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1. A transcriptome-wide association study identifies novel candidate susceptibility genes for pancreatic cancer.

Author

Hasan M., Zhang T., Xiao W., Albanes D., Andreotti G., Arslan A.A., Babic A., Bamlet W.R., Beane-Freeman L., Berndt S., Borgida A., Bracci P.M., Brais L., Brennan P., Bueno-De-Mesquita B., Buring J., Canzian F., Childs E.J., Cotterchio M., Du M., Duell E.J., Fuchs C., Gallinger S., Michael Gaziano J., Giles G.G., Giovannucci E., Goggins M., Goodman G.E., Goodman P.J., Haiman C., Hartge P., Helzlsouer K.J., Holly E.A., Klein E.A., Kogevinas M., Kurtz R.J., LeMarchand L., Malats N., Mannisto S., Milne R., Neale R.E., Ng K., Obazee O., Oberg A.L., Orlow I., Patel A.V., Peters U., Porta M., Rothman N., Scelo G., Sesso H.D., Severi G., Sieri S., Silverman D., Sund M., Tjonneland A., Thornquist M.D., Tobias G.S., Trichopoulou A., van Den Eeden S.K., Visvanathan K., Wactawski-Wende J., Wentzensen N., White E., Yu H., Yuan C., Zeleniuch-Jacquotte A., Hoover R., Brown K., Kooperberg C., Risch H.A., Jacobs E.J., Li D., Yu K., Shu X.-O., Chanock S.J., Wolpin B.M., Stolzenberg-Solomon R.Z., Chatterjee N., Klein A.P., Smith J.P., Kraft P., Shi J., Petersen G.M., Zheng W., Amundadottir L.T., Zhong J., Jermusyk A., Wu L., Hoskins J.W., Collins I., Mocci E., Zhang M., Song L., Chung C.C., Hasan M., Zhang T., Xiao W., Albanes D., Andreotti G., Arslan A.A., Babic A., Bamlet W.R., Beane-Freeman L., Berndt S., Borgida A., Bracci P.M., Brais L., Brennan P., Bueno-De-Mesquita B., Buring J., Canzian F., Childs E.J., Cotterchio M., Du M., Duell E.J., Fuchs C., Gallinger S., Michael Gaziano J., Giles G.G., Giovannucci E., Goggins M., Goodman G.E., Goodman P.J., Haiman C., Hartge P., Helzlsouer K.J., Holly E.A., Klein E.A., Kogevinas M., Kurtz R.J., LeMarchand L., Malats N., Mannisto S., Milne R., Neale R.E., Ng K., Obazee O., Oberg A.L., Orlow I., Patel A.V., Peters U., Porta M., Rothman N., Scelo G., Sesso H.D., Severi G., Sieri S., Silverman D., Sund M., Tjonneland A., Thornquist M.D., Tobias G.S., Trichopoulou A., van Den Eeden S.K., Visvanathan K., Wactawski-Wende J., Wentzensen N., White E., Yu H., Yuan C., Zeleniuch-Jacquotte A., Hoover R., Brown K., Kooperberg C., Risch H.A., Jacobs E.J., Li D., Yu K., Shu X.-O., Chanock S.J., Wolpin B.M., Stolzenberg-Solomon R.Z., Chatterjee N., Klein A.P., Smith J.P., Kraft P., Shi J., Petersen G.M., Zheng W., Amundadottir L.T., Zhong J., Jermusyk A., Wu L., Hoskins J.W., Collins I., Mocci E., Zhang M., Song L., and Chung C.C.

Abstract

Background: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Method(s): To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples). Result(s): We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate <.05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22:RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusion(s): By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.Copyright © 2020 Oxford University Press. All rights reserved.

