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105. Supplementary Table S5 from Combinatorial Screening of Pancreatic Adenocarcinoma Reveals Sensitivity to Drug Combinations Including Bromodomain Inhibitor Plus Neddylation Inhibitor

Author

Langdon, Casey G., primary, Platt, James T., primary, Means, Robert E., primary, Iyidogan, Pinar, primary, Mamillapalli, Ramanaiah, primary, Klein, Michael, primary, Held, Matthew A., primary, Lee, Jong Woo, primary, Koo, Ja Seok, primary, Hatzis, Christos, primary, Hochster, Howard S., primary, and Stern, David F., primary

Published
2023
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107. Supplementary Figure S1 from Combinatorial Screening of Pancreatic Adenocarcinoma Reveals Sensitivity to Drug Combinations Including Bromodomain Inhibitor Plus Neddylation Inhibitor

Author

Langdon, Casey G., primary, Platt, James T., primary, Means, Robert E., primary, Iyidogan, Pinar, primary, Mamillapalli, Ramanaiah, primary, Klein, Michael, primary, Held, Matthew A., primary, Lee, Jong Woo, primary, Koo, Ja Seok, primary, Hatzis, Christos, primary, Hochster, Howard S., primary, and Stern, David F., primary

Published
2023
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108. Data from Combinatorial Screening of Pancreatic Adenocarcinoma Reveals Sensitivity to Drug Combinations Including Bromodomain Inhibitor Plus Neddylation Inhibitor

Author

Langdon, Casey G., primary, Platt, James T., primary, Means, Robert E., primary, Iyidogan, Pinar, primary, Mamillapalli, Ramanaiah, primary, Klein, Michael, primary, Held, Matthew A., primary, Lee, Jong Woo, primary, Koo, Ja Seok, primary, Hatzis, Christos, primary, Hochster, Howard S., primary, and Stern, David F., primary

Published
2023
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109. Supplementary figure and table legends from Combinatorial Screening of Pancreatic Adenocarcinoma Reveals Sensitivity to Drug Combinations Including Bromodomain Inhibitor Plus Neddylation Inhibitor

Author

Langdon, Casey G., primary, Platt, James T., primary, Means, Robert E., primary, Iyidogan, Pinar, primary, Mamillapalli, Ramanaiah, primary, Klein, Michael, primary, Held, Matthew A., primary, Lee, Jong Woo, primary, Koo, Ja Seok, primary, Hatzis, Christos, primary, Hochster, Howard S., primary, and Stern, David F., primary

Published
2023
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111. Supplementary Figure Legends 1-7, Table Legends 1-9 from Genotype-Selective Combination Therapies for Melanoma Identified by High-Throughput Drug Screening

Author

Held, Matthew A., primary, Langdon, Casey G., primary, Platt, James T., primary, Graham-Steed, Tisheeka, primary, Liu, Zongzhi, primary, Chakraborty, Ashok, primary, Bacchiocchi, Antonella, primary, Koo, Andrew, primary, Haskins, Jonathan W., primary, Bosenberg, Marcus W., primary, and Stern, David F., primary

Published
2023
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121. Supplementary Table S2 from PDK1 and SGK3 Contribute to the Growth of BRAF-Mutant Melanomas and Are Potential Therapeutic Targets

Author

Scortegagna, Marzia, primary, Lau, Eric, primary, Zhang, Tongwu, primary, Feng, Yongmei, primary, Sereduk, Chris, primary, Yin, Hongwei, primary, De, Surya K., primary, Meeth, Katrina, primary, Platt, James T., primary, Langdon, Casey G., primary, Halaban, Ruth, primary, Pellecchia, Maurizio, primary, Davies, Michael A., primary, Brown, Kevin, primary, Stern, David F., primary, Bosenberg, Marcus, primary, and Ronai, Ze'ev A., primary

Published
2023
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122. Data from PDK1 and SGK3 Contribute to the Growth of BRAF-Mutant Melanomas and Are Potential Therapeutic Targets

Author

Scortegagna, Marzia, primary, Lau, Eric, primary, Zhang, Tongwu, primary, Feng, Yongmei, primary, Sereduk, Chris, primary, Yin, Hongwei, primary, De, Surya K., primary, Meeth, Katrina, primary, Platt, James T., primary, Langdon, Casey G., primary, Halaban, Ruth, primary, Pellecchia, Maurizio, primary, Davies, Michael A., primary, Brown, Kevin, primary, Stern, David F., primary, Bosenberg, Marcus, primary, and Ronai, Ze'ev A., primary

Published
2023
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123. Supplementary Figures S1-S6 from PDK1 and SGK3 Contribute to the Growth of BRAF-Mutant Melanomas and Are Potential Therapeutic Targets

Author

Scortegagna, Marzia, primary, Lau, Eric, primary, Zhang, Tongwu, primary, Feng, Yongmei, primary, Sereduk, Chris, primary, Yin, Hongwei, primary, De, Surya K., primary, Meeth, Katrina, primary, Platt, James T., primary, Langdon, Casey G., primary, Halaban, Ruth, primary, Pellecchia, Maurizio, primary, Davies, Michael A., primary, Brown, Kevin, primary, Stern, David F., primary, Bosenberg, Marcus, primary, and Ronai, Ze'ev A., primary

Published
2023
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124. Supplementary Table and Figure Legends from PDK1 and SGK3 Contribute to the Growth of BRAF-Mutant Melanomas and Are Potential Therapeutic Targets

Author

Scortegagna, Marzia, primary, Lau, Eric, primary, Zhang, Tongwu, primary, Feng, Yongmei, primary, Sereduk, Chris, primary, Yin, Hongwei, primary, De, Surya K., primary, Meeth, Katrina, primary, Platt, James T., primary, Langdon, Casey G., primary, Halaban, Ruth, primary, Pellecchia, Maurizio, primary, Davies, Michael A., primary, Brown, Kevin, primary, Stern, David F., primary, Bosenberg, Marcus, primary, and Ronai, Ze'ev A., primary

