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1. Estimates of benefits and harms of prophylactic use of aspirin in the general population

Author

Cuzick, J, Thorat, MA, Bosetti, C, Brown, PH, Burn, J, Cook, NR, Ford, LG, Jacobs, EJ, Jankowski, JA, La Vecchia, C, Law, M, Meyskens, F, Rothwell, PM, Senn, HJ, and Umar, A

Subjects
Patient Safety, Cancer, Cardiovascular, Clinical Research, Prevention, Prevention of disease and conditions, and promotion of well-being, 3.3 Nutrition and chemoprevention, 3.1 Primary prevention interventions to modify behaviours or promote wellbeing, Good Health and Well Being, Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Female, Gastrointestinal Hemorrhage, Humans, Male, Myocardial Infarction, Neoplasms, Stroke, aspirin, prevention, benefit-harm, cancer, cardiovascular disease, gastrointestinal bleeding, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

BackgroundAccumulating evidence supports an effect of aspirin in reducing overall cancer incidence and mortality in the general population. We reviewed current data and assessed the benefits and harms of prophylactic use of aspirin in the general population.MethodsThe effect of aspirin for site-specific cancer incidence and mortality, cardiovascular events was collated from the most recent systematic reviews. Studies identified through systematic Medline search provided data regarding harmful effects of aspirin and baseline rates of harms like gastrointestinal bleeding and peptic ulcer.ResultsThe effects of aspirin on cancer are not apparent until at least 3 years after the start of use, and some benefits are sustained for several years after cessation in long-term users. No differences between low and standard doses of aspirin are observed, but there were no direct comparisons. Higher doses do not appear to confer additional benefit but increase toxicities. Excess bleeding is the most important harm associated with aspirin use, and its risk and fatality rate increases with age. For average-risk individuals aged 50-65 years taking aspirin for 10 years, there would be a relative reduction of between 7% (women) and 9% (men) in the number of cancer, myocardial infarction or stroke events over a 15-year period and an overall 4% relative reduction in all deaths over a 20-year period.ConclusionsProphylactic aspirin use for a minimum of 5 years at doses between 75 and 325 mg/day appears to have favourable benefit-harm profile; longer use is likely to have greater benefits. Further research is needed to determine the optimum dose and duration of use, to identify individuals at increased risk of bleeding, and to test effectiveness of Helicobacter pylori screening-eradication before starting aspirin prophylaxis.

Published
2015

2. Hormone replacement therapy and colon cancer among members of a health maintenance organization.

Author

Jacobs, EJ, White, E, Weiss, NS, Heckbert, SR, LaCroix, A, and Barlow, WE

Subjects
Humans, Adenocarcinoma, Colonic Neoplasms, Estrogens, Conjugated (USP), Estrogen Replacement Therapy, Confidence Intervals, Odds Ratio, Risk Factors, Aged, Middle Aged, Health Maintenance Organizations, Washington, Female, Estrogen, Clinical Research, Digestive Diseases, Colo-Rectal Cancer, Cancer, Prevention, Patient Safety, Statistics, Public Health and Health Services, Epidemiology
Abstract

We investigated the association between hormone replacement therapy (HRT), primarily conjugated estrogens with or without medroxyprogesterone acetate, and colon cancer risk in a nested case-control study among women ages 55-79 years enrolled in Group Health Cooperative, a health maintenance organization in Washington state. Cases were diagnosed between 1984 and 1993. We selected controls randomly from enrollment files. HRT use was ascertained from a computerized database containing virtually all prescriptions dispensed since 1977. Among subjects with at least 5 years of pharmacy database information before reference date (1 year before diagnosis date), there were 341 cases of incident colon cancer and 1,679 controls. Estrogen use during the 5 years before reference date was not associated with risk of colon cancer [odds ratio (OR) = 0.85 and 95% confidence interval (CI) = 0.57-1.27 for 1-749 estrogen tablets; OR = 0.97 and 95% CI = 0.68-1.40 for > or =750 estrogen tablets]. An analysis including only women with at least 10 years of pharmacy database coverage found no association with use during the 10 years before reference date [OR = 1.07 (95% CI = 0.61-1.86) for 1-749 estrogen tablets; OR = 1.11 (95% CI = 0.69-1.80) for 750 or more estrogen tablets]. These results do not support the hypothesis that recent HRT use substantially reduces risk of colon cancer.