Published
2021

2. A transcriptome-wide association study identifies novel candidate susceptibility genes for pancreatic cancer.

Author

Hasan M., Zhang T., Xiao W., Albanes D., Andreotti G., Arslan A.A., Babic A., Bamlet W.R., Beane-Freeman L., Berndt S., Borgida A., Bracci P.M., Brais L., Brennan P., Bueno-De-Mesquita B., Buring J., Canzian F., Childs E.J., Cotterchio M., Du M., Duell E.J., Fuchs C., Gallinger S., Michael Gaziano J., Giles G.G., Giovannucci E., Goggins M., Goodman G.E., Goodman P.J., Haiman C., Hartge P., Helzlsouer K.J., Holly E.A., Klein E.A., Kogevinas M., Kurtz R.J., LeMarchand L., Malats N., Mannisto S., Milne R., Neale R.E., Ng K., Obazee O., Oberg A.L., Orlow I., Patel A.V., Peters U., Porta M., Rothman N., Scelo G., Sesso H.D., Severi G., Sieri S., Silverman D., Sund M., Tjonneland A., Thornquist M.D., Tobias G.S., Trichopoulou A., van Den Eeden S.K., Visvanathan K., Wactawski-Wende J., Wentzensen N., White E., Yu H., Yuan C., Zeleniuch-Jacquotte A., Hoover R., Brown K., Kooperberg C., Risch H.A., Jacobs E.J., Li D., Yu K., Shu X.-O., Chanock S.J., Wolpin B.M., Stolzenberg-Solomon R.Z., Chatterjee N., Klein A.P., Smith J.P., Kraft P., Shi J., Petersen G.M., Zheng W., Amundadottir L.T., Zhong J., Jermusyk A., Wu L., Hoskins J.W., Collins I., Mocci E., Zhang M., Song L., Chung C.C., Hasan M., Zhang T., Xiao W., Albanes D., Andreotti G., Arslan A.A., Babic A., Bamlet W.R., Beane-Freeman L., Berndt S., Borgida A., Bracci P.M., Brais L., Brennan P., Bueno-De-Mesquita B., Buring J., Canzian F., Childs E.J., Cotterchio M., Du M., Duell E.J., Fuchs C., Gallinger S., Michael Gaziano J., Giles G.G., Giovannucci E., Goggins M., Goodman G.E., Goodman P.J., Haiman C., Hartge P., Helzlsouer K.J., Holly E.A., Klein E.A., Kogevinas M., Kurtz R.J., LeMarchand L., Malats N., Mannisto S., Milne R., Neale R.E., Ng K., Obazee O., Oberg A.L., Orlow I., Patel A.V., Peters U., Porta M., Rothman N., Scelo G., Sesso H.D., Severi G., Sieri S., Silverman D., Sund M., Tjonneland A., Thornquist M.D., Tobias G.S., Trichopoulou A., van Den Eeden S.K., Visvanathan K., Wactawski-Wende J., Wentzensen N., White E., Yu H., Yuan C., Zeleniuch-Jacquotte A., Hoover R., Brown K., Kooperberg C., Risch H.A., Jacobs E.J., Li D., Yu K., Shu X.-O., Chanock S.J., Wolpin B.M., Stolzenberg-Solomon R.Z., Chatterjee N., Klein A.P., Smith J.P., Kraft P., Shi J., Petersen G.M., Zheng W., Amundadottir L.T., Zhong J., Jermusyk A., Wu L., Hoskins J.W., Collins I., Mocci E., Zhang M., Song L., and Chung C.C.

Abstract

Background: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Method(s): To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples). Result(s): We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate <.05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22:RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusion(s): By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.Copyright © 2020 Oxford University Press. All rights reserved.