Published
2023
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125. A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Author

Aglago, EK, Kim, A, Lin, Y, Qu, C, Evangelou, M, Ren, Y, Morrison, J, Albanes, D, Arndt, V, Barry, EL, Baurley, JW, Berndt, S, Bien, SA, Bishop, DT, Bouras, E, Brenner, H, Buchanan, DD, Budiarto, A, Carreras-Torres, R, Casey, G, Cenggoro, TW, Chen, AT, Chang-Claude, J, Chen, X, Conti, D, Devall, M, Diez-Obrero, V, Dimou, N, Drew, D, Figueiredo, JC, Gallinger, S, Giles, GG, Gruber, SB, Gsur, A, Gunter, MJ, Hampel, H, Harlid, S, Hidaka, A, Harrison, TA, Hoffmeister, M, Huyghe, JR, Jenkins, MA, Jordahl, K, Joshi, AD, Kawaguchi, ES, Keku, TO, Kundaje, A, Larsson, SC, Le Marchand, L, Lewinger, JP, Li, L, Lynch, BM, Mahesworo, B, Mandic, M, Obon-Santacana, M, Morento, V, Murphy, N, Men, H, Nassir, R, Newcomb, PA, Ogino, S, Ose, J, Pai, RK, Palmer, JR, Papadimitriou, N, Pardamean, B, Peoples, AR, Platz, EA, Potter, JD, Prentice, RL, Rennert, G, Ruiz-Narvaez, E, Sakoda, LC, Scacheri, PC, Schmit, SL, Schoen, RE, Shcherbina, A, Slattery, ML, Stern, MC, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Tian, Y, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, Vodicka, P, Wang, J, White, E, Wolk, A, Woods, MO, Wu, AH, Zemlianskaia, N, Hsu, L, Gauderman, WJ, Peters, U, Tsilidis, KK, Campbell, PT, Aglago, EK, Kim, A, Lin, Y, Qu, C, Evangelou, M, Ren, Y, Morrison, J, Albanes, D, Arndt, V, Barry, EL, Baurley, JW, Berndt, S, Bien, SA, Bishop, DT, Bouras, E, Brenner, H, Buchanan, DD, Budiarto, A, Carreras-Torres, R, Casey, G, Cenggoro, TW, Chen, AT, Chang-Claude, J, Chen, X, Conti, D, Devall, M, Diez-Obrero, V, Dimou, N, Drew, D, Figueiredo, JC, Gallinger, S, Giles, GG, Gruber, SB, Gsur, A, Gunter, MJ, Hampel, H, Harlid, S, Hidaka, A, Harrison, TA, Hoffmeister, M, Huyghe, JR, Jenkins, MA, Jordahl, K, Joshi, AD, Kawaguchi, ES, Keku, TO, Kundaje, A, Larsson, SC, Le Marchand, L, Lewinger, JP, Li, L, Lynch, BM, Mahesworo, B, Mandic, M, Obon-Santacana, M, Morento, V, Murphy, N, Men, H, Nassir, R, Newcomb, PA, Ogino, S, Ose, J, Pai, RK, Palmer, JR, Papadimitriou, N, Pardamean, B, Peoples, AR, Platz, EA, Potter, JD, Prentice, RL, Rennert, G, Ruiz-Narvaez, E, Sakoda, LC, Scacheri, PC, Schmit, SL, Schoen, RE, Shcherbina, A, Slattery, ML, Stern, MC, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Tian, Y, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, Vodicka, P, Wang, J, White, E, Wolk, A, Woods, MO, Wu, AH, Zemlianskaia, N, Hsu, L, Gauderman, WJ, Peters, U, Tsilidis, KK, and Campbell, PT

Abstract

UNLABELLED: Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.

Published
2023

126. Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry

Author

Darst, BF, Shen, J, Madduri, RK, Rodriguez, AA, Xiao, Y, Sheng, X, Saunders, EJ, Dadaev, T, Brook, MN, Hoffmann, TJ, Muir, K, Wan, P, Le Marchand, L, Wilkens, L, Wang, Y, Schleutker, J, MacInnis, RJ, Cybulski, C, Neal, DE, Nordestgaard, BG, Nielsen, SF, Batra, J, Clements, JA, Gronberg, H, Pashayan, N, Travis, RC, Park, JY, Albanes, D, Weinstein, S, Mucci, LA, Hunter, DJ, Penney, KL, Tangen, CM, Hamilton, RJ, Parent, M-E, Stanford, JL, Koutros, S, Wolk, A, Sorensen, KD, Blot, WJ, Yeboah, ED, Mensah, JE, Lu, Y-J, Schaid, DJ, Thibodeau, SN, West, CM, Maier, C, Kibel, AS, Cancel-Tassin, G, Menegaux, F, John, EM, Grindedal, EM, Khaw, K-T, Ingles, SA, Vega, A, Rosenstein, BS, Teixeira, MR, Kogevinas, M, Cannon-Albright, L, Huff, C, Multigner, L, Kaneva, R, Leach, RJ, Brenner, H, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Neuhausen, SL, Isaacs, WB, Nemesure, B, Hennis, AJ, Carpten, J, Pandha, H, De Ruyck, K, Xu, J, Razack, A, Teo, S-H, Newcomb, LF, Fowke, JH, Neslund-Dudas, C, Rybicki, BA, Gamulin, M, Usmani, N, Claessens, F, Gago-Dominguez, M, Castelao, JE, Townsend, PA, Crawford, DC, Petrovics, G, Casey, G, Roobol, MJ, Hu, JF, Berndt, SI, van den Eeden, SK, Easton, DF, Chanock, SJ, Cook, MB, Wiklund, F, Witte, JS, Eeles, RA, Kote-Jarai, Z, Watya, S, Gaziano, JM, Justice, AC, Conti, DV, Haiman, CA, Darst, BF, Shen, J, Madduri, RK, Rodriguez, AA, Xiao, Y, Sheng, X, Saunders, EJ, Dadaev, T, Brook, MN, Hoffmann, TJ, Muir, K, Wan, P, Le Marchand, L, Wilkens, L, Wang, Y, Schleutker, J, MacInnis, RJ, Cybulski, C, Neal, DE, Nordestgaard, BG, Nielsen, SF, Batra, J, Clements, JA, Gronberg, H, Pashayan, N, Travis, RC, Park, JY, Albanes, D, Weinstein, S, Mucci, LA, Hunter, DJ, Penney, KL, Tangen, CM, Hamilton, RJ, Parent, M-E, Stanford, JL, Koutros, S, Wolk, A, Sorensen, KD, Blot, WJ, Yeboah, ED, Mensah, JE, Lu, Y-J, Schaid, DJ, Thibodeau, SN, West, CM, Maier, C, Kibel, AS, Cancel-Tassin, G, Menegaux, F, John, EM, Grindedal, EM, Khaw, K-T, Ingles, SA, Vega, A, Rosenstein, BS, Teixeira, MR, Kogevinas, M, Cannon-Albright, L, Huff, C, Multigner, L, Kaneva, R, Leach, RJ, Brenner, H, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Neuhausen, SL, Isaacs, WB, Nemesure, B, Hennis, AJ, Carpten, J, Pandha, H, De Ruyck, K, Xu, J, Razack, A, Teo, S-H, Newcomb, LF, Fowke, JH, Neslund-Dudas, C, Rybicki, BA, Gamulin, M, Usmani, N, Claessens, F, Gago-Dominguez, M, Castelao, JE, Townsend, PA, Crawford, DC, Petrovics, G, Casey, G, Roobol, MJ, Hu, JF, Berndt, SI, van den Eeden, SK, Easton, DF, Chanock, SJ, Cook, MB, Wiklund, F, Witte, JS, Eeles, RA, Kote-Jarai, Z, Watya, S, Gaziano, JM, Justice, AC, Conti, DV, and Haiman, CA

