baosen, Song, Bao, Wang, Jiucun, Seow, Wei Jie, Song, Lei, Chang, I-Shou, Hu, Wei, Chien, Li-Hsin, Cai, Qiuyin, Hong, Yun-Chul, Kim, Hee Nam, Wu, Yi-Long, Wong, Maria Pik, Richardson, Brian Douglas, Funderburk, Karen M, Li, Shilan, Zhang, Tongwu, Breeze, Charles, Wang, Zhaoming, Blechter, Batel, Bassig, Bryan A, Kim, Jin Hee, Albanes, Demetrius, Wong, Jason Y Y, Shin, Min-Ho, Chung, Lap Ping, Yang, Yang, An, She-Juan, Zheng, Hong, Yatabe, Yasushi, Zhang, Xu-Chao, Kim, Young-Chul, Caporaso, Neil E, Chang, Jiang, Ho, James Chung Man, Kubo, Michiaki, Daigo, Yataro, Song, Minsun, Momozawa, Yukihide, Kamatani, Yoichiro, Kobayashi, Masashi, Okubo, Kenichi, Honda, Takayuki, Hosgood, Dean H, Kunitoh, Hideo, Patel, Harsh, Watanabe, Shun-Ichi, Miyagi, Yohei, Nakayama, Haruhiko, Matsumoto, Shingo, Horinouchi, Hidehito, Tsuboi, Masahiro, Hamamoto, Ryuji, Goto, Koichi, Ohe, Yuichiro, Takahashi, Atsushi, Goto, Akiteru, Minamiya, Yoshihiro, Hara, Megumi, Nishida, Yuichiro, Takeuchi, Kenji, Wakai, Kenji, Matsuda, Koichi, Murakami, Yoshinori, Shimizu, Kimihiro, Suzuki, Hiroyuki, Saito, Motonobu, Ohtaki, Yoichi, Tanaka, Kazumi, Wu, Tangchun, Wei, Fusheng, Dai, Hongji, Machiela, Mitchell J, Su, Jian, Kim, Yeul Hong, Oh, In-Jae, Lee, Victor Ho Fun, Chang, Gee-Chen, Tsai, Ying-Huang, Chen, Kuan-Yu, Huang, Ming-Shyan, Su, Wu-Chou, Chen, Yuh-Min, Seow, Adeline, Park, Jae Yong, Kweon, Sun-Seog, Chen, Kun-Chieh, Gao, Yu-Tang, Qian, Biyun, Wu, Chen, Lu, Daru, Liu, Jianjun, Schwartz, Ann G, Houlston, Richard, Spitz, Margaret R, Gorlov, Ivan P, Wu, Xifeng, Yang, Ping, Lam, Stephen, Tardon, Adonina, Chen, Chu, Bojesen, Stig E, Johansson, Mattias, Risch, Angela, Bickeböller, Heike, Ji, Bu-Tian, Wichmann, H-Erich, Christiani, David C, Rennert, Gadi, Arnold, Susanne, Brennan, Paul, McKay, James, Field, John K, Shete, Sanjay S, Le Marchand, Loic, Liu, Geoffrey, Andrew, Angeline, Kiemeney, Lambertus A, Zienolddiny-Narui, Shan, Grankvist, Kjell, Johansson, Mikael, Cox, Angela, Taylor, Fiona, Yuan, Jian-Min, Lazarus, Philip, Schabath, Matthew B, Aldrich, Melinda C, Jeon, Hyo-Sung, Jiang, Shih Sheng, Sung, Jae Sook, Chen, Chung-Hsing, Hsiao, Chin-Fu, Jung, Yoo Jin, Guo, Huan, Hu, Zhibin, Burdett, Laurie, Yeager, Meredith, Hutchinson, Amy, Hicks, Belynda, Liu, Jia, Zhu, Bin, Berndt, Sonja I, Wu, Wei, Wang, Junwen, Li, Yuqing, Choi, Jin Eun, Park, Kyong Hwa, Sung, Sook Whan, Liu, Li, Kang, Chang Hyun, Wang, Wen-Chang, Xu, Jun, Guan, Peng, Tan, Wen, Yu, Chong-Jen, Yang, Gong, Sihoe, Alan Dart Loon, Chen, Ying, Choi, Yi Young, Kim, Jun Suk, Yoon, Ho-Il, Park, In Kyu, Xu, Ping, He, Qincheng, Wang, Chih-Liang, Hung, Hsiao-Han, Vermeulen, Roel C H, Cheng, Iona, Wu, Junjie, Lim, Wei-Yen, Tsai, Fang-Yu, Chan, John K C, Li, Jihua, Chen, Hongyan, Lin, Hsien-Chih, Jin, Li, Liu, Jie, Sawada, Norie, Yamaji, Taiki, Wyatt, Kathleen, Li, Shengchao A, Ma, Hongxia, Zhu, Meng, Wang, Zhehai, Cheng, Sensen, Li, Xuelian, Ren, Yangwu, Chao, Ann, Iwasaki, Motoki, Zhu, Junjie, Jiang, Gening, Fei, Ke, Wu, Guoping, Chen, Chih-Yi, Chen, Chien-Jen, Yang, Pan-Chyr, Yu, Jinming, Stevens, Victoria L, Fraumeni, Joseph F, Chatterjee, Nilanjan, Gorlova, Olga Y, Hsiung, Chao Agnes, Amos, Christopher I, Shen, Hongbing, Chanock, Stephen J, Rothman, Nathaniel, Kohno, Takashi, Lan, Qing, and IRAS OH Epidemiology Chemical Agents

