Citations 7
Stratifying lung adenocarcinoma risk with multi-ancestry polygenic risk scores in East Asian never-smokers
Blechter, Batel , Wang, Xiaoyu , Karsonaki, Christiana, Shi, Jianxin , Shiraishi, Kouya , Choi, Jiyeon , Matsuo, Keitaro , Chen, Tzu‐Yu , Kim, Young Tae , Choudhury, Parichoy Pal , Williams, Jacob , Landi, Maria Teresa , Yin, Zhihua , Zhou, Baosen , Seow, Wei Jie , Song, Lei , Chang, I‐Shou , Chien, Li-Hsin , Wong, Maria Pik , Richardson, Brian Douglas , Li, Shilan , Breeze, Charles E. , Bassig, Bryan A. , Sm, Jason Yy Wong, Chung, Lap Ping, Zhang, Xu‐Chao , Caporaso, Neil E. , Chang, Jiang , Ho, Jcm , Momozawa, Yukihide , Kobayashi, Masashi , Okubo, Kenichi , Honda, Takayuki , Kunitoh, Hideo , Watanabe, Shun-ichi, Hamamoto, Ryuji , Goto, Kōichi , Minamiya, Yoshihiro, Wakai, Kenji , Murakami, Yoshinori , Shimizu, Kimihiro , Suzuki, Hiroyuki , Ohtaki, Yoichi , Tanaka, Kazumi , Wu, Tangchun , Wei, Fusheng, Kim, Yeul Hong , Chang, Gee-Chen , Chen, Kuan‐Yu, Chen, Yuh-Min, Park, Jae Yong , Kweon, Sun-Seog, Gao, Yu‐Tang , Schwartz, Ann G. , Gorlov, Ivan , Wu, Xifeng , Yang, Ping , Lam, Stephen , Bojesen, Stig E. , Ji, Bu‐Tian , Wichmann, H. E., Christiani, D.C., Brennan, Paul , McKay, James , Field, John K. , Shete, Sanjay , Marchand, Loı̈c Le, Liu, Geoffrey , Andrew, Angeline S. , Zienolddiny-Narui, Shan, Grankvist, Kjell , Taylor, Fiona, Aldrich, Melinda C. , Jeon, Hyo‐Sung, Hu, Zhibin , Burdett, Laura, Yeager, Meredith, Hutchinson, Amy , Hicks, Belynda , Liu, Jia , Berndt, Sonja I, Wu, Wei , Wang, Junwen , Choi, Jin Eun , Park, Kyong Hwa , Sung, Sook Whan , Tan, Wen , Sihoe, Alan , Choi, Yi Young, Hung, Hsiao-Han , Vermeulen, Roel , Wu, Junjie , Tsai, Fang-Yu , Chan, John K. C., Li, Jihua , Lin, Hsien-Chih, Liu, Jie , Sawada, Norie , Yamaji, Taiki , Wyatt, Kathleen , Qi, T. Y., Li, Xuelian , Ren, Yangwu , Chao, Ann, Zhu, Junjie , Chen, Chih‐Yi , ScD, Chien-Jen Chen, Stevens, Victoria L. , Fraumeni, Joseph F., Lin, Kuang , Walters, Robin G., Chen, Zhengming, Chatterjee, Nilanjan , Gorlova, Olga Y. , Hsiung, Chao A. , Chanock, Stephen J, Rothman, Nathaniel , Kohno, Takashi , Lan, Qing, Kartsonaki, Christiana , Liu, Geoffrey , Field, John K , Matsuo, Keitaro , Wang, Junwen , Bojesen, Stig E , Grankvist, Kjell , Chen, Chih-Yi , Dai, Juncheng , Hung, Rayjean J. , Chen, Kexin , Shu, Xiao-Ou , Choudhury, Parichoy Pal , Lin, Dongxin , Zheng, Wei , Wang, Jiucun , Hu, Wei , Cai, Qiuyin , Hong, Yun‐Chul , Kim, Hee Nam , Wu, Yi-Long Lung Cancer , Richardson, Brian Douglas , Zhang, Tongwu , Wang, Zhaoming , Kim, Jin Hee , Albanes, Demetrius , Shin, Min‐Ho , Chung, Lap-Ping, Yang, Yang , Zheng, Hong , Dai, Hong , Yatabe, Yasushi , Kim, Young‐Chul , Daigo, Yataro , Kamatani, Yoichiro , Kobayashi, Masashi , Hosgood, Howard Dean , WATANABE, Shun-ichi J. , Miyagi, Yohei , Matsumoto, Shingo , Horinouchi, Hidehito , Tsuboi, Masahiro , Takahashi, Atsushi , Goto, Akiteru , Hara, Megumi , Nishida, Yuichiro , Takeuchi, Kenji , Matsuda, Koichi , Murakami, Yoshinori, Suzuki, Hiroyuki , Saito, Motonobu , Machiela, Mitchell J. , Oh, In‐Jae , Lee, Victor , Su, Wu‐Chou , Seow, Adeline , Kweon, Sun-Seog , Liu, Jianjun , Houlston, Richard S. , Tardón, Adonina , Chen, Chu, Johansson, Mattias , Risch, Angela , Bickeböller, Heike , Rennert, Gad , Arnold, Susanne M. , Davies, Michael P.A. , Kiemeney, Lambertus A. , Cox, Angela , Yuan, Jian-Min , Lazarus, Philip J. , Schabath, Matthew B. , Jiang, Shih Sheng , Chen, Chung–Hsing , Hsiao, Chin‐Fu , Yeager, Meredith , Liu, Jia , Berndt, Sonja I. , Li, Yuqing , Kang, Chang Hyun , Wang, Wen‐Chang , Xu, Jun, Guan, Peng , Yu, Chong‐Jen , Yang, Gong , Park, In Kyu , Cheng, Iona C. , Song, Bao, Wyatt, Kathleen , Ma, Hongxia , Zhu, Meng , Wang, Yifan , Qi, Tianchen, Iwasaki, Motoki , Wu, Guoping , Yang, Pan‐Chyr , Walters, Robin G. , Chatterjee, Nilanjan , Amos, Christopher I. , Shen, Hongbing , Rothman, Nathaniel , Lan, Qing , Zhang, Haoyu
JNCI: Journal of the National Cancer Institute | September 18, 2025 | Volume: 118 | Issue: 2 | Pages: 231-249
Abstract Background Lung adenocarcinoma in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve lung adenocarcinoma risk prediction. Methods PRSs were developed using genome-wide association study summary statistics from East Asian (8002 cases; 20 782 controls) and European (2058 cases; 5575 controls) populations. Single-ancestry models included a PRS with 25 single nucleotide variants (PRS-25), PRS clumping and thresholding (CT), and LDpred2; multi-ancestry models included LDpred2 plus European PRS-128, PRS-CSx, and clumping and thresholding, super learning, empirical Bayes (CT-SLEB). Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium and externally validated in the Nanjing Lung Cancer Cohort. We assessed predictive accuracy via area under the curve operating procedure (AUC), with 10-year and (ages 30-80 years) absolute risks estimates. Results The best multi-ancestry PRS, using East Asian and European data via CT-SLEB, outperformed the best East Asian-only (LDpred2; AUC = 0.629, 95% confidence interval [CI] = 0.618 to 0.641), achieving an AUC of 0.640 (95% CI = 0.629 to 0.653) and odds ratio of 1.71 (95% CI = 1.61 to 1.82) per standard deviation increase. Nanjing Lung Cancer Cohort validation confirmed robust performance (AUC = 0.649, 95% CI = 0.623 to 0.676). The top 20% PRS group had a 3.92-fold higher lung adenocarcinoma risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year lung adenocarcinoma risk at age 50 years (0.42%) by age 41 years, 9 years earlier. Conclusions Multi-ancestry PRS approaches enhance lung adenocarcinoma risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.