Abstract

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.

Published
2023

127. Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response

Author

Carreras-Torres, R, Kim, AE, Lin, Y, Diez-Obrero, V, Bien, SA, Qu, C, Wang, J, Dimou, N, Aglago, EK, Albanes, D, Arndt, V, Baurley, JW, Berndt, SI, Bezieau, S, Bishop, DT, Bouras, E, Brenner, H, Budiarto, A, Campbell, PT, Casey, G, Chan, AT, Chang-Claude, J, Chen, X, Conti, D, Dampier, CH, Devall, MAM, Drew, DA, Figueiredo, JC, Gallinger, S, Giles, GG, Gruber, SB, Gsur, A, Gunter, MJ, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Jenkins, MA, Jordahl, KM, Kawaguchi, E, Keku, TO, Kundaje, A, Le Marchand, L, Lewinger, JP, Li, L, Mahesworo, B, Morrison, JL, Murphy, N, Nan, H, Nassir, R, Newcomb, PA, Obon-Santacana, M, Ogino, S, Ose, J, Pai, RK, Palmer, JR, Papadimitriou, N, Pardamean, B, Peoples, AR, Pharoah, PDP, Platz, EA, Rennert, G, Ruiz-Narvaez, E, Sakoda, LC, Scacheri, PC, Schmit, SL, Schoen, RE, Shcherbina, A, Slattery, ML, Stern, MC, Su, Y-R, Tangen, CM, Thomas, DC, Tian, Y, Tsilidis, KK, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, Vodicka, P, Cenggoro, TW, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Hsu, L, Peters, U, Moreno, V, Gauderman, WJ, Carreras-Torres, R, Kim, AE, Lin, Y, Diez-Obrero, V, Bien, SA, Qu, C, Wang, J, Dimou, N, Aglago, EK, Albanes, D, Arndt, V, Baurley, JW, Berndt, SI, Bezieau, S, Bishop, DT, Bouras, E, Brenner, H, Budiarto, A, Campbell, PT, Casey, G, Chan, AT, Chang-Claude, J, Chen, X, Conti, D, Dampier, CH, Devall, MAM, Drew, DA, Figueiredo, JC, Gallinger, S, Giles, GG, Gruber, SB, Gsur, A, Gunter, MJ, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Jenkins, MA, Jordahl, KM, Kawaguchi, E, Keku, TO, Kundaje, A, Le Marchand, L, Lewinger, JP, Li, L, Mahesworo, B, Morrison, JL, Murphy, N, Nan, H, Nassir, R, Newcomb, PA, Obon-Santacana, M, Ogino, S, Ose, J, Pai, RK, Palmer, JR, Papadimitriou, N, Pardamean, B, Peoples, AR, Pharoah, PDP, Platz, EA, Rennert, G, Ruiz-Narvaez, E, Sakoda, LC, Scacheri, PC, Schmit, SL, Schoen, RE, Shcherbina, A, Slattery, ML, Stern, MC, Su, Y-R, Tangen, CM, Thomas, DC, Tian, Y, Tsilidis, KK, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, Vodicka, P, Cenggoro, TW, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Hsu, L, Peters, U, Moreno, V, and Gauderman, WJ

Abstract

BACKGROUND: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer. METHODS: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia. RESULTS: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20-1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10-8) and 8q24.23 (rs7005722, P = 2.88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33). CONCLUSIONS: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response. IMPACT: These findings can guide potential prevention treatments.