Published
1999

3. Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3

Author

Mocci, E, Kundu, P, Wheeler, W, Arslan, AA, Beane-Freeman, LE, Bracci, PM, Brennan, P, Canzian, F, Du, M, Gallinger, S, Giles, GG, Goodman, PJ, Kooperberg, C, Le Marchand, L, Neale, RE, Shu, X-O, Visvanathan, K, White, E, Zheng, W, Albanes, D, Andreotti, G, Babic, A, Bamlet, WR, Berndt, S, Blackford, AL, Bueno-de-Mesquita, B, Buring, JE, Campa, D, Chanock, SJ, Childs, EJ, Duell, EJ, Fuchs, CS, Gaziano, JM, Giovannucci, EL, Goggins, MG, Hartge, P, Hassan, MM, Holly, EA, Hoover, RN, Hung, RJ, Kurtz, RC, Lee, I-M, Malats, N, Milne, RL, Ng, K, Oberg, AL, Panico, S, Peters, U, Porta, M, Rabe, KG, Riboli, E, Rothman, N, Scelo, G, Sesso, HD, Silverman, DT, Stevens, VL, Strobel, O, Thompson, IM, Tjonneland, A, Trichopoulou, A, Van den Eeden, SK, Wactawski-Wende, J, Wentzensen, N, Wilkens, LR, Yu, H, Yuan, F, Zeleniuch-Jacquotte, A, Amundadottir, LT, Li, D, Jacobs, EJ, Petersen, GM, Wolpin, BM, Risch, HA, Kraft, P, Chatterjee, N, Klein, AP, Stolzenberg-Solomon, R, Mocci, E, Kundu, P, Wheeler, W, Arslan, AA, Beane-Freeman, LE, Bracci, PM, Brennan, P, Canzian, F, Du, M, Gallinger, S, Giles, GG, Goodman, PJ, Kooperberg, C, Le Marchand, L, Neale, RE, Shu, X-O, Visvanathan, K, White, E, Zheng, W, Albanes, D, Andreotti, G, Babic, A, Bamlet, WR, Berndt, S, Blackford, AL, Bueno-de-Mesquita, B, Buring, JE, Campa, D, Chanock, SJ, Childs, EJ, Duell, EJ, Fuchs, CS, Gaziano, JM, Giovannucci, EL, Goggins, MG, Hartge, P, Hassan, MM, Holly, EA, Hoover, RN, Hung, RJ, Kurtz, RC, Lee, I-M, Malats, N, Milne, RL, Ng, K, Oberg, AL, Panico, S, Peters, U, Porta, M, Rabe, KG, Riboli, E, Rothman, N, Scelo, G, Sesso, HD, Silverman, DT, Stevens, VL, Strobel, O, Thompson, IM, Tjonneland, A, Trichopoulou, A, Van den Eeden, SK, Wactawski-Wende, J, Wentzensen, N, Wilkens, LR, Yu, H, Yuan, F, Zeleniuch-Jacquotte, A, Amundadottir, LT, Li, D, Jacobs, EJ, Petersen, GM, Wolpin, BM, Risch, HA, Kraft, P, Chatterjee, N, Klein, AP, and Stolzenberg-Solomon, R

Abstract

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 × 10-8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, P interaction = 3.08 × 10-9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r 2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.