Subjects
Humans, Genetic Predisposition to Disease, Asia, Eastern/epidemiology, Lung Neoplasms/epidemiology, Polymorphism, Single Nucleotide, Adenocarcinoma of Lung/genetics, Genome-Wide Association Study
Abstract

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P interaction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

Published
2023

11. Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types

Author

Sampson, Joshua N, Wheeler, William A, Yeager, Meredith, Panagiotou, Orestis, Wang, Zhaoming, Berndt, Sonja I, Lan, Qing, Abnet, Christian C, Amundadottir, Laufey T, Figueroa, Jonine D, Landi, Maria Teresa, Mirabello, Lisa, Savage, Sharon A, Taylor, Philip R, De Vivo, Immaculata, McGlynn, Katherine A, Purdue, Mark P, Rajaraman, Preetha, Adami, Hans-Olov, Ahlbom, Anders, Albanes, Demetrius, Amary, Maria Fernanda, An, She-Juan, Andersson, Ulrika, Andriole, Gerald, Andrulis, Irene L, Angelucci, Emanuele, Ansell, Stephen M, Arici, Cecilia, Armstrong, Bruce K, Arslan, Alan A, Austin, Melissa A, Baris, Dalsu, Barkauskas, Donald A, Bassig, Bryan A, Becker, Nikolaus, Benavente, Yolanda, Benhamou, Simone, Berg, Christine, Van Den Berg, David, Bernstein, Leslie, Bertrand, Kimberly A, Birmann, Brenda M, Black, Amanda, Boeing, Heiner, Boffetta, Paolo, Boutron-Ruault, Marie-Christine, Bracci, Paige M, Brinton, Louise, Brooks-Wilson, Angela R, Bueno-de-Mesquita, H Bas, Burdett, Laurie, Buring, Julie, Butler, Mary Ann, Cai, Qiuyin, Cancel-Tassin, Geraldine, Canzian, Federico, Carrato, Alfredo, Carreon, Tania, Carta, Angela, Chan, John KC, Chang, Ellen T, Chang, Gee-Chen, Chang, I-Shou, Chang, Jiang, Chang-Claude, Jenny, Chen, Chien-Jen, Chen, Chih-Yi, Chen, Chu, Chen, Chung-Hsing, Chen, Constance, Chen, Hongyan, Chen, Kexin, Chen, Kuan-Yu, Chen, Kun-Chieh, Chen, Ying, Chen, Ying-Hsiang, Chen, Yi-Song, Chen, Yuh-Min, Chien, Li-Hsin, Chirlaque, María-Dolores, Choi, Jin Eun, Choi, Yi Young, Chow, Wong-Ho, Chung, Charles C, Clavel, Jacqueline, Clavel-Chapelon, Françoise, Cocco, Pierluigi, Colt, Joanne S, Comperat, Eva, Conde, Lucia, Connors, Joseph M, Conti, David, Cortessis, Victoria K, Cotterchio, Michelle, Cozen, Wendy, Crouch, Simon, Crous-Bou, Marta, Cussenot, Olivier, and Davis, Faith G