Published
2023

128. Validation of a Genetic-Enhanced Risk Prediction Model for Colorectal Cancer in a Large Community-Based Cohort.

Author

Su, Y-R, Sakoda, LC, Jeon, J, Thomas, M, Lin, Y, Schneider, JL, Udaltsova, N, Lee, JK, Lansdorp-Vogelaar, I, Peterse, EFP, Zauber, AG, Zheng, J, Zheng, Y, Hauser, E, Baron, JA, Barry, EL, Bishop, DT, Brenner, H, Buchanan, DD, Burnett-Hartman, A, Campbell, PT, Casey, G, Castellví-Bel, S, Chan, AT, Chang-Claude, J, Figueiredo, JC, Gallinger, SJ, Giles, GG, Gruber, SB, Gsur, A, Gunter, MJ, Hampe, J, Hampel, H, Harrison, TA, Hoffmeister, M, Hua, X, Huyghe, JR, Jenkins, MA, Keku, TO, Marchand, LL, Li, L, Lindblom, A, Moreno, V, Newcomb, PA, Pharoah, PDP, Platz, EA, Potter, JD, Qu, C, Rennert, G, Schoen, RE, Slattery, ML, Song, M, van Duijnhoven, FJB, Van Guelpen, B, Vodicka, P, Wolk, A, Woods, MO, Wu, AH, Hayes, RB, Peters, U, Corley, DA, Hsu, L, Su, Y-R, Sakoda, LC, Jeon, J, Thomas, M, Lin, Y, Schneider, JL, Udaltsova, N, Lee, JK, Lansdorp-Vogelaar, I, Peterse, EFP, Zauber, AG, Zheng, J, Zheng, Y, Hauser, E, Baron, JA, Barry, EL, Bishop, DT, Brenner, H, Buchanan, DD, Burnett-Hartman, A, Campbell, PT, Casey, G, Castellví-Bel, S, Chan, AT, Chang-Claude, J, Figueiredo, JC, Gallinger, SJ, Giles, GG, Gruber, SB, Gsur, A, Gunter, MJ, Hampe, J, Hampel, H, Harrison, TA, Hoffmeister, M, Hua, X, Huyghe, JR, Jenkins, MA, Keku, TO, Marchand, LL, Li, L, Lindblom, A, Moreno, V, Newcomb, PA, Pharoah, PDP, Platz, EA, Potter, JD, Qu, C, Rennert, G, Schoen, RE, Slattery, ML, Song, M, van Duijnhoven, FJB, Van Guelpen, B, Vodicka, P, Wolk, A, Woods, MO, Wu, AH, Hayes, RB, Peters, U, Corley, DA, and Hsu, L

Abstract

BACKGROUND: Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance. METHODS: The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group). RESULTS: In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity. CONCLUSIONS: The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort. IMPACT: The proposed model has potential utility in risk-stratified colorectal cancer prevention.