Published
2021

4. Cumulative Burden of Colorectal Cancer Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer

Author

Archambault, AN, Su, Y-R, Jeon, J, Thomas, M, Lin, Y, Conti, DV, Win, AK, Sakoda, LC, Lansdorp-Vogelaar, I, Peterse, EFP, Zauber, AG, Duggan, D, Holowatyj, AN, Huyghe, JR, Brenner, H, Cotterchio, M, Bezieau, S, Schmit, SL, Edlund, CK, Southey, MC, MacInnis, RJ, Campbell, PT, Chang-Claude, J, Slattery, ML, Chan, AT, Joshi, AD, Song, M, Cao, Y, Woods, MO, White, E, Weinstein, SJ, Ulrich, CM, Hoffmeister, M, Bien, SA, Harrison, TA, Hampe, J, Li, CI, Schafmayer, C, Offit, K, Pharoah, PD, Moreno, V, Lindblom, A, Wolk, A, Wu, AH, Li, L, Gunter, MJ, Gsur, A, Keku, TO, Pearlman, R, Bishop, DT, Castellvi-Bel, S, Moreira, L, Vodicka, P, Kampman, E, Giles, GG, Albanes, D, Baron, JA, Berndt, SI, Brezina, S, Buch, S, Buchanan, DD, Trichopoulou, A, Severi, G, Chirlaque, M-D, Sanchez, M-J, Palli, D, Kuhn, T, Murphy, N, Cross, AJ, Burnett-Hartman, AN, Chanock, SJ, de la Chapelle, A, Easton, DF, Elliott, F, English, DR, Feskens, EJM, FitzGerald, LM, Goodman, PJ, Hopper, JL, Hudson, TJ, Hunter, DJ, Jacobs, EJ, Joshu, CE, Kury, S, Markowitz, SD, Milne, RL, Platz, EA, Rennert, G, Rennert, HS, Schumacher, FR, Sandler, RS, Seminara, D, Tangen, CM, Thibodeau, SN, Toland, AE, van Duijnhoven, FJB, Visvanathan, K, Vodickova, L, Potter, JD, Mannisto, S, Weigl, K, Figueiredo, J, Martin, V, Larsson, SC, Parfrey, PS, Huang, W-Y, Lenz, H-J, Castelao, JE, Gago-Dominguez, M, Munoz-Garzon, V, Mancao, C, Haiman, CA, Wilkens, LR, Siegel, E, Barry, E, Younghusband, B, Van Guelpen, B, Harlid, S, Zeleniuch-Jacquotte, A, Liang, PS, Du, M, Casey, G, Lindor, NM, Le Marchand, L, Gallinger, SJ, Jenkins, MA, Newcomb, PA, Gruber, SB, Schoen, RE, Hampel, H, Corley, DA, Hsu, L, Peters, U, Hayes, RB, Archambault, AN, Su, Y-R, Jeon, J, Thomas, M, Lin, Y, Conti, DV, Win, AK, Sakoda, LC, Lansdorp-Vogelaar, I, Peterse, EFP, Zauber, AG, Duggan, D, Holowatyj, AN, Huyghe, JR, Brenner, H, Cotterchio, M, Bezieau, S, Schmit, SL, Edlund, CK, Southey, MC, MacInnis, RJ, Campbell, PT, Chang-Claude, J, Slattery, ML, Chan, AT, Joshi, AD, Song, M, Cao, Y, Woods, MO, White, E, Weinstein, SJ, Ulrich, CM, Hoffmeister, M, Bien, SA, Harrison, TA, Hampe, J, Li, CI, Schafmayer, C, Offit, K, Pharoah, PD, Moreno, V, Lindblom, A, Wolk, A, Wu, AH, Li, L, Gunter, MJ, Gsur, A, Keku, TO, Pearlman, R, Bishop, DT, Castellvi-Bel, S, Moreira, L, Vodicka, P, Kampman, E, Giles, GG, Albanes, D, Baron, JA, Berndt, SI, Brezina, S, Buch, S, Buchanan, DD, Trichopoulou, A, Severi, G, Chirlaque, M-D, Sanchez, M-J, Palli, D, Kuhn, T, Murphy, N, Cross, AJ, Burnett-Hartman, AN, Chanock, SJ, de la Chapelle, A, Easton, DF, Elliott, F, English, DR, Feskens, EJM, FitzGerald, LM, Goodman, PJ, Hopper, JL, Hudson, TJ, Hunter, DJ, Jacobs, EJ, Joshu, CE, Kury, S, Markowitz, SD, Milne, RL, Platz, EA, Rennert, G, Rennert, HS, Schumacher, FR, Sandler, RS, Seminara, D, Tangen, CM, Thibodeau, SN, Toland, AE, van Duijnhoven, FJB, Visvanathan, K, Vodickova, L, Potter, JD, Mannisto, S, Weigl, K, Figueiredo, J, Martin, V, Larsson, SC, Parfrey, PS, Huang, W-Y, Lenz, H-J, Castelao, JE, Gago-Dominguez, M, Munoz-Garzon, V, Mancao, C, Haiman, CA, Wilkens, LR, Siegel, E, Barry, E, Younghusband, B, Van Guelpen, B, Harlid, S, Zeleniuch-Jacquotte, A, Liang, PS, Du, M, Casey, G, Lindor, NM, Le Marchand, L, Gallinger, SJ, Jenkins, MA, Newcomb, PA, Gruber, SB, Schoen, RE, Hampel, H, Corley, DA, Hsu, L, Peters, U, and Hayes, RB

Abstract

BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be mo

Published
2020

5. Genome-Wide Gene-Diabetes and Gene-Obesity Interaction Scan in 8,255 Cases and 11,900 Controls from PanScan and PanC4 Consortia