Lung Cancer in Ever- and Never-Smokers: Findings from Multi-Population GWAS Studies
Li, Yafang , Xiao, Xiangjun , Li, Jianrong , Han, Younghun , Cheng, Chao , Fernandes, Gail , Slewitzke, Shannon E. , Rosenberg, Susan M. , Zhu, Meng , Byun, Jinyoung , McKay, James , Lam, Stephen , Chen, Chu , Bojesen, Stig E. , Landi, Maria Teresa , Risch, Angela , Wichmann, H-Erich , Goodman, Gary E. , Field, John K. , Shete, Sanjay , Liu, Geoffrey , Andrew, Angeline S. , Grankvist, Kjell , Johansson, Mikael , Caporaso, Neil E. , Aldrich, Melinda C. , Schwartz, Ann G. , Gorlov, Ivan , Purrington, Kristen S. , Liu, Yanhong , Mandal, Diptasri , Gaba, Colette , Brennan, Paul , Xia, Jun , Fernandes, Gail F , Bossé, Yohan , McKay, James , Albanes, Demetrius , Lam, Stephen , Tardón, Adonina , Chen, Chu , Bojesen, Stig E , Landi, Maria T , Johansson, Mattias , Risch, Angela , Bickeböller, Heike , Wichmann, H-Erich , Christiani, David C. , Rennert, Gad , Arnold, Susanne M , Goodman, Gary E , Field, John K , Davies, Michael P A , Shete, Sanjay , Marchand, Loïc Le , Liu, Geoffrey , Hung, Rayjean J , Andrew, Angeline S , Kiemeney, Lambertus A , Sun, Ryan , Zienolddiny, Shanbeh , Grankvist, Kjell , Johansson, Mikael , Caporaso, Neil E , Cox, Angela , Hong, Yun‐Chul , Lazarus, Philip J. , Schabath, Matthew B , Aldrich, Melinda C , Schwartz, Ann G , Gorlov, Ivan , Purrington, Kristen S , Yang, Ping , Liu, Yanhong , Wilson, Richard K , Pinney, Susan M , Mandal, Diptasri , Willey, James C , Brennan, Paul , Xia, Jun , Shen, Hongbing , Amos, Christopher I , Han, Younghun , Cheng, Chao , Byun, Jinyoung , Bossé, Yohan , Albanes, Demetrius , Tardón, Adonina , Johansson, Mattias , Bickeböller, Heike , Rennert, Gad , Arnold, Susanne M. , Davies, Michael P.A. , Marchand, Loı̈c Le , Hung, Rayjean J. , Kiemeney, Lambertus A. , Zienolddiny, Shanbeh , Cox, Angela , Schabath, Matthew B. , Yang, Ping , Bailey‐Wilson, Joan E. , Pinney, Susan M. , Willey, James C. , Shen, Hongbing , Amos, Christopher I.
Cancer Epidemiology, Biomarkers & Prevention | January 5, 2024 | Volume: 33 | Issue: 3 | Pages: 389-399
Abstract Background: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer. Methods: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer. Results: Five novel independent loci, GABRA4, intergenic region 12q24.33, LRRC4C, LINC01088, and LCNL1 were identified with the association at two or three populations (P < 5 × 10−8). Further functional analysis provided multiple lines of evidence suggesting the variants affect lung cancer risk through excessive DNA damage (GABRA4) or cis-regulation of gene expression (LCNL1). The risk of variants from 12 independent regions, including the well-known CHRNA5, associated with ever-smoking lung cancer was evaluated for never-smokers, light-smokers (packyear ≤ 20), and moderate-to-heavy-smokers (packyear > 20). Different risk patterns were observed for the variants among the different groups by smoking behavior. Conclusions: We identified novel variants associated with lung cancer in only ever- or never-smoking groups that were missed by prior main-effect association studies. Impact: Our study highlights the genetic heterogeneity between ever- and never-smoking lung cancer and provides etiologic insights into the complicated genetic architecture of this deadly cancer.
Genome-wide interaction analysis identified low-frequency variants with sex disparity in lung cancer risk
Li, Yafang , Xiao, Xiangjun , Cheng, Chao , McKay, James , Lam, Stephen , Tardón, Adonina , Chen, Chu, Bojesen, Stig E. , Landi, Maria Teresa , Risch, Angela , Wichmann, H‐Erich, Rennert, Gad , Goodman, Gary E. , Field, John K. , Davies, Michael P.A. , Shete, Sanjay , Melander, Olle , Brunnström, Hans , Hung, Rayjean J, Andrew, Angeline S. , Shen, Hongbing , Zienolddiny, Shan, Grankvist, Kjell , Johansson, Mikael , Caporaso, Neil E. , Aldrich, Melinda C. , Schwartz, Ann G. , Gorlov, Ivan P. , Purrington, Kristen S. , Bailey‐Wilson, Joan E. , Mandal, Diptasri , Willey, James C. , Gaba, Colette , Brennan, Paul , Hung, Rayjean J. , Rennert, Gad , Cheng, Chao , Wilson, Richard K , Hung, Rayjean J , Field, John K , Tardón, Adonina , Davies, Michael P A , Bojesen, Stig E , Risch, Angela , Grankvist, Kjell , Purrington, Kristen S , Willey, James C , Shen, Hongbing , Li, Jianrong , Byun, Jinyoung , Bossé, Yohan , Albanes, Demetrius , Johansson, Mattias , Bickeböller, Heike , Christiani, David C. , Arnold, Susanne M. , Marchand, Loı̈c Le , Liu, Geoffrey , Kiemeney, Lambertus A. , Sun, Ryan , Teare, M. Dawn , Hong, Yun‐Chul , Lazarus, Philip J. , Schabath, Matthew B. , Yang, Ping , Liu, Yanhong , Han, Younghun , Pinney, Susan M. , Amos, Christopher I.
