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Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations.

ABSTRACT: Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103-14. ©2016 AACR.

SUBMITTER: Fehringer G

PROVIDER: S-EPMC5010493 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations.

Fehringer Gordon G Kraft Peter P Pharoah Paul D PD Eeles Rosalind A RA Chatterjee Nilanjan N Schumacher Fredrick R FR Schildkraut Joellen M JM Lindström Sara S Brennan Paul P Bickeböller Heike H Houlston Richard S RS Landi Maria Teresa MT Caporaso Neil N Risch Angela A Amin Al Olama Ali A Berndt Sonja I SI Giovannucci Edward L EL Grönberg Henrik H Kote-Jarai Zsofia Z Ma Jing J Muir Kenneth K Stampfer Meir J MJ Stevens Victoria L VL Wiklund Fredrik F Willett Walter C WC Goode Ellen L EL Permuth Jennifer B JB Risch Harvey A HA Reid Brett M BM Bezieau Stephane S Brenner Hermann H Chan Andrew T AT Chang-Claude Jenny J Hudson Thomas J TJ Kocarnik Jonathan K JK Newcomb Polly A PA Schoen Robert E RE Slattery Martha L ML White Emily E Adank Muriel A MA Ahsan Habibul H Aittomäki Kristiina K Baglietto Laura L Blomquist Carl C Canzian Federico F Czene Kamila K Dos-Santos-Silva Isabel I Eliassen A Heather AH Figueroa Jonine D JD Flesch-Janys Dieter D Fletcher Olivia O Garcia-Closas Montserrat M Gaudet Mia M MM Johnson Nichola N Hall Per P Hazra Aditi A Hein Rebecca R Hofman Albert A Hopper John L JL Irwanto Astrid A Johansson Mattias M Kaaks Rudolf R Kibriya Muhammad G MG Lichtner Peter P Liu Jianjun J Lund Eiliv E Makalic Enes E Meindl Alfons A Müller-Myhsok Bertram B Muranen Taru A TA Nevanlinna Heli H Peeters Petra H PH Peto Julian J Prentice Ross L RL Rahman Nazneen N Sanchez Maria Jose MJ Schmidt Daniel F DF Schmutzler Rita K RK Southey Melissa C MC Tamimi Rulla R Travis Ruth C RC Turnbull Clare C Uitterlinden Andre G AG Wang Zhaoming Z Whittemore Alice S AS Yang Xiaohong R XR Zheng Wei W Buchanan Daniel D DD Casey Graham G Conti David V DV Edlund Christopher K CK Gallinger Steven S Haile Robert W RW Jenkins Mark M Le Marchand Loïc L Li Li L Lindor Noralene M NM Schmit Stephanie L SL Thibodeau Stephen N SN Woods Michael O MO Rafnar Thorunn T Gudmundsson Julius J Stacey Simon N SN Stefansson Kari K Sulem Patrick P Chen Y Ann YA Tyrer Jonathan P JP Christiani David C DC Wei Yongyue Y Shen Hongbing H Hu Zhibin Z Shu Xiao-Ou XO Shiraishi Kouya K Takahashi Atsushi A Bossé Yohan Y Obeidat Ma'en M Nickle David D Timens Wim W Freedman Matthew L ML Li Qiyuan Q Seminara Daniela D Chanock Stephen J SJ Gong Jian J Peters Ulrike U Gruber Stephen B SB Amos Christopher I CI Sellers Thomas A TA Easton Douglas F DF Hunter David J DJ Haiman Christopher A CA Henderson Brian E BE Hung Rayjean J RJ

Cancer research 20160420 17

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving bre ...[more]