Published
2023

129. Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

Author

Fernandez-Rozadilla, C, Timofeeva, M, Chen, Z, Law, P, Thomas, M, Bien, S, Diez-Obrero, V, Li, L, Fernandez-Tajes, J, Palles, C, Sherwood, K, Harris, S, Svinti, V, McDonnell, K, Farrington, S, Studd, J, Vaughan-Shaw, P, Shu, X-O, Long, J, Cai, Q, Guo, X, Lu, Y, Scacheri, P, Huyghe, J, Harrison, T, Shibata, D, Haiman, C, Devall, M, Schumacher, F, Melas, M, Rennert, G, Obon-Santacana, M, Martin-Sanchez, V, Moratalla-Navarro, F, Oh, JH, Kim, J, Jee, SH, Jung, KJ, Kweon, S-S, Shin, M-H, Shin, A, Ahn, Y-O, Kim, D-H, Oze, I, Wen, W, Matsuo, K, Matsuda, K, Tanikawa, C, Ren, Z, Gao, Y-T, Jia, W-H, Potter, J, Jenkins, M, Win, AK, Pai, R, Figueiredo, J, Haile, R, Gallinger, S, Woods, M, Newcomb, P, Cheadle, J, Kaplan, R, Maughan, T, Kerr, R, Kerr, D, Kirac, I, Boehm, J, Mecklin, L-P, Jousilahti, P, Knekt, P, Aaltonen, L, Rissanen, H, Pukkala, E, Eriksson, J, Cajuso, T, Hanninen, U, Kondelin, J, Palin, K, Tanskanen, T, Renkonen-Sinisalo, L, Zanke, B, Mannisto, S, Albanes, D, Weinstein, S, Ruiz-Narvaez, E, Palmer, J, Buchanan, D, Platz, E, Visvanathan, K, Ulrich, C, Siegel, E, Brezina, S, Gsur, A, Campbell, P, Chang-Claude, J, Hoffmeister, M, Brenner, H, Slattery, M, Tsilidis, K, Schulze, M, Gunter, M, Murphy, N, Castells, A, Castellvi-Bel, S, Moreira, L, Arndt, V, Shcherbina, A, Stern, M, Pardamean, B, Bishop, T, Giles, G, Southey, M, Idos, G, Abu-Ful, Z, Greenson, J, Shulman, K, Lejbkowicz, F, Offit, K, Su, Y-R, Steinfelder, R, Keku, T, van Guelpen, B, Hudson, T, Hampel, H, Pearlman, R, Berndt, S, Hayes, R, Martinez, ME, Thomas, S, Corley, D, Pharoah, P, Larsson, S, Yen, Y, Lenz, H-J, White, E, Doheny, K, Pugh, E, Shelford, T, Chan, A, Cruz-Correa, M, Lindblom, A, Joshi, A, Schafmayer, C, Kundaje, A, Nickerson, D, Schoen, R, Hampe, J, Stadler, Z, Vodicka, P, Vodickova, L, Vymetalkova, V, Papadopoulos, N, Edlund, C, Gauderman, W, Thomas, D, Toland, A, Markowitz, S, Kim, A, Gruber, S, van Duijnhoven, F, Feskens, E, Sakoda, L, Gago-Dominguez, M, Wolk, A, Naccarati, A, Pardini, B, FitzGerald, L, Lee, SC, Ogino, S, Kooperberg, C, Li, C, Lin, Y, Prentice, R, Qu, C, Bezieau, S, Tangen, C, Mardis, E, Yamaji, T, Sawada, N, Iwasaki, M, Le Marchand, L, Wu, A, McNeil, C, Coetzee, G, Hayward, C, Deary, I, Theodoratou, E, Reid, S, Walker, M, Ooi, LY, Moreno, V, Casey, G, Tomlinson, I, Zheng, W, Dunlop, M, Houlston, R, Peters, U, Fernandez-Rozadilla, C, Timofeeva, M, Chen, Z, Law, P, Thomas, M, Bien, S, Diez-Obrero, V, Li, L, Fernandez-Tajes, J, Palles, C, Sherwood, K, Harris, S, Svinti, V, McDonnell, K, Farrington, S, Studd, J, Vaughan-Shaw, P, Shu, X-O, Long, J, Cai, Q, Guo, X, Lu, Y, Scacheri, P, Huyghe, J, Harrison, T, Shibata, D, Haiman, C, Devall, M, Schumacher, F, Melas, M, Rennert, G, Obon-Santacana, M, Martin-Sanchez, V, Moratalla-Navarro, F, Oh, JH, Kim, J, Jee, SH, Jung, KJ, Kweon, S-S, Shin, M-H, Shin, A, Ahn, Y-O, Kim, D-H, Oze, I, Wen, W, Matsuo, K, Matsuda, K, Tanikawa, C, Ren, Z, Gao, Y-T, Jia, W-H, Potter, J, Jenkins, M, Win, AK, Pai, R, Figueiredo, J, Haile, R, Gallinger, S, Woods, M, Newcomb, P, Cheadle, J, Kaplan, R, Maughan, T, Kerr, R, Kerr, D, Kirac, I, Boehm, J, Mecklin, L-P, Jousilahti, P, Knekt, P, Aaltonen, L, Rissanen, H, Pukkala, E, Eriksson, J, Cajuso, T, Hanninen, U, Kondelin, J, Palin, K, Tanskanen, T, Renkonen-Sinisalo, L, Zanke, B, Mannisto, S, Albanes, D, Weinstein, S, Ruiz-Narvaez, E, Palmer, J, Buchanan, D, Platz, E, Visvanathan, K, Ulrich, C, Siegel, E, Brezina, S, Gsur, A, Campbell, P, Chang-Claude, J, Hoffmeister, M, Brenner, H, Slattery, M, Tsilidis, K, Schulze, M, Gunter, M, Murphy, N, Castells, A, Castellvi-Bel, S, Moreira, L, Arndt, V, Shcherbina, A, Stern, M, Pardamean, B, Bishop, T, Giles, G, Southey, M, Idos, G, Abu-Ful, Z, Greenson, J, Shulman, K, Lejbkowicz, F, Offit, K, Su, Y-R, Steinfelder, R, Keku, T, van Guelpen, B, Hudson, T, Hampel, H, Pearlman, R, Berndt, S, Hayes, R, Martinez, ME, Thomas, S, Corley, D, Pharoah, P, Larsson, S, Yen, Y, Lenz, H-J, White, E, Doheny, K, Pugh, E, Shelford, T, Chan, A, Cruz-Correa, M, Lindblom, A, Joshi, A, Schafmayer, C, Kundaje, A, Nickerson, D, Schoen, R, Hampe, J, Stadler, Z, Vodicka, P, Vodickova, L, Vymetalkova, V, Papadopoulos, N, Edlund, C, Gauderman, W, Thomas, D, Toland, A, Markowitz, S, Kim, A, Gruber, S, van Duijnhoven, F, Feskens, E, Sakoda, L, Gago-Dominguez, M, Wolk, A, Naccarati, A, Pardini, B, FitzGerald, L, Lee, SC, Ogino, S, Kooperberg, C, Li, C, Lin, Y, Prentice, R, Qu, C, Bezieau, S, Tangen, C, Mardis, E, Yamaji, T, Sawada, N, Iwasaki, M, Le Marchand, L, Wu, A, McNeil, C, Coetzee, G, Hayward, C, Deary, I, Theodoratou, E, Reid, S, Walker, M, Ooi, LY, Moreno, V, Casey, G, Tomlinson, I, Zheng, W, Dunlop, M, Houlston, R, and Peters, U

Abstract

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

Published
2023

130. Probing the diabetes and colorectal cancer relationship using gene - environment interaction analyses

Author

Dimou, N, Kim, AE, Flanagan, O, Murphy, N, Diez-Obrero, V, Shcherbina, A, Aglago, EK, Bouras, E, Campbell, PT, Casey, G, Gallinger, S, Gruber, SB, Jenkins, MA, Lin, Y, Moreno, V, Ruiz-Narvaez, E, Stern, MC, Tian, Y, Tsilidis, KK, Arndt, V, Barry, EL, Baurley, JW, Berndt, SI, Bezieau, S, Bien, SA, Bishop, DT, Brenner, H, Budiarto, A, Carreras-Torres, R, Cenggoro, TW, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, X, Conti, DV, Dampier, CH, Devall, M, Drew, DA, Figueiredo, JC, Giles, GG, Gsur, A, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Jordahl, K, Kawaguchi, E, Keku, TO, Larsson, SC, Le Marchand, L, Lewinger, JP, Li, L, Mahesworo, B, Morrison, J, Newcomb, PA, Newton, CC, Obon-Santacana, M, Ose, J, Pai, RK, Palmer, JR, Papadimitriou, N, Pardamean, B, Peoples, AR, Pharoah, PDP, Platz, EA, Potter, JD, Rennert, G, Scacheri, PC, Schoen, RE, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Ulrich, CM, Um, CY, van Duijnhoven, FJB, Visvanathan, K, Vodicka, P, Vodickova, L, White, E, Wolk, A, Woods, MO, Qu, C, Kundaje, A, Hsu, L, Gauderman, WJ, Gunter, MJ, Peters, U, Dimou, N, Kim, AE, Flanagan, O, Murphy, N, Diez-Obrero, V, Shcherbina, A, Aglago, EK, Bouras, E, Campbell, PT, Casey, G, Gallinger, S, Gruber, SB, Jenkins, MA, Lin, Y, Moreno, V, Ruiz-Narvaez, E, Stern, MC, Tian, Y, Tsilidis, KK, Arndt, V, Barry, EL, Baurley, JW, Berndt, SI, Bezieau, S, Bien, SA, Bishop, DT, Brenner, H, Budiarto, A, Carreras-Torres, R, Cenggoro, TW, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, X, Conti, DV, Dampier, CH, Devall, M, Drew, DA, Figueiredo, JC, Giles, GG, Gsur, A, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Jordahl, K, Kawaguchi, E, Keku, TO, Larsson, SC, Le Marchand, L, Lewinger, JP, Li, L, Mahesworo, B, Morrison, J, Newcomb, PA, Newton, CC, Obon-Santacana, M, Ose, J, Pai, RK, Palmer, JR, Papadimitriou, N, Pardamean, B, Peoples, AR, Pharoah, PDP, Platz, EA, Potter, JD, Rennert, G, Scacheri, PC, Schoen, RE, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Ulrich, CM, Um, CY, van Duijnhoven, FJB, Visvanathan, K, Vodicka, P, Vodickova, L, White, E, Wolk, A, Woods, MO, Qu, C, Kundaje, A, Hsu, L, Gauderman, WJ, Gunter, MJ, and Peters, U