Author

Tang, H, Jiang, L, Stolzenberg-Solomon, RZ, Arslan, AA, Freeman, LEB, Bracci, PM, Brennan, P, Canzian, F, Du, M, Gallinger, S, Giles, GG, Goodman, PJ, Kooperberg, C, Le Marchand, L, Neale, RE, Shu, X-O, Visvanathan, K, White, E, Zheng, W, Albanes, D, Andreotti, G, Babic, A, Bamlet, WR, Berndt, S, Blackford, A, Bueno-de-Mesquita, B, Buring, JE, Campa, D, Chanock, SJ, Childs, E, Duell, EJ, Fuchs, C, Gaziano, JM, Goggins, M, Hartge, P, Hassam, MH, Holly, EA, Hoover, RN, Hung, RJ, Kurtz, RC, Lee, I-M, Malats, N, Milne, RL, Ng, K, Oberg, AL, Orlow, I, Peters, U, Porta, M, Rabe, KG, Rothman, N, Scelo, G, Sesso, HD, Silverman, DT, Thompson, IM, Tjonneland, A, Trichopoulou, A, Wactawski-Wende, J, Wentzensen, N, Wilkens, LR, Yu, H, Zeleniuch-Jacquotte, A, Amundadottir, LT, Jacobs, EJ, Petersen, GM, Wolpin, BM, Risch, HA, Chatterjee, N, Klein, AP, Li, D, Kraft, P, Wei, P, Tang, H, Jiang, L, Stolzenberg-Solomon, RZ, Arslan, AA, Freeman, LEB, Bracci, PM, Brennan, P, Canzian, F, Du, M, Gallinger, S, Giles, GG, Goodman, PJ, Kooperberg, C, Le Marchand, L, Neale, RE, Shu, X-O, Visvanathan, K, White, E, Zheng, W, Albanes, D, Andreotti, G, Babic, A, Bamlet, WR, Berndt, S, Blackford, A, Bueno-de-Mesquita, B, Buring, JE, Campa, D, Chanock, SJ, Childs, E, Duell, EJ, Fuchs, C, Gaziano, JM, Goggins, M, Hartge, P, Hassam, MH, Holly, EA, Hoover, RN, Hung, RJ, Kurtz, RC, Lee, I-M, Malats, N, Milne, RL, Ng, K, Oberg, AL, Orlow, I, Peters, U, Porta, M, Rabe, KG, Rothman, N, Scelo, G, Sesso, HD, Silverman, DT, Thompson, IM, Tjonneland, A, Trichopoulou, A, Wactawski-Wende, J, Wentzensen, N, Wilkens, LR, Yu, H, Zeleniuch-Jacquotte, A, Amundadottir, LT, Jacobs, EJ, Petersen, GM, Wolpin, BM, Risch, HA, Chatterjee, N, Klein, AP, Li, D, Kraft, P, and Wei, P

Abstract

BACKGROUND: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. METHODS: We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. RESULTS: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 × 10-6) was observed in the meta-analysis (P GxE = 1.2 ×10-6, P Joint = 4.2 ×10-7). CONCLUSIONS: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. IMPACT: This study may con

Published
2020

6. Meta-analysis of 16 studies of the association of alcohol with colorectal cancer

Author

McNabb, S, Harrison, TA, Albanes, D, Berndt, SI, Brenner, H, Caan, BJ, Campbell, PT, Cao, Y, Chang-Claude, J, Chan, A, Chen, Z, English, DR, Giles, GG, Giovannucci, EL, Goodman, PJ, Hayes, RB, Hoffmeister, M, Jacobs, EJ, Joshi, AD, Larsson, SC, Le Marchand, L, Li, L, Lin, Y, Mannisto, S, Milne, RL, Nan, H, Newton, CC, Ogino, S, Parfrey, PS, Petersen, PS, Potter, JD, Schoen, RE, Slattery, ML, Su, Y-R, Tangen, CM, Tucker, TC, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Phipps, AI, Peters, U, McNabb, S, Harrison, TA, Albanes, D, Berndt, SI, Brenner, H, Caan, BJ, Campbell, PT, Cao, Y, Chang-Claude, J, Chan, A, Chen, Z, English, DR, Giles, GG, Giovannucci, EL, Goodman, PJ, Hayes, RB, Hoffmeister, M, Jacobs, EJ, Joshi, AD, Larsson, SC, Le Marchand, L, Li, L, Lin, Y, Mannisto, S, Milne, RL, Nan, H, Newton, CC, Ogino, S, Parfrey, PS, Petersen, PS, Potter, JD, Schoen, RE, Slattery, ML, Su, Y-R, Tangen, CM, Tucker, TC, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Phipps, AI, and Peters, U

Abstract

Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.