Human Molecular Genetics | February 1, 2022 | Volume: 31 | Issue: 16 | Pages: 2831-2843
Abstract Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene–sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 [odds ratio (OR) = 0.71, P = 4.29×10−8); rs79942605 (OR = 2.17, P = 2.81×10−8) and rs208908 (OR = 0.70, P = 4.54×10−8) were identified with different risk effect of lung cancer between men and women. Further expression quantitative trait loci and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of Coxsackie virus and adenovirus receptor gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.
Accounting for EGFR Mutations in Epidemiologic Analyses of Non–Small Cell Lung Cancers: Examples Based on the International Lung Cancer Consortium Data
Schmid, Sabine , Jiang, Mei , Brown, M. Catherine , Fares, Aline Fusco , García-Pardo, Miguel , Soriano, Joelle , Dong, Mei , Thomas, Sera , Kohno, Takashi , Leal, Letícia Ferro , Diao, Nancy , Xie, Juntao , Wang, Zhichao , Заридзе, Давид , Świątkowska, Beata , Savić, Milan , Wenzlaff, Angela S. , Harris, Curtis C. , Caporaso, Neil E. , Ma, Hongxia , Fernández‐Tardón, Guillermo , Barnett, Matthew J, Goodman, Gary E. , Davies, Michael P.A. , Pérez‐Ríos, Mónica , Taylor, Fiona, Schoettker, Ben, Brenner, Hermann , Andrew, Angeline S. , Cox, Angela , Field, John K. , Wang, Ying , Chen, Chu , Tardón, Adonina , Shete, Sanjay , Shen, Hongbing , Landi, Maria Teresa , Schwartz, Ann G. , Qi, Lihong , Brennan, Paul , Reis, Rui Manuel , Liu, Geoffrey , Świątkowska, Beata , Mates, Dana , Wenzlaff, Angela S , Fernandez-Tardon, Guillermo , Barnett, Matthew J , Davies, Michael P A , Duell, Eric J , Brenner, Hermann , Cox, Angela , Ruano-Ravina, Alberto , Field, John K , Tardón, Adonina , Schabath, Matthew B , Schwartz, Ann G , Sakoda, Lori C , Brennan, Paul , Yang, Ping , Christiani, David C. , Reis, Rui Manuel , Hung, Rayjean J , Liu, Geoffrey , Shen, Hongbing , Dong, Mei , Holcátová, Ivana , Lissowska, Jolanta , Mateș, Dana , Duell, Eric J. , Marchand, Loı̈c Le , Schabath, Matthew B. , Ryan, Bríd M. , Sakoda, Lori C. , Yang, Ping , Zhang, Jie , Shiraishi, Kouya , Hung, Rayjean J. , Xu, Wei
Cancer Epidemiology, Biomarkers & Prevention | January 13, 2022 | Volume: 31 | Issue: 3 | Pages: 679-687
Abstract Background: Somatic EGFR mutations define a subset of non–small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches. Methods: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status. Results: Of 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4,231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance index of 0.75 (95% CI, 0.74–0.77) in the training and 0.77 (95% CI, 0.74–0.79) in the testing dataset. At an optimal cut-point of probability-score = 0.335, sensitivity = 69% and specificity = 72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of patients with NSCLC, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients. Conclusions: We introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC. Impact: The proposed method is generalizable in the common occurrence in which EGFR-status data are missing.
