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Background: Over 180 genetic variants have been identified as risk loci for breast cancer. However, most loci were discovered using European ancestry populations. As some common susceptibility loci are shared across populations, we aim to discover new risk loci for breast cancer using a cross-ancestry genome-wide association study (GWAS) approach. Methods: Data from five GWAS studies in women of African ancestry with a combined sample size of 9241 cases and 10192 controls were used to generate pooled breast cancer risk estimates in a fixed effect meta-analysis, and this served as the discovery dataset. Summary statistics from the GWAS conducted in European ancestry populations (Breast Cancer Association Consortium, 122977 cases and 105974 controls) served as the validation dataset. The variants that were associated with breast cancer risk at P < 0.01 in the GWAS of African ancestry were meta-analyzed with the GWAS in European ancestry. A locus was considered novel if the lead index variant was genome-wide significant (5 × 10−8) in the cross-ancestry meta-analysis and >500kb away from known breast cancer risk loci. Conditional on the lead index variants, we searched for additional signals in each locus using multivariable logistic regression. Analyses were done separately for ER-positive, ER-negative and overall breast cancer risk. Results: We discovered four novel loci for overall breast cancer risk (1p13.3, 5q31.1, 15q24, and 15q26.3) and two novel loci for ER-negative breast cancer (1q41 and 7q11.23) at the genome-wide significance level of P < 5 × 10−8. Three index single nucleotide polymorphism (SNPs) lie within introns of genes (KCNK2, C5orf56, and SIN3A) and the other index SNPs are located in intergenic regions (close to GSTM4 and AMPD2, CASTOR2, and the antisense DNA RP11-168G16.2). The direction of the associations was consistent between the GWASs of African and European descendants. At the 15q24 locus, we found an additional SNP (in the intron of the SCAMP2 gene) to be independently associated with overall breast cancer risk. Conclusions: We have identified six new risk loci that may contribute to better prediction of breast cancer risk in African ancestry populations and provide new insights into mechanisms of breast cancer carcinogenesis. Replication of these loci in multiple populations and functional studies can help to identify causal variants. Citation Format: Babatunde Adedokun, Zhaohui Du, Guimin Gao, Thomas Ahearn, Kathryn L. Lunetta, Gary Zirpoli, Jonine Figueroa, Esther M. John, Leslie Bernstein, Wei Zheng, Jennifer J. Hu, Regina G. Ziegler, Sarah Nyante, Elisa V. Bandera, Sue A. Ingles, Michael F. Press, Sandra L. Deming, Jorge L. Rodriguez-Gil, Song Yao, Temidayo O. Ogundiran, Oladosu Ojengbede, William Blot, Melissa Troester, Katherine L. Nathanson, Anselm Hennis, Barbara Nemesure, Stefan Ambs, Lara E. Sucheston-Campbell, Jeannette T. Bensen, Stephen J. Chanock, Andrew F. Olshan, Christine B. Ambrosone, David V. Conti, Olufunmilayo I. Olopade, Montserrat Garcia-Closas, Julie R. Palmer, Christopher A. Haiman, Dezheng Huo. Cross-ancestry genome-wide association study identifies six new loci for breast cancer in women of African and european ancestry [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4613.

Emerging evidence indicates that germline variations may interact with somatic events in carcinogenesis. However, the germline-somatic interaction in lung cancer remains largely unknown. In the present study, we investigated whether lung cancer driver genes (CDGs) were more likely to locate within cancer susceptibility regions. Additional pathway enrichment analysis was performed to identify common pathways underlying CDGs and cancer susceptibility genes (CSGs). Next, we analyzed the associations between lung cancer risk SNPs and somatic alterations, including mutations and copy number alterations, in the level of genes, pathways, and overall burden of alterations. Enrichment analysis showed that lung CDGs are more likely to locate within cancer susceptibility regions (P = 8.40×10-3). Both of lung CSGs and CDGs showed significant enrichment in pathways such as cell cycle and p53 signaling pathway. Gene-based analysis showed that rs36600 (22q12.2) was associated with somatic mutations within ARID1A (OR = 2.45, 95%CI: 1.47-4.08, P = 5.78×10-4). Pathway-based analysis identified rs2395185 and rs3817963 at 6p22.1 were associated with somatic truncation mutations in cell cycle pathway (OR = 1.56, P = 3.61×10-4 for rs2395185; OR = 1.58, P = 4.15×10-4 for rs3817963), and rs3817963 was also associated with somatic truncation mutations in MAPK signaling pathway (OR = 1.54, P = 8.58×10-4). Further analysis associated rs2395185 at 6p22.1 (HLA class II genes) with increased APOBEC3A expression (P = 9.50×10-3) and elevated APOBEC mutagenesis (P = 3.58×10-3). These results provide evidence for the germline-somatic interactions on lung tumorigenesis. This can help to uncover the molecular mechanisms by which risk SNPs influence lung cancer risk. Citation Format: Yuzhuo Wang, Cheng Wang, Meng Zhu, Guangfu Jin, Hongbing Shen. Interaction analysis between germline susceptibility loci and somatic alterations in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 238.