Published
2020

7. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Author

Zhang, YD, Hurson, AN, Zhang, H, Choudhury, PP, Easton, DF, Milne, RL, Simard, J, Hall, P, Michailidou, K, Dennis, J, Schmidt, MK, Chang-Claude, J, Gharahkhani, P, Whiteman, D, Campbell, PT, Hoffmeister, M, Jenkins, M, Peters, U, Hsu, L, Gruber, SB, Casey, G, Schmit, SL, O'Mara, TA, Spurdle, AB, Thompson, DJ, Tomlinson, I, De Vivo, I, Landi, MT, Law, MH, Iles, MM, Demenais, F, Kumar, R, MacGregor, S, Bishop, DT, Ward, SV, Bondy, ML, Houlston, R, Wiencke, JK, Melin, B, Barnholtz-Sloan, J, Kinnersley, B, Wrensch, MR, Amos, CI, Hung, RJ, Brennan, P, McKay, J, Caporaso, NE, Berndt, SI, Birmann, BM, Camp, NJ, Kraft, P, Rothman, N, Slager, SL, Berchuck, A, Pharoah, PDP, Sellers, TA, Gayther, SA, Pearce, CL, Goode, EL, Schildkraut, JM, Moysich, KB, Amundadottir, LT, Jacobs, EJ, Klein, AP, Petersen, GM, Risch, HA, Stolzenberg-Solomon, RZ, Wolpin, BM, Li, D, Eeles, RA, Haiman, CA, Kote-Jarai, Z, Schumacher, FR, Al Olama, AA, Purdue, MP, Scelo, G, Dalgaard, MD, Greene, MH, Grotmol, T, Kanetsky, PA, McGlynn, KA, Nathanson, KL, Turnbull, C, Wiklund, F, Chanock, SJ, Chatterjee, N, Garcia-Closas, M, Zhang, YD, Hurson, AN, Zhang, H, Choudhury, PP, Easton, DF, Milne, RL, Simard, J, Hall, P, Michailidou, K, Dennis, J, Schmidt, MK, Chang-Claude, J, Gharahkhani, P, Whiteman, D, Campbell, PT, Hoffmeister, M, Jenkins, M, Peters, U, Hsu, L, Gruber, SB, Casey, G, Schmit, SL, O'Mara, TA, Spurdle, AB, Thompson, DJ, Tomlinson, I, De Vivo, I, Landi, MT, Law, MH, Iles, MM, Demenais, F, Kumar, R, MacGregor, S, Bishop, DT, Ward, SV, Bondy, ML, Houlston, R, Wiencke, JK, Melin, B, Barnholtz-Sloan, J, Kinnersley, B, Wrensch, MR, Amos, CI, Hung, RJ, Brennan, P, McKay, J, Caporaso, NE, Berndt, SI, Birmann, BM, Camp, NJ, Kraft, P, Rothman, N, Slager, SL, Berchuck, A, Pharoah, PDP, Sellers, TA, Gayther, SA, Pearce, CL, Goode, EL, Schildkraut, JM, Moysich, KB, Amundadottir, LT, Jacobs, EJ, Klein, AP, Petersen, GM, Risch, HA, Stolzenberg-Solomon, RZ, Wolpin, BM, Li, D, Eeles, RA, Haiman, CA, Kote-Jarai, Z, Schumacher, FR, Al Olama, AA, Purdue, MP, Scelo, G, Dalgaard, MD, Greene, MH, Grotmol, T, Kanetsky, PA, McGlynn, KA, Nathanson, KL, Turnbull, C, Wiklund, F, Chanock, SJ, Chatterjee, N, and Garcia-Closas, M

Abstract

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.

Published
2020

8. Exploratory Genome-Wide Interaction Analysis of Nonsteroidal Anti-inflammatory Drugs and Predicted Gene Expression on Colorectal Cancer Risk

Author

Wang, X, Su, Y-R, Petersen, PS, Bien, S, Schmit, SL, Drew, DA, Albanes, D, Berndt, S, Brenner, H, Campbell, PT, Casey, G, Cheng-Claude, J, Gallinger, S, Gruber, SB, Haile, RW, Harrison, TA, Hoffmeister, M, Jacobs, EJ, Jenkins, MA, Joshi, AD, Li, L, Lin, Y, Lindor, NM, Le Marchand, L, Martin, V, Milne, R, Maclnnis, R, Moreno, V, Nan, H, Newcomb, PA, Potter, JD, Rennert, G, Rennert, HS, Slattery, ML, Thibodeau, SN, Weinstein, SJ, Woods, MO, Chan, AT, White, E, Hsu, L, Peters, U, Wang, X, Su, Y-R, Petersen, PS, Bien, S, Schmit, SL, Drew, DA, Albanes, D, Berndt, S, Brenner, H, Campbell, PT, Casey, G, Cheng-Claude, J, Gallinger, S, Gruber, SB, Haile, RW, Harrison, TA, Hoffmeister, M, Jacobs, EJ, Jenkins, MA, Joshi, AD, Li, L, Lin, Y, Lindor, NM, Le Marchand, L, Martin, V, Milne, R, Maclnnis, R, Moreno, V, Nan, H, Newcomb, PA, Potter, JD, Rennert, G, Rennert, HS, Slattery, ML, Thibodeau, SN, Weinstein, SJ, Woods, MO, Chan, AT, White, E, Hsu, L, and Peters, U