Published
2021

3. Composition, spatial characteristics, and prognostic significance of myeloid cell infiltration in pancreatic cancer

Author

Väyrynen, S. A. (Sara A.), Zhang, J. (Jinming), Yuan, C. (Chen), Väyrynen, J. P. (Juha P.), Dias Costa, A. (Andressa), Williams, H. (Hannah), Morales-Oyarvide, V. (Vicente), Lau, M. C. (Mai Chan), Rubinson, D. A. (Douglas A.), Dunne, R. F. (Richard F.), Kozak, M. M. (Margaret M.), Wang, W. (Wenjia), Agostini-Vulaj, D. (Diana), Drage, M. G. (Michael G.), Brais, L. (Lauren), Reilly, E. (Emma), Rahma, O. (Osama), Clancy, T. (Thomas), Wang, J. (Jiping), Linehan, D. C. (David C.), Aguirre, A. J. (Andrew J.), Fuchs, C. S. (Charles, S.), Coussens, L. M. (Lisa M.), Chang, D. T. (Daniel T.), Koong, A. C. (Albert C.), Hezel, A. F. (Aram F.), Ogino, S. (Shuji), Nowak, J. A. (Jonathan A.), Wolpin, B. M. (Brian M.), Väyrynen, S. A. (Sara A.), Zhang, J. (Jinming), Yuan, C. (Chen), Väyrynen, J. P. (Juha P.), Dias Costa, A. (Andressa), Williams, H. (Hannah), Morales-Oyarvide, V. (Vicente), Lau, M. C. (Mai Chan), Rubinson, D. A. (Douglas A.), Dunne, R. F. (Richard F.), Kozak, M. M. (Margaret M.), Wang, W. (Wenjia), Agostini-Vulaj, D. (Diana), Drage, M. G. (Michael G.), Brais, L. (Lauren), Reilly, E. (Emma), Rahma, O. (Osama), Clancy, T. (Thomas), Wang, J. (Jiping), Linehan, D. C. (David C.), Aguirre, A. J. (Andrew J.), Fuchs, C. S. (Charles, S.), Coussens, L. M. (Lisa M.), Chang, D. T. (Daniel T.), Koong, A. C. (Albert C.), Hezel, A. F. (Aram F.), Ogino, S. (Shuji), Nowak, J. A. (Jonathan A.), and Wolpin, B. M. (Brian M.)

Abstract

Purpose: Although abundant myeloid cell populations in the pancreatic ductal adenocarcinoma (PDAC) microenvironment have been postulated to suppress antitumor immunity, the composition of these populations, their spatial locations, and how they relate to patient outcomes are poorly understood. Experimental Design: To generate spatially resolved tumor and immune cell data at single-cell resolution, we developed two quantitative multiplex immunofluorescence assays to interrogate myeloid cells (CD15, CD14, ARG1, CD33, HLA-DR) and macrophages [CD68, CD163, CD86, IFN regulatory factor 5, MRC1 (CD206)] in the PDAC tumor microenvironment. Spatial point pattern analyses were conducted to assess the degree of colocalization between tumor cells and immune cells. Multivariable-adjusted Cox proportional hazards regression was used to assess associations with patient outcomes. Results: In a multi-institutional cohort of 305 primary PDAC resection specimens, myeloid cells were abundant, enriched within stromal regions, highly heterogeneous across tumors, and differed by somatic genotype. High densities of CD15⁺ARG1⁺ immunosuppressive granulocytic cells and M2-polarized macrophages were associated with worse patient survival. Moreover, beyond cell density, closer proximity of M2-polarized macrophages to tumor cells was strongly associated with disease-free survival, revealing the clinical significance and biologic importance of immune cell localization within tumor areas. Conclusions: A diverse set of myeloid cells are present within the PDAC tumor microenvironment and are distributed heterogeneously across patient tumors. Not only the densities but also the spatial locations of myeloid immune cells are associated with patient outcomes, highlighting the potential role of spatially resolved myeloid cell subtypes as quantitative biomarkers for PDAC prognosis and therapy.