Ewing sarcoma (EWS) is a rare pediatric tumor predominantly occurring in children of European ancestry and is characterized by the pathognomonic EWSR1-FLI1 fusion oncogene. To identify germline susceptibility loci associated with EWS risk, we performed a genome-wide association study (GWAS) meta-analysis of 749 EWS cases and 1,378 unaffected individuals of European ancestry from sample collections within the Institut Curie, National Cancer Institute and the Childhood Cancer Survivor Study. Our study replicated previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1 as well as identified novel loci at 6p25.1, 8q24.23, 20p11.22 and 20p11.23 (P-values Citation Format: Mitchell J. Machiela, Thomas G. Grünewald, Didier Surdez, Stephanie Reynaud, Olivier Mirabeau, Eric Karlins, Rebeca Alba Rubio, Sakina Zaidi, Sandrine Grossetete-Lalami, Stelly Ballet, Eve Lapouble, Valérie Laurence, Jean Michon, Gaelle Pierron, Heinrich Kovar, Nathalie Gaspar, Udo Kontny, Anna González-Neira, Piero Picci, Javier Alonso, Ana Patino-Garcia, Nadège Corradini, Neal D. Freedman, Nathaniel Rothman, Casey L. Dagnall, Laurie Burdette, Kristine Jones, Michelle Manning, Kathleen Wyatt, Weiyin Zhou, Meredith Yeager, David G. Cox, Robert N. Hoover, Javed Khan, Gregory T. Armstrong, Wendy M. Leisenring, Smita Bhatia, Leslie L. Robison, Uta Dirksen, Markus Metzler, Wolfgang Hartmann, Konstantin Strauch, Thomas Kirchner, Andreas E. Kulozik, Lindsay M. Morton, Lisa Mirabello, Margaret A. Tucker, Franck Tirode, Stephen J. Chanock, Olivier Delattre. Multiple new susceptibility loci identified in genome-wide association study of Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2970.

GWAS is an important tool for discovering regions in the genome associated with cancer susceptibility. For renal cell carcinoma (RCC), only two loci have had their functional basis explained (11q13 and 12p12). Here, we used a massively parallel reporter assay (MPRA) to investigate enhancer activity in 20 GWAS regions that had an RCC association p-value of at least 10-7. We selected 784 SNPs with an r2>0.4 or D’>0.5 and MAF Citation Format: Leandro Machado Colli, Lea Jessop, Mitchell Machiela, Jiyeon Choi, Timothy Myers, Stephen Chanock. Identification of enhancer elements at kidney cancer susceptibility loci using MPRA [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 1443. doi:10.1158/1538-7445.AM2017-1443