PMID: 27197191

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Project description:Genome-wide association studies (GWASs) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with cancer risk, several of which have shown pleiotropic effects across cancers. Therefore, we performed a systematic cross-cancer pleiotropic analysis to detect the effects of GWAS-identified variants from non-lung cancers on lung cancer risk in 12,843 cases and 12,639 controls from four lung cancer GWASs. The overall association between variants in each cancer and risk of lung cancer was explored using sequential kernel association test (SKAT) analysis. For single variant analysis, we combined the result of specific study using fixed-effect meta-analysis. We performed functional exploration of significant associations based on features from public databases. To further detect the biological mechanism underlying identified observations, pathway enrichment analysis were conducted with R package "clusterProfiler." SNP-set analysis revealed the overall associations between variants of 8 cancer types and lung cancer risk. Single variant analysis identified 6 novel SNPs related to lung cancer risk after multiple correction (P fdr < 0.10), including rs1707302 (1p34.1, OR = 0.93, 95% CI: 0.90-0.97, P = 7.60 × 10-4), rs2516448 (6p21.33, OR = 1.07, 95% CI: 1.03-1.11, P = 1.00 × 10-3), rs3869062 (6p22.1, OR = 0.91, 95% CI: 0.86-0.96, P = 7.10 × 10-4), rs174549 (11q12.2, OR = 0.90, 95% CI: 0.87-0.94, P = 1.00 × 10-7), rs7193541 (16q23.1, OR = 0.93, 95% CI: 0.90-0.96, P = 1.20 × 10-4), and rs8064454 (17q12, OR = 1.07, 95% CI: 1.03-1.11, P = 4.30 × 10-4). The eQTL analysis and functional annotation suggested that these variants might modify lung cancer susceptibility through regulating the expression of related genes. Pathway enrichment analysis showed that genes modulated by these variants play important roles in cancer carcinogenesis. Our findings demonstrate the pleiotropic associations between non-lung cancer susceptibility loci and lung cancer risk, providing important insights into the shared mechanisms of carcinogenesis across cancers.

Project description:BackgroundThe 5-year overall survival rate of lung cancer patients is approximately 15%. Most patients are diagnosed with advanced-stage disease and have shorter survival rates than patients with early-stage disease. Although screening for lung cancer has the potential to increase early diagnosis, it has not been shown to reduce lung cancer mortality rates. In 1993, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was initiated specifically to determine whether screening would reduce mortality rates from PLCO cancers.MethodsA total of 77 464 participants, aged 55-74 years, were randomly assigned to the intervention arm of the PLCO Cancer Screening Trial between November 8, 1993, and July 2, 2001. Participants received a baseline chest radiograph (CXR), followed by three annual single-view CXRs at the 10 US screening centers. Cancers were classified as screen detected and nonscreen detected (interval or never screened) and according to tumor histology. The positivity rates of screen-detected cancers and positive predictive values (PPVs) were calculated. Because 51.6% of the participants were current or former smokers, logistic regression analysis was performed to control for smoking status. All statistical tests were two-sided.ResultsCompliance with screening decreased from 86.6% at baseline to 78.9% at the last screening. Overall positivity rates were 8.9% at baseline and 6.6%-7.1% at subsequent screenings; positivity rates increased modestly with smoking risk categories (P(trend) < .001). The PPVs for all participants were 2.0% at baseline and 1.1%, 1.5%, and 2.4% at years 1, 2, and 3, respectively; PPVs in current smokers were 5.9% at baseline and 3.3%, 4.2%, and 5.6% at years 1, 2, and 3, respectively. A total of 564 lung cancers were diagnosed, of which 306 (54%) were screen-detected cancers and 87% were non-small cell lung cancers. Among non-small cell lung cancers, 59.6% of screen-detected cancers and 33.3% of interval cancers were early (I-II) stage.ConclusionsThe PLCO Cancer Screening Trial demonstrated the ability to recruit, retain, and screen a large population over multiple years at multiple centers. A higher proportion of screen-detected lung cancers were early stage, but a conclusion on the effectiveness of CXR screening must await final PLCO results, which are anticipated at the end of 2015.

Dataset Information

Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations.

Publications

Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations.

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