Published
2021

4. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer

Author

Klein, AP, Wolpin, BM, Risch, HA, Stolzenberg-Solomon, RZ, Mocci, E, Zhang, M, Canzian, F, Childs, EJ, Hoskins, JW, Jermusyk, A, Zhong, J, Chen, F, Albanes, D, Andreotti, G, Arslan, AA, Babic, A, Bamlet, WR, Beane-Freeman, L, Berndt, SI, Blackford, A, Borges, M, Borgida, A, Bracci, PM, Brais, L, Brennan, P, Brenner, H, Bueno-de-Mesquita, B, Buring, J, Campa, D, Capurso, G, Cavestro, GM, Chaffee, KG, Chung, CC, Cleary, S, Cotterchio, M, Dijk, F, Duell, EJ, Foretova, L, Fuchs, C, Funel, N, Gallinger, S, Gaziano, JMM, Gazouli, M, Giles, GG, Giovannucci, E, Goggins, M, Goodman, GE, Goodman, PJ, Hackert, T, Haiman, C, Hartge, P, Hasan, M, Hegyi, P, Helzlsouer, KJ, Herman, J, Holcatova, I, Holly, EA, Hoover, R, Hung, RJ, Jacobs, EJ, Jamroziak, K, Janout, V, Kaaks, R, Khaw, K-T, Klein, EA, Kogevinas, M, Kooperberg, C, Kulke, MH, Kupcinskas, J, Kurtz, RJ, Laheru, D, Landi, S, Lawlor, RT, Lee, I-M, LeMarchand, L, Lu, L, Malats, N, Mambrini, A, Mannisto, S, Milne, RL, Mohelnikova-Duchonova, B, Neale, RE, Neoptolemos, JP, Oberg, AL, Olson, SH, Orlow, I, Pasquali, C, Patel, AV, Peters, U, Pezzilli, R, Porta, M, Real, FX, Rothman, N, Scelo, G, Sesso, HD, Severi, G, Shu, X-O, Silverman, D, Smith, JP, Soucek, P, Sund, M, Talar-Wojnarowska, R, Tavano, F, Thornquist, MD, Tobias, GS, Van Den Eeden, SK, Vashist, Y, Visvanathan, K, Vodicka, P, Wactawski-Wende, J, Wang, Z, Wentzensen, N, White, E, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Zheng, W, Kraft, P, Li, D, Chanock, S, Obazee, O, Petersen, GM, Amundadottir, LT, Klein, AP, Wolpin, BM, Risch, HA, Stolzenberg-Solomon, RZ, Mocci, E, Zhang, M, Canzian, F, Childs, EJ, Hoskins, JW, Jermusyk, A, Zhong, J, Chen, F, Albanes, D, Andreotti, G, Arslan, AA, Babic, A, Bamlet, WR, Beane-Freeman, L, Berndt, SI, Blackford, A, Borges, M, Borgida, A, Bracci, PM, Brais, L, Brennan, P, Brenner, H, Bueno-de-Mesquita, B, Buring, J, Campa, D, Capurso, G, Cavestro, GM, Chaffee, KG, Chung, CC, Cleary, S, Cotterchio, M, Dijk, F, Duell, EJ, Foretova, L, Fuchs, C, Funel, N, Gallinger, S, Gaziano, JMM, Gazouli, M, Giles, GG, Giovannucci, E, Goggins, M, Goodman, GE, Goodman, PJ, Hackert, T, Haiman, C, Hartge, P, Hasan, M, Hegyi, P, Helzlsouer, KJ, Herman, J, Holcatova, I, Holly, EA, Hoover, R, Hung, RJ, Jacobs, EJ, Jamroziak, K, Janout, V, Kaaks, R, Khaw, K-T, Klein, EA, Kogevinas, M, Kooperberg, C, Kulke, MH, Kupcinskas, J, Kurtz, RJ, Laheru, D, Landi, S, Lawlor, RT, Lee, I-M, LeMarchand, L, Lu, L, Malats, N, Mambrini, A, Mannisto, S, Milne, RL, Mohelnikova-Duchonova, B, Neale, RE, Neoptolemos, JP, Oberg, AL, Olson, SH, Orlow, I, Pasquali, C, Patel, AV, Peters, U, Pezzilli, R, Porta, M, Real, FX, Rothman, N, Scelo, G, Sesso, HD, Severi, G, Shu, X-O, Silverman, D, Smith, JP, Soucek, P, Sund, M, Talar-Wojnarowska, R, Tavano, F, Thornquist, MD, Tobias, GS, Van Den Eeden, SK, Vashist, Y, Visvanathan, K, Vodicka, P, Wactawski-Wende, J, Wang, Z, Wentzensen, N, White, E, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Zheng, W, Kraft, P, Li, D, Chanock, S, Obazee, O, Petersen, GM, and Amundadottir, LT