Common genetic variants in over 150 loci have been found to be associated with prostate cancer (PrCa) risk through GWAS. These variants, however, explain only a small fraction of PrCa heritability, and the genes responsible for the detected associations remain largely unknown. It has been suggested that many GWAS-identified associations may be driven by the regulation of risk variants on the expression of disease causal genes. To identify novel PrCa risk loci and possible causal genes at known risk loci, we performed a transcriptome-wide association study (TWAS) to evaluate associations of genetically predicted gene expressions with PrCa risk. We used RNA sequencing data from normal prostate tissues and high-density genotyping from 73 European descendants included in the Genotype-Tissue Expression Project and established genetic models to predict gene expression level. Given that the regulatory mechanisms for most genes are similar across most human tissues, we also built cross-tissue models using gene expression data generated in all tissues from 369 European descendants to increase the statistical power. Based on prediction performance, we selected 22,126 genes and conducted association analyses of their predicted expression with PrCa risk using GWAS data obtained from more than 143,000 subjects included in PRACTICAL/ELLIPSE consortia. We identified 140 genes showing an association of their predicted expression levels with PrCa risk at P < 2.26×10-6, a Bonferroni-corrected significance threshold, including 105 protein-coding genes, 33 long non-coding RNAs, and 2 processed transcripts. Seven of these associated genes are located more than 1Mb away from any of the risk variants identified in PrCa GWAS, representing potential novel risk loci. Of the remaining 133 genes located in known risk loci, 100 have not been reported from previous eQTL analyses. The associations for 25 of these genes remained significant at P < 3.76×10-4 (0.05/133) after adjusting for the risk variants reported in the initial GWAS. Our study also identified 33 genes that were previously reported based on eQTL and fine-mapping analyses. For many of the identified genes, somatic changes of indels, nonsense mutations, splice site variants, translation start site variants, or missense mutations were detected in PrCa patients in the TCGA, including known PrCa driver genes NKX3-1 and PLXNA1. Pathway enrichment analysis showed that cancer related functions were significantly enriched for the identified genes. The top canonical pathways identified included prostate cancer signaling, ATM signaling, AMPK signaling, protein ubiquitination pathway, and antigen presentation pathway. In summary, we conducted the first large PrCa TWAS and identified multiple novel susceptibility loci and genes for PrCa risk. Our study provided substantial new information towards the understanding of PrCa genetics and biology. Citation Format: Lang Wu, Jirong Long, Yingchang Lu, Xingyi Guo, Bogdan Pasaniuc, Kathryn L. Penney, Zsofia Kote-Jarai, Christopher A. Haiman, Rosalind A. Eeles, Wei Zheng, the PRACTICAL consortium. Identification of novel susceptibility loci and genes for prostate cancer risk: A large transcriptome-wide association study in over 143,000 subjects [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 1301. doi:10.1158/1538-7445.AM2017-1301

Genome-wide association studies (GWAS) have identified 58 susceptibility alleles across 37 regions associated with the incidence of colorectal cancer (CRC) with P Citation Format: Stephanie L. Schmit, Fredrick R. Schumacher, Christopher K. Edlund, Jian Gong, Gad Rennert, Wei Zheng, Loic Le Marchand, Ulrike Peters, Graham Casey, Li Hsu, Stephen B. Gruber, David V. Conti, CORECT, GECCO, CCFR, ACCC, and MEC. Novel susceptibility loci for colorectal cancer: Findings from the colorectal transdisciplinary (CORECT) study OncoArray analysis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-365.

Importance: Reducing lung cancer risk by modifying diet is highly desirable. However, the association of different U.S. dietary patterns with lung cancer risk is poorly understood, especially for regional dietary patterns. Objective: We investigated whether different U.S. dietary patterns were associated with lung cancer risk and whether the associations could be modified by genome-wide association study identified susceptibility loci. Design, Setting, and Participants: Study participants were accrued from a large ongoing case-control study of lung cancer initiated in 1995. Cases were newly-diagnosed and histologically confirmed non-small cell lung cancer patients from The University of Texas MD Anderson Cancer Center, and healthy controls without a history of cancer were from the Kelsey-Seybold Clinics. We limited the analysis to non-Hispanic whites, and after exclusion, 2,139 cases and 2,163 frequency-matched controls on age (±5 years), sex, and smoking status (current, former, never) were included in the final analysis. Exposures: Dietary intake was assessed with a validated food frequency questionnaire. Three dietary patterns (i.e., “Tex-Mex”, “fruits and vegetables”, and “American/Western”) were derived using exploratory factor analysis, and factor scores of derived dietary patterns were categorized into quintiles. Main Outcome and Measure: The association between dietary patterns and lung cancer risk. Results: The adjusted odds ratios comparing the highest to the lowest quintile of the factor scores of “Tex-Mex”, “fruits and vegetables”, and “American/Western” patterns were 0.45 (95% CI = 0.37-0.56), 0.68 (95% CI = 0.55-0.85), and 1.45 (95% CI = 1.18-1.78), respectively. The effects were stronger for squamous cell carcinoma and among former or current smokers for the “fruits and vegetables” pattern, and stronger for other non-small cell lung cancer and among never smokers for the “American/Western” pattern. Additionally, a variant (rs2808630) of the C-reactive protein gene significantly modified the associations of the “fruits and vegetables” (P for interaction = 0.03) and “American/Western” (P for interaction = 0.02) patterns with lung cancer risk. Conclusions and Relevance: Our study provides the first evidence that the “Tex-Mex” dietary pattern is associated with reduced lung cancer risk. Also, the “fruits and vegetables” and “American/Western” patterns affects lung cancer risk, and the effects are further modified by host genetic background. Our results support modifying diet to reduce lung cancer risk. Citation Format: Huakang Tu, John V. Heymach, Chi-Pang Weng, Yuanqing Ye, Jeanne A. Pierzynski, Jack A. Roth, Xifeng Wu. Different dietary patterns and reduction of lung cancer risk: a large case-control study in the U.S. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1749.