Abstract

BACKGROUND: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis. METHODS: We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test). RESULTS: Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 - ORAA: 1.62, 95% CI: 1.34-1.96; ORAG: 1.41, 95% CI: 1.30-1.54; ORGG: 1.22, 95% CI: 1.13-1.31; p-value3-d.f.: 5.46 × 10-11) and 13q14.13 (rs9526201, LRCH1 - ORGG: 2.11, 95% CI: 1.56-2.83; ORGA: 1.52, 95% CI: 1.38-1.68; ORAA: 1.13, 95% CI: 1.06-1.21; p-value2-d.f.: 7.84 × 10-09). DISCUSSION: These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.

Published
2023

131. Genome-wide interaction analysis of folate for colorectal cancer risk

Author

Bouras, E, Kim, AE, Lin, Y, Morrison, J, Du, M, Albanes, D, Barry, EL, Baurley, JW, Berndt, SI, Bien, SA, Bishop, TD, Brenner, H, Budiarto, A, Burnett-Hartman, A, Campbell, PT, Carreras-Torres, R, Casey, G, Cenggoro, TW, Chan, AT, Chang-Claude, J, Conti, DV, Cotterchio, M, Devall, M, Diez-Obrero, V, Dimou, N, Drew, DA, Figueiredo, JC, Giles, GG, Gruber, SB, Gunter, MJ, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Joshi, AD, Kawaguchi, ES, Keku, TO, Kundaje, A, Le Marchand, L, Lewinger, JP, Li, L, Lynch, BM, Mahesworo, B, Mannisto, S, Moreno, V, Murphy, N, Newcomb, PA, Obon-Santacana, M, Ose, J, Palmer, JR, Papadimitriou, N, Pardamean, B, Pellatt, AJ, Peoples, AR, Platz, EA, Potter, JD, Qi, L, Qu, C, Rennert, G, Ruiz-Narvaez, E, Sakoda, LC, Schmit, SL, Shcherbina, A, Stern, MC, Su, Y-R, Tangen, CM, Thomas, DC, Tian, Y, Um, CY, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, Wang, J, White, E, Wolk, A, Woods, MO, Ulrich, CM, Hsu, L, Gauderman, WJ, Peters, U, Tsilidis, KK, Bouras, E, Kim, AE, Lin, Y, Morrison, J, Du, M, Albanes, D, Barry, EL, Baurley, JW, Berndt, SI, Bien, SA, Bishop, TD, Brenner, H, Budiarto, A, Burnett-Hartman, A, Campbell, PT, Carreras-Torres, R, Casey, G, Cenggoro, TW, Chan, AT, Chang-Claude, J, Conti, DV, Cotterchio, M, Devall, M, Diez-Obrero, V, Dimou, N, Drew, DA, Figueiredo, JC, Giles, GG, Gruber, SB, Gunter, MJ, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Joshi, AD, Kawaguchi, ES, Keku, TO, Kundaje, A, Le Marchand, L, Lewinger, JP, Li, L, Lynch, BM, Mahesworo, B, Mannisto, S, Moreno, V, Murphy, N, Newcomb, PA, Obon-Santacana, M, Ose, J, Palmer, JR, Papadimitriou, N, Pardamean, B, Pellatt, AJ, Peoples, AR, Platz, EA, Potter, JD, Qi, L, Qu, C, Rennert, G, Ruiz-Narvaez, E, Sakoda, LC, Schmit, SL, Shcherbina, A, Stern, MC, Su, Y-R, Tangen, CM, Thomas, DC, Tian, Y, Um, CY, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, Wang, J, White, E, Wolk, A, Woods, MO, Ulrich, CM, Hsu, L, Gauderman, WJ, Peters, U, and Tsilidis, KK

Abstract

BACKGROUND: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC. OBJECTIVES: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. METHODS: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). RESULTS: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. CONCLUSIONS: Variation in 3p25.2 locus may modify the assoc

Published
2023

132. Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.