Abstract

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.

Published
2018

5. Plasma inflammatory cytokines and survival of pancreatic cancer patients.

Author

Babic, A., Schnure, N., Neupane, N. P., Zaman, M. M., Rifai, N., Welch, M. W., Brais, L. K., Rubinson, D. A., Morales-Oyarvide, V., Yuan, C., Zhang, S., Poole, E. M., Wolpin, B. M., Kulke, M. H., Barbie, D. A., Wong, K., Fuchs, C. S., Ng, K., Babic, A., Schnure, N., Neupane, N. P., Zaman, M. M., Rifai, N., Welch, M. W., Brais, L. K., Rubinson, D. A., Morales-Oyarvide, V., Yuan, C., Zhang, S., Poole, E. M., Wolpin, B. M., Kulke, M. H., Barbie, D. A., Wong, K., Fuchs, C. S., and Ng, K.

Abstract

OBJECTIVES: Inflammation and inflammatory conditions have been associated with pancreatic cancer risk and progression in a number of clinical, epidemiological, and animal model studies. The goal of the present study is to identify plasma markers of inflammation associated with survival of pancreatic cancer patients, and assess their joint contribution to patient outcome. METHODS: We measured circulating levels of four established markers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), soluble tumor necrosis factor receptor type II (sTNF-RII), and macrophage inhibitory cytokine-1 (MIC-1)) in 446 patients enrolled in an ongoing prospective clinic-based study. Hazard ratios (HRs) and 95% confidence intervals (CI) for death were estimated using multivariate Cox proportional hazards models. RESULTS: Overall mortality was significantly increased in patients in the top quartile of CRP (HR = 2.52, 95% CI: 1.82-3.49), IL-6 (HR = 2.78, 95% CI: 2.03-3.81), sTNF-RII (HR = 2.00, 95% CI: 1.46-2.72), and MIC-1 (HR = 2.53, 95% CI: 1.83-3.50), compared to those in the bottom quartile (P-trend CONCLUSION: Individual elevated plasma inflammatory cytokines are associated with significant and dramatic reductions in pancreatic cancer patient survival. Furthermore, we observed an independent combined effect of those cytokines on patient survival, suggesting that multiple inflammatory pathways are likely involved in PDAC progression. Future research efforts to target the inflammatory state using combination strategies in pancreatic cancer patients are warranted.