Bladder cancer is one of the most frequent cancers, which causes ∼150 000 death per year in the world. Both environmental and genetic factors are involved in the development of bladder cancer, and tobacco smoking is known to be the most important factor to increase the risk of bladder cancer; Recent genome-wide association studies (GWASs) in European populations have identified multiple genetic factors associated with bladder cancer. However, no GWAS has yet been conducted in Asian populations. Through genome wide association analysis and an independent replication study using a total of 1,131 bladder cancer cases and 12,558 non-cancer controls of Japanese populations, here we identified a SNP rs11543198 on chromosome 15q24 as a bladder cancer susceptibility locus. Rs1154319 was associated with bladder cancer risk with odds ratio (OR) of 1.41 and P value of 4.03 × 10-9. Subgroup analysis revealed rs11543198 to have a stronger effect in male smokers with OR of 1.66. Imputational analysis in this region suggested CYP1A2, which metabolizes tobacco-derived carcinogen, as a causative gene. We also confirmed the association of previously-reported loci, SLC14A1, APOBEC3A, PSCA, and MYC, with bladder cancer. Our finding implies the crucial roles of genetic variations on the chemically-associated development of bladder cancer. Citation Format: Koichi Matsuda, Atsushi Takahashi, Chizu Tanikawa, Michiaki Kubo, Yusuke Nakamrua. Genome wide association analysis identified 15q24 as a bladder cancer susceptibility locus. [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 4616. doi:10.1158/1538-7445.AM2015-4616

Genome-wide association studies (GWAS) of multiple myeloma (MM) in Northern Europeans have identified seven novel risk loci (2p23.3, 3p22.1, 3q26.2, 6p21.33, 7p15.3, 17p11.2, 22q13.1). We performed a multiethnic meta-analysis of these regions in 1,274 MM patients and 1,486 controls of European ancestry (EA) and 1,049 MM patients and 7,080 controls of African ancestry (AA), leveraging the differential linkage-disequilibrium of these populations in order to better localize the putative functional variants. We observed directionally consistent effects for all seven index SNPs in both populations, with four significantly associated (p Table 1.Most significant associations for each region in the multiethnic meta-analysis.Individuals of European AncestryIndividuals of African AncestryMulitethnic Metar2 with IndexcCHRSNPRAaFreqbORP-valueFreqbORP-valueORP-valueP-het2rs732075G0.591.222.0×10−30.621.122.0×10−21.162.6×10−40.280.09/0.283rs73069394A0.191.243.0×10−30.621.181.5×10−21.201.3×10−50.550.77/0.963rs12637184G0.761.136.0×10−20.921.192.7×10−11.151.0×10−20.640.94/1.007rs4487645C0.671.237.0×10−40.891.485.5×10−51.308.7×10−80.07-d17rs34562254A0.121.452.4×10−50.131.212.2×10−31.312.5×10−60.120.33/0.9022rs139400T0.491.224.0×10−40.531.172.1×10−31.191.2×10−60.630.63/0.96aRisk allelebFrequency of the risk allele in European and African ancestry studiescr2 metrics based on 1000 Genomes Project AFR/EUR populationsdIndex SNP Citation Format: Kristin A. Rand, Chi Song, Eric Dean, Daniel Serie, Karen Curtin, Dennis Hazelett, Amie E. Hwang, Xin Sheng, Alex Stram, David J. Van Den Berg, Carol Ann Huff, Leon Bernal-Mizrachi, Michael H. Tomasson, Sikander Ailawadhi, Anneclaire De Roos, Seema Singhal, Karen Pawlish, Edward Peters, Catherine Bock, David V. Conti, Graham Colditz, Todd Zimmerman, Scott Huntsman, John Graff, African Ancestry Prostate Cancer GWAS Consortium,African Ancestry Breast Cancer GWAS Consortium, Stephen J. Chanock, Michael Lieber, Jayesh Mehta, Eric A. Klein, Nalini Janakiraman, Richard K. Severson, Angela R. Brooks-Wilson, Vincent Rajkumar, Elizabeth E. Brown, Laurence Kolonel, Susan Slager, Brian E. Henderson, Graham G. Giles, John J. Spinelli, Brian Chiu, Kenneth C. Anderson, Jeffrey Zonder, Robert Z. Orlowski, Sagar Lonial, Nicola Camp, Celine Vachon, Elad Ziv, Dan O. Stram, Christopher A. Haiman, Wendy Cozen. Multiple myeloma susceptibility loci examined in African and European ancestry populations. [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 4629. doi:10.1158/1538-7445.AM2015-4629