Abstract

BACKGROUND: Regular use of nonsteroidal anti-inflammatory drugs (NSAID) is associated with lower risk of colorectal cancer. Genome-wide interaction analysis on single variants (G × E) has identified several SNPs that may interact with NSAIDs to confer colorectal cancer risk, but variations in gene expression levels may also modify the effect of NSAID use. Therefore, we tested interactions between NSAID use and predicted gene expression levels in relation to colorectal cancer risk. METHODS: Genetically predicted gene expressions were tested for interaction with NSAID use on colorectal cancer risk among 19,258 colorectal cancer cases and 18,597 controls from 21 observational studies. A Mixed Score Test for Interactions (MiSTi) approach was used to jointly assess G × E effects which are modeled via fixed interaction effects of the weighted burden within each gene set (burden) and residual G × E effects (variance). A false discovery rate (FDR) at 0.2 was applied to correct for multiple testing. RESULTS: Among the 4,840 genes tested, genetically predicted expression levels of four genes modified the effect of any NSAID use on colorectal cancer risk, including DPP10 (PG×E = 1.96 × 10-4), KRT16 (PG×E = 2.3 × 10-4), CD14 (PG×E = 9.38 × 10-4), and CYP27A1 (PG×E = 1.44 × 10-3). There was a significant interaction between expression level of RP11-89N17 and regular use of aspirin only on colorectal cancer risk (PG×E = 3.23 × 10-5). No interactions were observed between predicted gene expression and nonaspirin NSAID use at FDR < 0.2. CONCLUSIONS: By incorporating functional information, we discovered several novel genes that interacted with NSAID use. IMPACT: These findings provide preliminary support that could help understand the chemopreventive mechanisms of NSAIDs on colorectal cancer.

Published
2020

9. Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer (vol 138, pg 307, 2019)

Author

Bien, SA, Su, Y-R, Conti, DV, Harrison, TA, Qu, C, Guo, X, Lu, Y, Albanes, D, Auer, PL, Banbury, BL, Berndt, SI, Bezieau, S, Brenner, H, Buchanan, DD, Caan, BJ, Campbell, PT, Carlson, CS, Chan, AT, Chang-Claude, J, Chen, S, Connolly, CM, Easton, DF, Feskens, EJM, Gallinger, S, Giles, GG, Gunter, MJ, Hampe, J, Huyghe, JR, Hoffmeister, M, Hudson, TJ, Jacobs, EJ, Jenkins, MA, Kampman, E, Kang, HM, Kuehn, T, Kury, S, Lejbkowicz, F, Le Marchand, L, Milne, RL, Li, L, Li, CI, Lindblom, A, Lindor, NM, Martin, V, McNeil, CE, Melas, M, Moreno, V, Newcomb, PA, Offit, K, Pharaoh, PDP, Potter, JD, Riboli, E, Rennert, G, Sala, N, Schafmayer, C, Scacheri, PC, Schmit, SL, Severi, G, Slattery, ML, Smith, JD, Trichopoulou, A, Tumino, R, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Abecasis, GR, Casey, G, Nickerson, DA, Gruber, SB, Hsu, L, Zheng, W, Peters, U, Bien, SA, Su, Y-R, Conti, DV, Harrison, TA, Qu, C, Guo, X, Lu, Y, Albanes, D, Auer, PL, Banbury, BL, Berndt, SI, Bezieau, S, Brenner, H, Buchanan, DD, Caan, BJ, Campbell, PT, Carlson, CS, Chan, AT, Chang-Claude, J, Chen, S, Connolly, CM, Easton, DF, Feskens, EJM, Gallinger, S, Giles, GG, Gunter, MJ, Hampe, J, Huyghe, JR, Hoffmeister, M, Hudson, TJ, Jacobs, EJ, Jenkins, MA, Kampman, E, Kang, HM, Kuehn, T, Kury, S, Lejbkowicz, F, Le Marchand, L, Milne, RL, Li, L, Li, CI, Lindblom, A, Lindor, NM, Martin, V, McNeil, CE, Melas, M, Moreno, V, Newcomb, PA, Offit, K, Pharaoh, PDP, Potter, JD, Riboli, E, Rennert, G, Sala, N, Schafmayer, C, Scacheri, PC, Schmit, SL, Severi, G, Slattery, ML, Smith, JD, Trichopoulou, A, Tumino, R, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Abecasis, GR, Casey, G, Nickerson, DA, Gruber, SB, Hsu, L, Zheng, W, and Peters, U

Abstract

Every author has erroneously been assigned to the affiliation "62". The affiliation 62 belongs to the author Graham Casey.

