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List of tag SNPs for the TDP1 gene region

Distribution of rs942190 and rs2401863 by race

Description of the participant studies

Patient characteristics by study site

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.

ILCCO Data Repository was supported by Cancer Care Ontario Research Chair of Population Health, National Institute of Health (U19 CA148127), and Lunenfeld-Tanenbuaum Research Institute, Sinai Health System. The Cancer de Pulmon en Asturias (CAPUA) study (PI: Adonina Tardón) was supported by Fondo de investigación sanitaria. Instituto de Salud Carlos III. Consorcio de Investigación Biomédica en Red (CIBER) del Área de Epidemiología y Salud Pública and University of Oviedo. The Environment And Genetics in Lung cancer Etiology (EAGLE) study (PI: Maria Teresa Landi) was supported by the Intramural Research Program of NIH, NCI, Division of Cancer Epidemiology and Genetics. The Epidemiology & Genetics of Lung cancer (EGLC) study (PI: Ping Yang) was supported by the National Cancer Institute and National Institute of Health (R03-CA77118, R01s-CA80127, CA84354, and HL107612). The Carotene and Retinol Efficacy Trial (CARET) (PIs: Gary E. Goodman, Chu Chen) was supported by the National Cancer Institute and National Institute of Health (5-UM1-CA-167462, U01-CA63673, and R01-CA111703) The Harvard Lung Cancer Study (LCS) (PI: David C. Christiani) was supported by National Institute of Health grants (R01CA092824, R01CA074386, and P30 ES000002) The Japan lung cancer study (PI: Kouya Shiraishi) was supported by the National Cancer Center Research and Development Fund (NCC Biobank). Kentucky Lung Cancer Research Initiative (LCRI) (PI: Susanne M. Arnold) was supported by the Department of Defense [Congressionally Directed Medical Research Program, U.S. Army Medical Research and Materiel Command Program] under award number: 10153006 (W81XWH-11-1-0781). This research was also supported by unrestricted infrastructure funds from the UK Center for Clinical and Translational Science, NIH grant UL1TR000117 and Markey Cancer Center NCI Cancer Center Support Grant (P30 CA177558) Shared Resource Facilities: Cancer Research Informatics, Biospecimen and Tissue Procurement, and Biostatistics and Bioinformatics. The Liverpool Lung Project (LLP) (PI: John K. Field) is supported by the Roy Castle Lung Cancer Foundation, UK. The work performed for the Toronto lung cancer study (PIs: Rayjean J. Hung, Geoffrey Liu) was supported by Ontario Institute for Cancer Research, the Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The Total Lung Cancer (TLC) study (PI: Matthew B. Schabath) was supported by the following funding sources: James & Esther King Biomedical Research Program Grant (09KN-15), National Institutes of Health Specialized Programs of Research Excellence (SPORE) Grant (P50 CA119997), and an American Cancer Society Institutional Research Grant (93-032-13)., Lohavanichbutr, P., Sakoda, L.C., Amos, C.I., Arnold, S.M., Christiani, D.C., Davies, M.P.A., Field, J.K., Haura, E.B., Hung, R.J., Kohno, T., Landi, M.T., Liu, G., Liu, Y., Marcus, M.W., O'Kane, G.M., Schabath, M.B., Shiraishi, K., Slone, S.A., Tardón, A., Yang, P., Yoshida, K., Zhang, R., Zong, X., Goodman, G.E., Weiss, N.S., Chen, C.