To identify genetic variants that contribute to colorectal cancer (CRC) susceptibility, we performed a meta-analysis of two genome-wide association studies in 2,627 cases and 3,797 controls of Japanese ancestry and 1,894 cases and 4,703 controls of African ancestry, followed by a replication of genome-wide statistically significant associations (P < 5E-8) in 16,823 cases and 18,211 controls of European ancestry. This study revealed a new pan-ethnic CRC risk locus at 10q25 (rs12241008, intronic to VTI1A; P=1.5E-9), providing additional insight into the etiology of CRC and highlighting the value of association mapping in diverse populations. Citation Format: Hansong Wang, Terrilea Burnett, Suminori Kono, Christopher Haiman, Motoki Iwasaki, Lynne Wilkens, Lenora Loo, David Van Den Berg, Laurence Kolonel, Brian Henderson, Temitope Keku, Robert Sandler, Lisa Signorello, William Blot, Polly Newcomb, Mala Pande, Christopher Amos, Dee West, Stéphane Bézieau, Sonja Berndt, Brent Zanke, Li Hsu, Noralane Lindor, Robert Haile, John Hopper, Mark Jenkins, Steven Gallinger, Graham Casey, Stephanie Stenzel, Fredrick Schumacher, Ulrike Peters, Stephen Gruber, Shoichiro Tsugane, Dan Stram, Loic Le Marchand. Transethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-282. doi:10.1158/1538-7445.AM2014-LB-282

Pancreatic cancer is a highly lethal cancer with few well established risk factors. A genome wide association study (GWAS) of pancreatic cancer (PanScan) is being conducted within the framework of the NCI-sponsored Cohort Consortium and the Pancreatic Cancer Case-Control Consortium (PANC4). Susceptibility loci discovered to date in PanScan are non-coding variants that lie in intronic or intergenic regions, suggesting that the underlying signals may function through regulatory mechanisms that influence gene expression or splicing. Alternatively, these may lie in unannotated transcripts and directly affect their function. Epigenetic mechanisms, such as DNA methylation, can affect the regulation of gene expression and plays a critical role in the development of many human diseases including cancer. Powerful methods exist to analyze DNA methylation patterns in higher eukaryotes including methylated DNA immunoprecipitation (MeDIP), an affinity based approach to enrich methylated DNA regions from genomic DNA, which can be combined with microarrays to profile genomic DNA methylation patterns. We created a new semi-custom MeDIP-optimized array design based on our Human DNA Methylation 3×720K CpG Island Plus RefSeq Promoter array by tiling additional regions associated with pancreatic cancer that were identified in the PanScan study. To complement DNA methylation data a genome-wide transcriptome analysis was performed with RNA-sequencing (RNA-seq). Here we describe a comprehensive genome wide analysis of 8 pancreatic cancer cell lines to examine methylation patterns of Refseq promoters and annotated CpG islands as well as transcribed sequences. One of the susceptibility loci from PanScan is in the vicinity of the ABO gene on Chr9q34 where four SNPs (rs505922, rs495828, rs657152 and rs630014) are associated with a significantly increased risk of pancreatic cancer. As a pilot study, DNA methylation patterns and expressed sequences in this locus were investigated in cell lines derived from pancreatic tumors and normal pancreatic tissues. Our genome wide DNA methylation and RNA-seq analysis aims at establishing a comprehensive catalog of epigenetic patterns in pancreatic cell lines that could provide plausibility for the association signal in the ABO gene and other GWAS regions and thereby, initiate the characterization of the molecular phenotype of the susceptibility alleles for pancreatic cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 164.