Genome-wide interaction analysis identified low-frequency variants with sex disparity in lung cancer risk
Li, Yafang , Xiao, Xiangjun , Byun, Jinyoung , Cheng, Chao , Bossé, Yohan , McKay, James , Lam, Stephen , Tardón, Adonina , Chen, Chu , Landi, Maria Teresa , Wichmann, Erich, Goodman, Gary, Field, John K. , Shete, Sanjay , Melander, Olle , Andrew, Angeline S. , Grankvist, Kjell , Johansson, Mikael , Caporaso, Neil E. , Aldrich, Melinda C. , Schwartz, Ann G. , Gorlov, Ivan P. , Purrington, Kristen S. , Yang, Ping , Bailey‐Wilson, Joan E. , Liu, Yanhong , Mandal, Diptasri , Gaba, Colette , Brennan, Paul , Cheng, Chao , Wilson, Richard K , Field, John K , Tardón, Adonina , Bossé, Yohan , Grankvist, Kjell , Purrington, Kristen S , Byun, Jinyoung , Li, Jianrong , Albanes, Demetrius , Bojesen, Stig E. , Johansson, Mattias , Risch, Angela , Bickeböller, Heike , Christiani, David C. , Rennert, Gad , Arnold, Susanne M. , Marchand, Loı̈c Le , Brunnström, Hans , Liu, Geoffrey , Hung, Rayjean J. , Kiemeney, Lambertus A. , Shen, Hongbing , Sun, Ryan , Zienolddiny, Shanbeh , Teare, M. Dawn , Hong, Yun‐Chul , Davies, Michael P.A. , Lazarus, Philip J. , Schabath, Matthew B. , Han, Younghun , Pinney, Susan M. , Willey, James C. , Amos, Christopher I.
No container title available | July 13, 2021 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract There is growing evidence showing that sex disparity in lung cancer risk cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotype from a lung cancer cohort including ~ 47,000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 (OR=0.71, p=4.29x10-8); rs79942605 (OR=2.17, p=2.81x10-8); and rs208908 (OR=0.70, p=4.54x10-8), were identified with different risk effect of lung cancer between men and women. Further eQTL and functional annotation analysis suggested rs208908 affect lung cancer risk through differential regulation of CXADR (Coxsackie Virus And Adenovirus Receptor) gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.
Common TDP1 Polymorphisms in Relation to Survival among Small Cell Lung Cancer Patients: A Multicenter Study from the International Lung Cancer Consortium
Lohavanichbutr, Pawadee, Arnold, Susanne M. , Davies, Michael P.A. , Field, John K. , Haura, Eric B. , Hung, Rayjean J., Kohno, Takashi , Landi, Maria Teresa , Liu, Geoffrey , Marcus, Michael W. , O’Kane, Grainne M. , Schabath, Matthew B. , Slone, Stacey , Tardón, Adonina , Yoshida, Kazushi, Zong, Xuchen, Goodman, Gary E. , Chen, Chu , Hung, Rayjean J. , Hung, Rayjean J , Liu, Geoffrey , Field, John K , Tardón, Adonina , Davies, Michael P A , Schabath, Matthew B , Sakoda, Lori C. , Amos, Christopher I. , Christiani, David C. , Liu, Yi , Shiraishi, Kouya , Yang, Ping , Zhang, Ruyang , Weiss, Noel S , Arnold, Susanne M , O'Kane, Grainne M.
Clinical Cancer Research | October 3, 2017 | Volume: 23 | Issue: 24 | Pages: 7550-7557
Abstract Purpose: DNA topoisomerase inhibitors are commonly used for treating small-cell lung cancer (SCLC). Tyrosyl-DNA phosphodiesterase (TDP1) repairs DNA damage caused by this class of drugs and may therefore influence treatment outcome. In this study, we investigated whether common TDP1 single-nucleotide polymorphisms (SNP) are associated with overall survival among SCLC patients. Experimental Design: Two TDP1 SNPs (rs942190 and rs2401863) were analyzed in 890 patients from 10 studies in the International Lung Cancer Consortium (ILCCO). The Kaplan–Meier method and Cox regression analyses were used to evaluate genotype associations with overall mortality at 36 months postdiagnosis, adjusting for age, sex, race, and tumor stage. Results: Patients homozygous for the minor allele (GG) of rs942190 had poorer survival compared with those carrying AA alleles, with a HR of 1.36 [95% confidence interval (CI): 1.08–1.72, P = 0.01), but no association with survival was observed for patients carrying the AG genotype (HR = 1.04, 95% CI, 0.84–1.29, P = 0.72). For rs2401863, patients homozygous for the minor allele (CC) tended to have better survival than patients carrying AA alleles (HR = 0.79; 95% CI, 0.61–1.02, P = 0.07). Results from the Genotype Tissue Expression (GTEx) Project, the Encyclopedia of DNA Elements (ENCODE), and the ePOSSUM web application support the potential function of rs942190. Conclusions: We found the rs942190 GG genotype to be associated with relatively poor survival among SCLC patients. Further investigation is needed to confirm the result and to determine whether this genotype may be a predictive marker for treatment efficacy of DNA topoisomerase inhibitors. Clin Cancer Res; 23(24); 7550–7. ©2017 AACR.