Published
2019

10. Novel Common Genetic Susceptibility Loci for Colorectal Cancer

Author

Schmit, SL, Edlund, CK, Schumacher, FR, Gong, J, Harrison, TA, Huyghe, JR, Qu, C, Melas, M, Van den Berg, DJ, Wang, H, Tring, S, Plummer, SJ, Albanes, D, Alonso, MH, Amos, CI, Anton, K, Aragaki, AK, Arndt, V, Barry, EL, Berndt, SI, Bezieau, S, Bien, S, Bloomer, A, Boehm, J, Boutron-Ruault, M-C, Brenner, H, Brezina, S, Buchanan, DD, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castelao, JE, Chan, AT, Chang-Claude, J, Chanock, SJ, Cheng, I, Cheng, Y-W, Chin, LS, Church, JM, Church, T, Coetzee, GA, Cotterchio, M, Correa, MC, Curtis, KR, Duggan, D, Easton, DF, English, D, Feskens, EJM, Fischer, R, FitzGerald, LM, Fortini, BK, Fritsche, LG, Fuchs, CS, Gago-Dominguez, M, Gala, M, Gallinger, SJ, Gauderman, WJ, Giles, GG, Giovannucci, EL, Gogarten, SM, Gonzalez-Villalpando, C, Gonzalez-Villalpando, EM, Grady, WM, Greenson, JK, Gsur, A, Gunter, M, Haiman, CA, Hampe, J, Harlid, S, Harju, JF, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Huang, S-C, Huerta, JM, Hudson, TJ, Hunter, DJ, Idos, GE, Iwasaki, M, Jackson, RD, Jacobs, EJ, Jee, SH, Jenkins, MA, Jia, W-H, Jiao, S, Joshi, AD, Kolonel, LN, Kono, S, Kooperberg, C, Krogh, V, Kuehn, T, Kury, S, LaCroix, A, Laurie, CA, Lejbkowicz, F, Lemire, M, Lenz, H-J, Levine, D, Li, CI, Li, L, Lieb, W, Lin, Y, Lindor, NM, Liu, Y-R, Loupakis, F, Lu, Y, Luh, F, Ma, J, Mancao, C, Manion, FJ, Markowitz, SD, Martin, V, Matsuda, K, Matsuo, K, McDonnell, KJ, McNeil, CE, Milne, R, Molina, AJ, Mukherjee, B, Murphy, N, Newcomb, PA, Offit, K, Omichessan, H, Palli, D, Cotore, JPP, Perez-Mayoral, J, Pharoah, PD, Potter, JD, Raskin, L, Rennert, G, Rennert, HS, Riggs, BM, Schafmayer, C, Schoen, RE, Sellers, TA, Seminara, D, Severi, G, Shi, W, Shibata, D, Shu, X-O, Siegel, EM, Slattery, ML, Southey, M, Stadler, ZK, Stern, MC, Stintzing, S, Taverna, D, Thibodeau, SN, Thomas, DC, Trichopoulou, A, Tsugane, S, Ulrich, CM, van Duijnhoven, FJB, van Guelpan, B, Vijai, J, Virtamo, J, Weinstein, SJ, White, E, Win, AK, Wolk, A, Woods, M, Wu, AH, Wu, K, Xiang, Y-B, Yen, Y, Zanke, BW, Zeng, Y-X, Zhang, B, Zubair, N, Kweon, S-S, Figueiredo, JC, Zheng, W, Le Marchand, L, Lindblom, A, Moreno, V, Peters, U, Casey, G, Hsu, L, Conti, DV, Gruber, SB, Schmit, SL, Edlund, CK, Schumacher, FR, Gong, J, Harrison, TA, Huyghe, JR, Qu, C, Melas, M, Van den Berg, DJ, Wang, H, Tring, S, Plummer, SJ, Albanes, D, Alonso, MH, Amos, CI, Anton, K, Aragaki, AK, Arndt, V, Barry, EL, Berndt, SI, Bezieau, S, Bien, S, Bloomer, A, Boehm, J, Boutron-Ruault, M-C, Brenner, H, Brezina, S, Buchanan, DD, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castelao, JE, Chan, AT, Chang-Claude, J, Chanock, SJ, Cheng, I, Cheng, Y-W, Chin, LS, Church, JM, Church, T, Coetzee, GA, Cotterchio, M, Correa, MC, Curtis, KR, Duggan, D, Easton, DF, English, D, Feskens, EJM, Fischer, R, FitzGerald, LM, Fortini, BK, Fritsche, LG, Fuchs, CS, Gago-Dominguez, M, Gala, M, Gallinger, SJ, Gauderman, WJ, Giles, GG, Giovannucci, EL, Gogarten, SM, Gonzalez-Villalpando, C, Gonzalez-Villalpando, EM, Grady, WM, Greenson, JK, Gsur, A, Gunter, M, Haiman, CA, Hampe, J, Harlid, S, Harju, JF, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Huang, S-C, Huerta, JM, Hudson, TJ, Hunter, DJ, Idos, GE, Iwasaki, M, Jackson, RD, Jacobs, EJ, Jee, SH, Jenkins, MA, Jia, W-H, Jiao, S, Joshi, AD, Kolonel, LN, Kono, S, Kooperberg, C, Krogh, V, Kuehn, T, Kury, S, LaCroix, A, Laurie, CA, Lejbkowicz, F, Lemire, M, Lenz, H-J, Levine, D, Li, CI, Li, L, Lieb, W, Lin, Y, Lindor, NM, Liu, Y-R, Loupakis, F, Lu, Y, Luh, F, Ma, J, Mancao, C, Manion, FJ, Markowitz, SD, Martin, V, Matsuda, K, Matsuo, K, McDonnell, KJ, McNeil, CE, Milne, R, Molina, AJ, Mukherjee, B, Murphy, N, Newcomb, PA, Offit, K, Omichessan, H, Palli, D, Cotore, JPP, Perez-Mayoral, J, Pharoah, PD, Potter, JD, Raskin, L, Rennert, G, Rennert, HS, Riggs, BM, Schafmayer, C, Schoen, RE, Sellers, TA, Seminara, D, Severi, G, Shi, W, Shibata, D, Shu, X-O, Siegel, EM, Slattery, ML, Southey, M, Stadler, ZK, Stern, MC, Stintzing, S, Taverna, D, Thibodeau, SN, Thomas, DC, Trichopoulou, A, Tsugane, S, Ulrich, CM, van Duijnhoven, FJB, van Guelpan, B, Vijai, J, Virtamo, J, Weinstein, SJ, White, E, Win, AK, Wolk, A, Woods, M, Wu, AH, Wu, K, Xiang, Y-B, Yen, Y, Zanke, BW, Zeng, Y-X, Zhang, B, Zubair, N, Kweon, S-S, Figueiredo, JC, Zheng, W, Le Marchand, L, Lindblom, A, Moreno, V, Peters, U, Casey, G, Hsu, L, Conti, DV, and Gruber, SB