Subjects
Adult, Asian Continental Ancestry Group, Male, Lung Neoplasms, Lymphoma, European Continental Ancestry Group, Oncology and Carcinogenesis, Bone Neoplasms, Testicular Neoplasms, Neoplasms, Large B-Cell, Humans, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Polymorphism, Chronic, Aged, Osteosarcoma, Leukemia, Smoking, B-Cell, Single Nucleotide, Middle Aged, Diffuse, Kidney Neoplasms, Lymphocytic, Urinary Bladder Neoplasms, Tissue Array Analysis, Female, Genome-Wide Association Study
Abstract

BackgroundStudies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.MethodsBetween 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.ResultsGWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.ConclusionOur results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

Published
2015

12. Analysis of heritability and shared heritability based on Genome-Wide Association Studies for 13 Cancer Types

Author

Sampson, Joshua N., Wheeler, William A., Yeager, Meredith, Panagiotou, Orestis, Wang, Zhaoming, Berndt, Sonja I., Lan, Qing, Abnet, Christian C., Amundadottir, Laufey T., Figueroa, Jonine D., Landi, Maria Teresa, Mirabello, Lisa, Savage, Sharon A., Taylor, Philip R., Vivo, Immaculata De, McGlynn, Katherine A., Purdue, Mark P., Rajaraman, Preetha, Adami, Hans-Olov, Ahlbom, Anders, Albanes, Demetrius, Amary, Maria Fernanda, An, She-Juan, Andersson, Ulrika, Andriole, Gerald, Andrulis, Irene L., Angelucci, Emanuele, Ansell, Stephen M., Arici, Cecilia, Armstrong, Bruce K., Arslan, Alan A., Austin, Melissa A., Baris, Dalsu, Barkauskas, Donald A., Bassig, Bryan A., Becker, Nikolaus, Benavente, Yolanda, Benhamou, Simone, Berg, Christine, Van Den Berg, David, Bernstein, Leslie, Bertrand, Kimberly A., Birmann, Brenda M., Black, Amanda, Boeing, Heiner, Boffetta, Paolo, Boutron-Ruault, Marie-Christine, Bracci, Paige M., Brinton, Louise, Brooks-Wilson, Angela R., Bueno-de-Mesquita, H. Bas, Burdett, Laurie, Buring, Julie, Butler, Mary Ann, Cai, Qiuyin, Cancel-Tassin, Geraldine, Canzian, Federico, Carrato, Alfredo, Carreon, Tania, Carta, Angela, Chan, John K. C., Chang, Ellen T., Chang, Gee-Chen, Chang, I-Shou, Chang, Jiang, Chang-Claude, Jenny, Chen, Chien-Jen, Chen, Chih-Yi, Chen, Chu, Chen, Chung-Hsing, Chen, Constance, Chen, Hongyan, Chen, Kexin, Chen, Kuan-Yu, Chen, Kun-Chieh, Chen, Ying, Chen, Ying-Hsiang, Chen, Yi-Song, Chen, Yuh-Min, Chien, Li-Hsin, Chirlaque, María-Dolores, Choi, Jin Eun, Choi, Yi Young, Chow, Wong-Ho, Chung, Charles C., Clavel, Jacqueline, Clavel-Chapelon, Françoise, Cocco, Pierluigi, Colt, Joanne S., Comperat, Eva, Conde, Lucia, Connors, Joseph M., Conti, David, Cortessis, Victoria K., Cotterchio, Michelle, Cozen, Wendy, Crouch, Simon, Crous-Bou, Marta, Cussenot, Olivier, Davis, Faith G., Ding, Ti, Diver, W. Ryan, Dorronsoro, Miren, Dossus, Laure, Duell, Eric J., Ennas, Maria Grazia, Erickson, Ralph L., Feychting, Maria, Flanagan, Adrienne M., Foretova, Lenka, Fraumeni, Joseph F., Freedman, Neal D., Beane Freeman, Laura E., Fuchs, Charles, Gago-Dominguez, Manuela, Gallinger, Steven, Gao, Yu-Tang, Gapstur, Susan M., Garcia-Closas, Montserrat, García-Closas, Reina, Gascoyne, Randy D., Gastier-Foster, Julie, Gaudet, Mia M., Gaziano, J. Michael, Giffen, Carol, Giles, Graham G., Giovannucci, Edward, Glimelius, Bengt, Goggins, Michael, Gokgoz, Nalan, Goldstein, Alisa M., Gorlick, Richard, Gross, Myron, Grubb, Robert, Gu, Jian, Guan, Peng, Gunter, Marc, Guo, Huan, Habermann, Thomas M., Haiman, Christopher A., Halai, Dina, Hallmans, Goran, Hassan, Manal, Hattinger, Claudia, He, Qincheng, He, Xingzhou, Helzlsouer, Kathy, Henderson, Brian, Henriksson, Roger, Hjalgrim, Henrik, Hoffman-Bolton, Judith, Hohensee, Chancellor, Holford, Theodore R., Holly, Elizabeth A., Hong, Yun-Chul, Hoover, Robert N., Horn-Ross, Pamela L., Hosain, G. M. Monawar, Hosgood, H. Dean, Hsiao, Chin-Fu, Hu, Nan, Hu, Wei, Hu, Zhibin, Huang, Ming-Shyan, Huerta, Jose-Maria, Hung, Jen-Yu, Hutchinson, Amy, Inskip, Peter D., Jackson, Rebecca D., Jacobs, Eric