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

INTRODUCTION Developments in both low-dose CT-screening within populations at high risk of lung cancer and sequencing analysis of lung tumours have improved the prospects for early detection and clinical management of lung cancer. Such approaches potentially could provide biological insight into the early stages of lung cancer development, which until now have been refractory to genomic analysis, since lung tumours are rarely identified at a presymptomatic timepoint. BRIEF DESCRIPTION OF PERTINENT EXPERIMENTAL PROCEDURES Individuals with at least a 5% risk of developing lung cancer within 5 years (according to the LLPv2 lung cancer risk score) were recruited to the UK Lung low dose CT Screening (UKLS) trial. Ten of the early stage NSCLC UKLS tumours were prepared for exome sequencing. Tumour DNA was extracted from FFPE material and DNA was also extracted from matched blood samples. Tumour and blood libraries were prepared using an Agilent SureSelect exome-capture kit and sequenced to 100x and 50x, depth respectively, on the Illumina HiSeq platform (Oxford Gene Technology, UK). Sequence data were aligned against the GRCh37 human reference and matched samples were subject to local realignment in pairs. Somatic variants were identified using a combination of EBCall, MuTect and VarScan2 and were post-filtered to remove false positive variants (alignment artifacts and FFPE-hypersensitive sites) by comparison between samples. TCGA (The Cancer Genome Atlas) lung adenocarcinoma and squamous cell carcinoma samples from smokers and former smokers (who had complete data for a minimal set of clinical and epidemiological variables) were compared to the UKLS samples described above. To ensure comparable genomic regions were studied, both the UKLS and TCGA somatic variants were restricted to protein-coding regions covered by the Agilent SureSelect array but disjoint from simple-repetitive regions. SUMMARY OF THE NEW, UNPUBLISHED DATA Despite detection at an early stage, somatic mutations were identified in all CT-detected tumours, including non-synonymous variants in known driver genes. Between 71 and 471 variants were detected within non-repetitive protein-coding regions, which is comparable to, if somewhat lower than, the number of variants in the same regions in the TCGA ever-smoker samples (p = 0.17; Kruskal-Wallis). The results suggest that the majority of somatic variants exist in lung tumours prior to the evolution of symptoms and are consistent with recent studies of lung cancer heterogeneity wherein the majority of mutations occur prior to subclonal branching. STATEMENT OF CONCLUSIONS Somatic variations in the host genome are readily detected in FFPE material from pre-symptomatic lung tumours. Mutational burden is comparable to lung adenocarcinoma and squamous carcinoma from mature symptomatic individuals providing further evidence for the long latency of lung tumour development. Citation Format: Russell Hyde, Michael Davies, Martin Ledson, John A. Holemans, Richard D. Page, John Gosney, David R. Baldwin, Anand Devaraj, David M. Hansell, Stephen W. Duffy, John K. Field. Exome sequencing of UKLS lung cancer CT screened early stage cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4602. doi:10.1158/1538-7445.AM2015-4602

Introduction: Early detection of lung cancer by screening of high risk populations (identified by epidemiological and life-style factors) has the potential to save many lives. However, effective screening is reliant on minimally invasive techniques, such as CT screening, bronchioalveolar lavage (BAL) and blood tests, and the identification of suitable biomarkers. CT screening is effective in reducing mortality, but generates a large proportion of indeterminate nodules that must be further characterised. MicroRNAs (miRNA) have great potential as biomarkers due to their tissue-specific and cancer-specific expression patterns. We have identified tumour-specific miRNAs for non-small cell lung cancer (NSCLC), using a combination of screening on TaqMan microRNA TLDA cards and validation with qRTPCR assays, with the aim of utilising these as biomarkers in the early detection setting. Methods: Our sample group consisted of 31 frozen samples from 20 Liverpool Lung Project (LLP) NSCLC patients, including 10 adenocarcinomas (Ad), 10 squamous cell carcinomas (SCC) & matched normal tissue. Two further validation sets consisted of equal numbers of Ad and SCC tumour/normal pairs (124 in total). MiRNA was prepared from tumour and normal specimens using Qiagen MicroRNeasy kits. Reverse transcription and pre-amplification was performed using Applied Biosystems MegaPlex Pools and miRNAs were quantified on a 7900HT Real-Time PCR System with TaqMan Array Human MiRNA Card Set v3.0 (covering 754 human miRNAs). Ct values were exported using SDS v2.3 data and RQ Manager software and further analysed in Bioconductor. Validation qRTPCR was performed with individual miRNA assays, following reverse transcription with MegaPlex pools. Results: When Benjamin-Hoechst-adjusted-p value 4.0 fold-change in the cancer group. A subset of 22 miRNAs including miR-34a, miR-96, let-7g and miR-183 was identified with the greatest expression in tumours. Differential expression of all 22 miRNAs was confirmed in an independent set of 24 tumour/normal pairs. Using these 22 validated miRNAs we performed discriminative modelling and identified a model based on just 8 markers that gave a specificity of 100% and a sensitivity of 98%. This panel was validated, with 97% specificity and 91% sensitivity, in a 2nd independent sample set containing 48 tumours and paired normal samples. Conclusion: A number of miRNAs was identified that showed good discriminatory power individually, but greatest sensitivity and specificity when combined as an 8 member panel. The lung cancer specific miRNAs we have identified provide a potential source of early detection biomarkers. Their applicability to minimally-invasive samples is being evaluated in a range of samples including plasma and bronchial lavage. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4133. doi:1538-7445.AM2012-4133