Published
2018

6. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

Author

Zhang, M, Wang, Z, Obazee, O, Jia, J, Childs, EJ, Hoskins, J, Figlioli, G, Mocci, E, Collins, I, Chung, CC, Hautman, C, Arslan, AA, Beane-Freeman, L, Bracci, PM, Buring, J, Duell, EJ, Gallinger, S, Giles, GG, Goodman, GE, Goodman, PJ, Kamineni, A, Kolonel, LN, Kulke, MH, Malats, N, Olson, SH, Sesso, HD, Visvanathan, K, White, E, Zheng, W, Abnet, CC, Albanes, D, Andreotti, G, Brais, L, Bueno-de-Mesquita, HB, Basso, D, Berndt, SI, Boutron-Ruault, M-C, Bijlsma, MF, Brenner, H, Burdette, L, Campa, D, Caporaso, NE, Capurso, G, Cavestro, GM, Cotterchio, M, Costello, E, Elena, J, Boggi, U, Gaziano, JM, Gazouli, M, Giovannucci, EL, Goggins, M, Gross, M, Haiman, CA, Hassan, M, Helzlsouer, KJ, Hu, N, Hunter, DJ, Iskierka-Jazdzewska, E, Jenab, M, Kaaks, R, Key, TJ, Khaw, K-T, Klein, EA, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, RC, Landi, MT, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, RL, Neale, RE, Oberg, AL, Panico, S, Patel, AV, Peeters, PHM, Peters, U, Pezzilli, R, Porta, M, Purdue, M, Ramon Quiros, J, Riboli, E, Rothman, N, Scarpa, A, Scelo, G, Shu, X-O, Silverman, DT, Soucek, P, Strobel, O, Sund, M, Malecka-Panas, E, Taylor, PR, Tavano, F, Travis, RC, Thornquist, M, Tjonneland, A, Tobias, GS, Trichopoulos, D, Vashist, Y, Vodicka, P, Wactawski-Wende, J, Wentzensen, N, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Kooperberg, C, Risch, HA, Jacobs, EJ, Li, D, Fuchs, C, Hoover, R, Hartge, P, Chanock, SJ, Petersen, GM, Stolzenberg-Solomon, RS, Wolpin, BM, Kraft, P, Klein, AP, Canzian, F, Amundadottir, LT, Zhang, M, Wang, Z, Obazee, O, Jia, J, Childs, EJ, Hoskins, J, Figlioli, G, Mocci, E, Collins, I, Chung, CC, Hautman, C, Arslan, AA, Beane-Freeman, L, Bracci, PM, Buring, J, Duell, EJ, Gallinger, S, Giles, GG, Goodman, GE, Goodman, PJ, Kamineni, A, Kolonel, LN, Kulke, MH, Malats, N, Olson, SH, Sesso, HD, Visvanathan, K, White, E, Zheng, W, Abnet, CC, Albanes, D, Andreotti, G, Brais, L, Bueno-de-Mesquita, HB, Basso, D, Berndt, SI, Boutron-Ruault, M-C, Bijlsma, MF, Brenner, H, Burdette, L, Campa, D, Caporaso, NE, Capurso, G, Cavestro, GM, Cotterchio, M, Costello, E, Elena, J, Boggi, U, Gaziano, JM, Gazouli, M, Giovannucci, EL, Goggins, M, Gross, M, Haiman, CA, Hassan, M, Helzlsouer, KJ, Hu, N, Hunter, DJ, Iskierka-Jazdzewska, E, Jenab, M, Kaaks, R, Key, TJ, Khaw, K-T, Klein, EA, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, RC, Landi, MT, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, RL, Neale, RE, Oberg, AL, Panico, S, Patel, AV, Peeters, PHM, Peters, U, Pezzilli, R, Porta, M, Purdue, M, Ramon Quiros, J, Riboli, E, Rothman, N, Scarpa, A, Scelo, G, Shu, X-O, Silverman, DT, Soucek, P, Strobel, O, Sund, M, Malecka-Panas, E, Taylor, PR, Tavano, F, Travis, RC, Thornquist, M, Tjonneland, A, Tobias, GS, Trichopoulos, D, Vashist, Y, Vodicka, P, Wactawski-Wende, J, Wentzensen, N, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Kooperberg, C, Risch, HA, Jacobs, EJ, Li, D, Fuchs, C, Hoover, R, Hartge, P, Chanock, SJ, Petersen, GM, Stolzenberg-Solomon, RS, Wolpin, BM, Kraft, P, Klein, AP, Canzian, F, and Amundadottir, LT

Abstract

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

Published
2016

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