J., Jenab, Mazda, Jeon, Hyo-Sung, Ji, Bu-Tian, Jin, Guangfu, Jin, Li, Johansen, Christoffer, Johnson, Alison, Jung, Yoo Jin, Kaaks, Rudolph, Kamineni, Aruna, Kane, Eleanor, Kang, Chang Hyun, Karagas, Margaret R., Kelly, Rachel S., Khaw, Kay-Tee, Kim, Christopher, Kim, Hee Nam, Kim, Jin Hee, Kim, Jun Suk, Kim, Yeul Hong, Kim, Young Tae, Kim, Young-Chul, Kitahara, Cari M., Klein, Alison P., Klein, Robert J., Kogevinas, Manolis, Kohno, Takashi, Kolonel, Laurence N., Kooperberg, Charles, Kricker, Anne, Krogh, Vittorio, Kunitoh, Hideo, Kurtz, Robert C., Kweon, Sun-Seog, LaCroix, Andrea, Lawrence, Charles, Lecanda, Fernando, Lee, Victor Ho Fun, Li, Donghui, Li, Haixin, Li, Jihua, Li, Yao-Jen, Li, Yuqing, Liao, Linda M., Liebow, Mark, Lightfoot, Tracy, Lim, Wei-Yen, Lin, Chien-Chung, Lin, Dongxin, Lindstrom, Sara, Linet, Martha S., Link, Brian K., Liu, Chenwei, Liu, Jianjun, Liu, Li, Ljungberg, Börje, Lloreta, Josep, Lollo, Simonetta Di, Lu, Daru, Lund, Eiluv, Malats, Nuria, Mannisto, Satu, Marchand, Loic Le, Marina, Neyssa, Masala, Giovanna, Mastrangelo, Giuseppe, Matsuo, Keitaro, Maynadie, Marc, McKay, James, McKean-Cowdin, Roberta, Melbye, Mads, Melin, Beatrice S., Michaud, Dominique S., Mitsudomi, Tetsuya, Monnereau, Alain, Montalvan, Rebecca, Moore, Lee E., Mortensen, Lotte Maxild, Nieters, Alexandra, North, Kari E., Novak, Anne J., Oberg, Ann L., Offit, Kenneth, Oh, In-Jae, Olson, Sara H., Palli, Domenico, Pao, William, Park, In Kyu, Park, Jae Yong, Park, Kyong Hwa, Patiño-Garcia, Ana, Pavanello, Sofia, Peeters, Petra H. M., Perng, Reury-Perng, Peters, Ulrike, Petersen, Gloria M., Picci, Piero, Pike, Malcolm C., Porru, Stefano, Prescott, Jennifer, Prokunina-Olsson, Ludmila, Qian, Biyun, Qiao, You-Lin, Rais, Marco, Riboli, Elio, Riby, Jacques, Risch, Harvey A., Rizzato, Cosmeri, Rodabough, Rebecca, Roman, Eve, Roupret, Morgan, Ruder, Avima M., de Sanjose, Silvia, Scelo, Ghislaine, Schned, Alan, Schumacher, Fredrick, Schwartz, Kendra, Schwenn, Molly, Scotlandi, Katia, Seow, Adeline, Serra, Consol, Serra, Massimo, Sesso, Howard D., Setiawan, Veronica Wendy, Severi, Gianluca, Severson, Richard K., Shanafelt, Tait D., Shen, Hongbing, Shen, Wei, Shin, Min-Ho, Shiraishi, Kouya, Shu, Xiao-Ou, Siddiq, Afshan, Sierrasesúmaga, Luis, Sihoe, Alan Dart Loon, Skibola, Christine F., Smith, Alex, Smith, Martyn T., Southey, Melissa C., Spinelli, John J., Staines, Anthony, Stampfer, Meir, Stern, Marianna C., Stevens, Victoria L., Stolzenberg-Solomon, Rachael S., Su, Jian, Su, Wu-Chou, Sund, Malin, Sung, Jae Sook, Sung, Sook Whan, Tan, Wen, Tang, Wei, Tardón, Adonina, Thomas, David, Thompson, Carrie A., Tinker, Lesley F., Tirabosco, Roberto, Tjønneland, Anne, Travis, Ruth C., Trichopoulos, Dimitrios, Tsai, Fang-Yu, Tsai, Ying-Huang, Tucker, Margaret, Turner, Jenny, Vajdic, Claire M., Vermeulen, Roel C. H., Villano, Danylo J., Vineis, Paolo, Virtamo, Jarmo, Visvanathan, Kala, Wactawski-Wende, Jean, Wang, Chaoyu, Wang, Chih-Liang, Wang, Jiu-Cun, Wang, Junwen, Wei, Fusheng, Weiderpass, Elisabete, Weiner, George J., Weinstein, Stephanie, Wentzensen, Nicolas, White, Emily, Witzig, Thomas E., Wolpin, Brian M., Wong, Maria Pik, Wu, Chen, Wu, Guoping, Wu, Junjie, Wu, Tangchun, Wu, Wei, Wu, Xifeng, Wu, Yi-Long, Wunder, Jay S., Xiang, Yong-Bing, Xu, Jun, Xu, Ping, Yang, Pan-Chyr, Yang, Tsung-Ying, Ye, Yuanqing, Yin, Zhihua, Yokota, Jun, Yoon, Ho-Il, Yu, Chong-Jen, Yu, Herbert, Yu, Kai, Yuan, Jian-Min, Zelenetz, Andrew, Zeleniuch-Jacquotte, Anne, Zhang, Xu-Chao, Zhang, Yawei, Zhao, Xueying, Zhao, Zhenhong, Zheng, Hong, Zheng, Tongzhang, Zheng, Wei, Zhou, Baosen, Zhu, Meng, Zucca, Mariagrazia, Boca, Simina M., Cerhan, James R., Ferri, Giovanni M., Hartge, Patricia, Hsiung, Chao Agnes, Magnani, Corrado, Miligi, Lucia, Morton, Lindsay M., Smedby, Karin E., Teras, Lauren R., Vijai, Joseph, Wang, Sophia S., Brennan, Paul, Caporaso, Neil E., Hunter, David J., Kraft, Peter, Rothman, Nathaniel, Silverman, Debra T., Slager, Susan L., Chanock, Stephen J., and Chatterjee, Nilanjan