Author

Wang, A, Shen, J, Rodriguez, AA, Saunders, EJ, Chen, F, Janivara, R, Darst, BF, Sheng, X, Xu, Y, Chou, AJ, Benlloch, S, Dadaev, T, Brook, MN, Plym, A, Sahimi, A, Hoffman, TJ, Takahashi, A, Matsuda, K, Momozawa, Y, Fujita, M, Laisk, T, Figuerêdo, J, Muir, K, Ito, S, Liu, X, Biobank Japan Project, Uchio, Y, Kubo, M, Kamatani, Y, Lophatananon, A, Wan, P, Andrews, C, Lori, A, Choudhury, PP, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokolorczyk, D, Lubinski, J, Rentsch, CT, Cho, K, Mcmahon, BH, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Røder, A, Stroomberg, HV, Batra, J, Chambers, S, Horvath, L, Clements, JA, Tilly, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordstrom, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, S, Cook, MB, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-É, Stanford, JL, Ostrander, EA, Koutros, S, Beane Freeman, LE, Stampfer, M, Wolk, A, Håkansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sørensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, Lu, Y-J, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gómez-Caamaño, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandão, A, Watya, S, Lubwama, A, Bensen, JT, Butler, EN, Mohler, JL, Taylor, JA, Kogevinas, M, Dierssen-Sotos, T, Castaño-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Pilie, P, Yu, Y, Bohlender, RJ, Gu, J, Strom, SS, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Brenner, H, Chen, X, Holleczek, B, Schöttker, B, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, CM, Rybicki, BA, Gamulin, M, Lessel, D, Kulis, T, Usmani, N, Abraham, A, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, J, Petrovics, G, Casey, G, Wang, Y, Tettey, Y, Lachance, J, Tang, W, Biritwum, RB, Adjei, AA, Tay, E, Truelove, A, Niwa, S, Yamoah, K, Govindasami, K, Chokkalingam, AP, Keaton, JM, Hellwege, JN, Clark, PE, Jalloh, M, Gueye, SM, Niang, L, Ogunbiyi, O, Shittu, O, Amodu, O, Adebiyi, AO, Aisuodionoe-Shadrach, OI, Ajibola, HO, Jamda, MA, Oluwole, OP, Nwegbu, M, Adusei, B, Mante, S, Darkwa-Abrahams, A, Diop, H, Gundell, SM, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Kachuri, L, Varma, R, McKean-Cowdin, R, Torres, M, Preuss, MH, Loos, RJF, Zawistowski, M, Zöllner, S, Lu, Z, Van Den Eeden, SK, Easton, DF, Ambs, S, Edwards, TL, Mägi, R, Rebbeck, TR, Fritsche, L, Chanock, SJ, Berndt, SI, Wiklund, F, Nakagawa, H, Witte, JS, Gaziano, JM, Justice, AC, Mancuso, N, Terao, C, Eeles, RA, Kote-Jarai, Z, Madduri, RK, Conti, DV, Haiman, CA, Wang, A, Shen, J, Rodriguez, AA, Saunders, EJ, Chen, F, Janivara, R, Darst, BF, Sheng, X, Xu, Y, Chou, AJ, Benlloch, S, Dadaev, T, Brook, MN, Plym, A, Sahimi, A, Hoffman, TJ, Takahashi, A, Matsuda, K, Momozawa, Y, Fujita, M, Laisk, T, Figuerêdo, J, Muir, K, Ito, S, Liu, X, Biobank Japan Project, Uchio, Y, Kubo, M, Kamatani, Y, Lophatananon, A, Wan, P, Andrews, C, Lori, A, Choudhury, PP, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokolorczyk, D, Lubinski, J, Rentsch, CT, Cho, K, Mcmahon, BH, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Røder, A, Stroomberg, HV, Batra, J, Chambers, S, Horvath, L, Clements, JA, Tilly, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordstrom, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, S, Cook, MB, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-É, Stanford, JL, Ostrander, EA, Koutros, S, Beane Freeman, LE, Stampfer, M, Wolk, A, Håkansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sørensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, Lu, Y-J, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gómez-Caamaño, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandão, A, Watya, S, Lubwama, A, Bensen, JT, Butler, EN, Mohler, JL, Taylor, JA, Kogevinas, M, Dierssen-Sotos, T, Castaño-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Pilie, P, Yu, Y, Bohlender, RJ, Gu, J, Strom, SS, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Brenner, H, Chen, X, Holleczek, B, Schöttker, B, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, CM, Rybicki, BA, Gamulin, M, Lessel, D, Kulis, T, Usmani, N, Abraham, A, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, J, Petrovics, G, Casey, G, Wang, Y, Tettey, Y, Lachance, J, Tang, W, Biritwum, RB, Adjei, AA, Tay, E, Truelove, A, Niwa, S, Yamoah, K, Govindasami, K, Chokkalingam, AP, Keaton, JM, Hellwege, JN, Clark, PE, Jalloh, M, Gueye, SM, Niang, L, Ogunbiyi, O, Shittu, O, Amodu, O, Adebiyi, AO, Aisuodionoe-Shadrach, OI, Ajibola, HO, Jamda, MA, Oluwole, OP, Nwegbu, M, Adusei, B, Mante, S, Darkwa-Abrahams, A, Diop, H, Gundell, SM, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Kachuri, L, Varma, R, McKean-Cowdin, R, Torres, M, Preuss, MH, Loos, RJF, Zawistowski, M, Zöllner, S, Lu, Z, Van Den Eeden, SK, Easton, DF, Ambs, S, Edwards, TL, Mägi, R, Rebbeck, TR, Fritsche, L, Chanock, SJ, Berndt, SI, Wiklund, F, Nakagawa, H, Witte, JS, Gaziano, JM, Justice, AC, Mancuso, N, Terao, C, Eeles, RA, Kote-Jarai, Z, Madduri, RK, Conti, DV, and Haiman, CA

Abstract

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.