Abstract 2248: Common TDP1 polymorphisms in relation to survival among small cell lung cancer patients in a multicenter study from the International Lung Cancer Consortium
Lohavanichbutr, Pawadee, Field, John K. , Haura, Eric B. , Hung, Rayjean J., Kohno, Takashi , Landi, Maria Teresa , Schabath, Matthew B. , Tardón, Adonina , Yoshida, Kazushi, Zong, Xuchen, Chen, Chu , Sakoda, Lori C. , Amos, Christopher I. , Arnold, Susanne M. , Christiani, David C. , Davies, Michael P.A. , Hung, Rayjean J., Liu, Geoffrey , Marcus, Michael W. , O’Kane, Grainne M. , Shiraishi, Kouya , Slone, Stacey , Yang, Ping , Zhang, Ruyang , Weiss, Noel S , Field, John K , Tardón, Adonina , Schabath, Matthew B
Cancer Research | July 31, 2017 | Volume: 77 | Issue: 13_Supplement | Pages: 2248-2248
Abstract Introduction: DNA topoisomerase inhibitors (e.g. etoposide, irinotecan, teniposide, topotecan) are commonly used for treating small cell lung cancer (SCLC). Tyrosyl-DNA phosphodiesterase (TDP1) plays a role in repairing DNA damage caused by DNA topoisomerase inhibitors and it is believed to be responsible for resistance to this class of drugs. The purpose of this study was to determine whether common TDP1 polymorphisms are associated with overall survival among SCLC patients. Method: Two common TDP1 SNPs (rs942190 and rs2401863, r2(European)=0.63 and r2(East Asian)=0.26) were analyzed in 898 patients from 10 studies in the International Lung Cancer Consortium, conducted in the U.S., Canada, Japan, Italy, Spain and the United Kingdom. Genotype data were obtained from either the OncoArray Consortium or other existing genome-wide association studies. Cox proportional hazard regression models with robust standard error were used to evaluate genotype associations for overall survival at 36 months post-diagnosis, adjusting for age, sex, race and tumor stage. Results: Patients homozygous for the minor allele (GG) of TDP1 SNP rs942190 were associated with poorer survival compared to those carrying both major alleles (AA), with a hazard ratio (HR) of 1.36 (95% confidence interval (CI): 1.07-1.72, p-value=0.01), but there was no association with survival for patients with the heterozygous genotype (HR=1.02, 95% CI: 0.83-1.27, p-value=0.83). For rs2401863, patients carrying both minor alleles (CC) tended to have better survival than patients carrying AA alleles, but this was within the limits of chance given no significant association (HR=0.79, 95% CI: 0.61-1.02, p-value=0.07). In addition, multi-tissue expression quantitative trait loci (eQTL) analyses from the Genotype-Tissue Expression Project indicated a potential effect of rs942190 on lung tissue, with higher TDP1 gene expression for the GG than AG or AA genotypes. Conclusion: We found that among SCLC patients the TDP1 rs942190 GG genotype was associated with poor overall survival. Further study could determine if this genotype can serve as a predictive marker for the treatment efficacy of DNA topoisomerase inhibitors in SCLC. Citation Format: Pawadee Lohavanichbutr, Lori C. Sakoda, Christopher I. Amos, Susanne M. Arnold, David C. Christiani, Michael P. Davies, John K. Field, Eric B. Haura, Rayjean J. Hung, Takashi Kohno, Maria Teresa Landi, Geoffrey Liu, Yi Liu, Michael W. Marcus, Grainne M. O'Kane, Matthew B. Schabath, Kouya Shiraishi, Stacey A. Slone, Adonina Tardón, Ping Yang, Kazushi Yoshida, Ruyang Zhang, Xuchen Zong, Noel S. Weiss, Chu Chen. Common TDP1 polymorphisms in relation to survival among small cell lung cancer patients in a multicenter study from the International Lung Cancer Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2248. doi:10.1158/1538-7445.AM2017-2248