Subjects
Adult, Asian Continental Ancestry Group, Male, Lung Neoplasms, DATABASE, European Continental Ancestry Group, RELATIVES, Bone Neoplasms, Polymorphism, Single Nucleotide, Article, LUNG-CANCER, Testicular Neoplasms, Neoplasms, SWEDEN, LYMPHOMA, Humans, Genetic Predisposition to Disease, FAMILIAL RISK, Oncology & Carcinogenesis, Aged, Osteosarcoma, Science & Technology, MUTATIONS, Smoking, Middle Aged, Leukemia, Lymphocytic, Chronic, B-Cell, PANCREATIC-CANCER, Kidney Neoplasms, MULTIPLE SUSCEPTIBILITY LOCI, INDIVIDUALS, Oncology, Urinary Bladder Neoplasms, Tissue Array Analysis, Female, Lymphoma, Large B-Cell, Diffuse, Life Sciences & Biomedicine, 1112 Oncology And Carcinogenesis, Genome-Wide Association Study
Abstract

Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common SNPs for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49,492 cancer cases and 34,131 controls. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl2, on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% CI = 14% - 37%) and 7% (4% - 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ=0.73, SE=0.28), Diffuse Large B-Cell Lymphoma (DLBCL) and pediatric osteosarcoma (ρ=0.53, SE=0.21), DLBCL and Chronic Lymphocytic Leukemia (CLL) (ρ=0.51, SE=0.18), and bladder and lung (ρ=0.35, SE=0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a non-smoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