Published
2023

138. Supplementary Figures 1-7 from Genotype-Selective Combination Therapies for Melanoma Identified by High-Throughput Drug Screening

Author

David F. Stern, Marcus W. Bosenberg, Jonathan W. Haskins, Andrew Koo, Antonella Bacchiocchi, Ashok Chakraborty, Zongzhi Liu, Tisheeka Graham-Steed, James T. Platt, Casey G. Langdon, and Matthew A. Held

Abstract

PDF file - 1.1MB, Figure S1. Single agent concentration-effect curves, related to Figure 1; Figure S2. Drug class and concentration choices for combinatorial drug screening, related to Figure 2; Figure S3, Mutant BRAF and mutant RAS selective drug pairs, related to Figure 3; Figure S4. Analysis of drug combinations by target class, related to Figure 4D; Figure S5. Sensitization of mutant BRAF lines with lapatinib and MK-2206, related to Figure 5; Figure S6. Immunoblot analyses of vemurafenib-resistant lines after drug treatments, related to Figure 5; Figure S7. Signaling and biological effects of simvastatin and flavopiridol in vitro and in vivo, related to Figure 6

Published
2023

139. Data from Combinatorial Screening of Pancreatic Adenocarcinoma Reveals Sensitivity to Drug Combinations Including Bromodomain Inhibitor Plus Neddylation Inhibitor

Author

David F. Stern, Howard S. Hochster, Christos Hatzis, Ja Seok Koo, Jong Woo Lee, Matthew A. Held, Michael Klein, Ramanaiah Mamillapalli, Pinar Iyidogan, Robert E. Means, James T. Platt, and Casey G. Langdon

Abstract

Pancreatic adenocarcinoma (PDAC) is the fourth most common cause of cancer-related death in the United States. PDAC is difficult to manage effectively, with a five-year survival rate of only 5%. PDAC is largely driven by activating KRAS mutations, and as such, cannot be directly targeted with therapeutic agents that affect the activated protein. Instead, inhibition of downstream signaling and other targets will be necessary to effectively manage PDAC. Here, we describe a tiered single-agent and combination compound screen to identify targeted agents that impair growth of a panel of PDAC cell lines. Several of the combinations identified from the screen were further validated for efficacy and mechanism. Combination of the bromodomain inhibitor JQ1 and the neddylation inhibitor MLN4294 altered the production of reactive oxygen species in PDAC cells, ultimately leading to defects in the DNA damage response. Dual bromodomain/neddylation blockade inhibited in vivo growth of PDAC cell line xenografts. Overall, this work revealed novel combinatorial regimens, including JQ1 plus MLN4294, which show promise for the treatment of RAS-driven PDAC. Mol Cancer Ther; 16(6); 1041–53. ©2017 AACR.

Published
2023

140. Supplementary Tables 1-7, 9 from Genotype-Selective Combination Therapies for Melanoma Identified by High-Throughput Drug Screening

Author

David F. Stern, Marcus W. Bosenberg, Jonathan W. Haskins, Andrew Koo, Antonella Bacchiocchi, Ashok Chakraborty, Zongzhi Liu, Tisheeka Graham-Steed, James T. Platt, Casey G. Langdon, and Matthew A. Held

Abstract

PDF file - 169K, Table S1. Agents used in single-agent HTS; Table S2. Melanoma cell lines and mutation status; Table S3. Concentrations required to inhibit 50% of cell growth (GI50) in single-agent screens; Table S4. Single agents with significant genotype-selective efficacy; Table S5. Agents and concentrations chosen for cHTS; Table S6. Partial list of drug pairs showing genotype selectivity; Table S7. Genotype-selective combinations with simvastatin; Table S9. Combination index (CI) values for select drug combinations

Published
2023

145. Data from Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer

Author

Christos Hatzis, David F. Stern, Lajos Pusztai, Bilge Aktas, Anton Safonov, Gauri A. Patwardhan, James T. Platt, Matthew A. Held, Casey G. Langdon, and Vikram B. Wali

Abstract

Triple-negative breast cancer (TNBC) remains an aggressive disease without effective targeted therapies. In this study, we addressed this challenge by testing 128 FDA-approved or investigational drugs as either single agents or in 768 pairwise drug combinations in TNBC cell lines to identify synergistic combinations tractable to clinical translation. Medium-throughput results were scrutinized and extensively analyzed for sensitivity patterns, synergy, anticancer activity, and were validated in low-throughput experiments. Principal component analysis revealed that a fraction of all upregulated or downregulated genes of a particular targeted pathway could partly explain cell sensitivity toward agents targeting that pathway. Combination therapies deemed immediately tractable to translation included ABT-263/crizotinib, ABT-263/paclitaxel, paclitaxel/JQ1, ABT-263/XL-184, and paclitaxel/nutlin-3, all of which exhibited synergistic antiproliferative and apoptotic activity in multiple TNBC backgrounds. Mechanistic investigations of the ABT-263/crizotinib combination offering a potentially rapid path to clinic demonstrated RTK blockade, inhibition of mitogenic signaling, and proapoptotic signal induction in basal and mesenchymal stem–like TNBC. Our findings provide preclinical proof of concept for several combination treatments of TNBC, which offer near-term prospects for clinical translation. Cancer Res; 77(2); 566–78. ©2016 AACR.

Published
2023

150. Supplementary Figures 1 through 9 from Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer

Author

Christos Hatzis, David F. Stern, Lajos Pusztai, Bilge Aktas, Anton Safonov, Gauri A. Patwardhan, James T. Platt, Matthew A. Held, Casey G. Langdon, and Vikram B. Wali

Abstract

Supplementary Figure 1. Effect of panel A drugs on TNBC cell growth in 96-well format. Supplementary Figure 2. Effect of panel B drugs alone and in combination with panel A drugs on TNBC cell growth. Supplementary Figure 3. Summary of growth inhibition by pairwise drug combinations. Supplementary Figure 4. Hierarchical clustering of cell lines based on response to drug treatments and based on expression of drug targets. Supplementary Figure 5. Principal component analysis to associate patterns of target expression with patterns of drug response. Supplementary Figure 6. Assessment of superadditivity of drug combinations. Supplementary Figure 7. A: Comparison of crizotinib versus XL-184 dose response curves when combined with ABT-263 in the six TNBC cell lines. Supplementary Figure 8. ABT-263 and crizotinib induce apoptosis in TNBC cells. Supplementary Figure 9. Expression of MET and AXL in a cohort of 59 TNBC samples from the TCGA breast cancer cohort relative to the median expression of each gene in all breast cancer samples in TCGA.

Published
2023

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