Published
2015

13. Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: a report from the female lung cancer consortium in Asia

Author

Machiela, Mitchell J, Hsiung, Chao Agnes, Shu, Xiao-Ou, Seow, Wei Jie, Wang, Zhaoming, Matsuo, Keitaro, Hong, Yun-Chul, Seow, Adeline, Wu, Chen, Hosgood, H Dean, Chen, Kexin, Wang, Jiu-Cun, Wen, Wanqing, Cawthon, Richard, Chatterjee, Nilanjan, Hu, Wei, Caporaso, Neil E, Park, Jae Yong, Chen, Chien-Jen, Kim, Yeul Hong, Kim, Young Tae, Landi, Maria Teresa, Shen, Hongbing, Lawrence, Charles, Burdett, Laurie, Yeager, Meredith, Chang, I-Shou, Mitsudomi, Tetsuya, Kim, Hee Nam, Chang, Gee-Chen, Bassig, Bryan A, Tucker, Margaret, Wei, Fusheng, Yin, Zhihua, An, She-Juan, Qian, Biyun, Lee, Victor Ho Fun, Lu, Daru, Liu, Jianjun, Jeon, Hyo-Sung, Hsiao, Chin-Fu, Sung, Jae Sook, Kim, Jin Hee, Gao, Yu-Tang, Tsai, Ying-Huang, Jung, Yoo Jin, Guo, Huan, Hu, Zhibin, Hutchinson, Amy, Wang, Wen-Chang, Klein, Robert J, Chung, Charles C, Oh, In-Jae, Chen, Kuan-Yu, Berndt, Sonja I, Wu, Wei, Chang, Jiang, Zhang, Xu-Chao, Huang, Ming-Shyan, Zheng, Hong, Wang, Junwen, Zhao, Xueying, Li, Yuqing, Choi, Jin Eun, Su, Wu-Chou, Park, Kyong Hwa, Sung, Sook Whan, Chen, Yuh-Min, Liu, Li, Kang, Chang Hyun, Hu, Lingmin, Chen, Chung-Hsing, Pao, William, Kim, Young-Chul, Yang, Tsung-Ying, Xu, Jun, Guan, Peng, Tan, Wen, Su, Jian, Wang, Chih-Liang, Li, Haixin, Sihoe, Alan Dart Loon, Zhao, Zhenhong, Chen, Ying, Choi, Yi Young, Hung, Jen-Yu, Kim, Jun Suk, Yoon, Ho-Il, Cai, Qiuyin, Lin, Chien-Chung, Park, In Kyu, Xu, Ping, Dong, Jing, Kim, Christopher, He, Qincheng, Perng, Reury-Perng, Kohno, Takashi, Kweon, Sun-Seog, Chen, Chih-Yi, Vermeulen, Roel C H, Wu, Junjie, Lim, Wei-Yen, Chen, Kun-Chieh, Chow, Wong-Ho, Ji, Bu-Tian, Chan, John K C, Chu, Minjie, Li, Yao-Jen, Yokota, Jun, Li, Jihua, Chen, Hongyan, Xiang, Yong-Bing, Yu, Chong-Jen, Kunitoh, Hideo, Wu, Guoping, Jin, Li, Lo, Yen-Li, Shiraishi, Kouya, Chen, Ying-Hsiang, Lin, Hsien-Chih, Wu, Tangchun, Wong, Maria Pik, Wu, Yi-Long, Yang, Pan-Chyr, Zhou, Baosen, Shin, Min-Ho, Fraumeni, Joseph F, Zheng, Wei, Lin, Dongxin, Chanock, Stephen J, Rothman, Nathaniel, Lan, Qing, Risk Assessment, Infection & Immunity, dIRAS RA-2, dIRAS RA-I&I RA, and LS IRAS EEPI GRA (Gezh.risico-analyse)

Subjects
Adult, Asian Continental Ancestry Group, China, Singapore, Lung Neoplasms, Smoking, Taiwan, Telomere Homeostasis, Middle Aged, Telomere, Polymorphism, Single Nucleotide, Japan, Risk Factors, Republic of Korea, Odds Ratio, Hong Kong, Humans, Female, Genetic Predisposition to Disease, Prospective Studies, Aged, Genome-Wide Association Study
Abstract

Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10(-14) ) even after removing rs2736100 (p value = 4.81 × 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk.

Published
2015

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