Abstract

BACKGROUND: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. METHODS: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. RESULTS: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. CONCLUSIONS: T

Published
2019

11. Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer

Author

Bien, SA, Su, Y-R, Conti, DV, Harrison, TA, Qu, C, Guo, X, Lu, Y, Albanes, D, Auer, PL, Banbury, BL, Berndt, SI, Bezieau, S, Brenner, H, Buchanan, DD, Caan, BJ, Campbell, PT, Carlson, CS, Chan, AT, Chang-Claude, J, Chen, S, Connolly, CM, Easton, DF, Feskens, EJM, Gallinger, S, Giles, GG, Gunter, MJ, Hampe, J, Huyghe, JR, Hoffmeister, M, Hudson, TJ, Jacobs, EJ, Jenkins, MA, Kampman, E, Kang, HM, Kuehn, T, Kury, S, Lejbkowicz, F, Le Marchand, L, Milne, RL, Li, L, Li, CI, Lindblom, A, Lindor, NM, Martin, V, McNeil, CE, Melas, M, Moreno, V, Newcomb, PA, Offit, K, Pharaoh, PDP, Potter, JD, Riboli, E, Rennert, G, Sala, N, Schafmayer, C, Scacheri, PC, Schmit, SL, Severi, G, Slattery, ML, Smith, JD, Trichopoulou, A, Tumino, R, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Abecasis, GR, Casey, G, Nickerson, DA, Gruber, SB, Hsu, L, Zheng, W, Peters, U, Bien, SA, Su, Y-R, Conti, DV, Harrison, TA, Qu, C, Guo, X, Lu, Y, Albanes, D, Auer, PL, Banbury, BL, Berndt, SI, Bezieau, S, Brenner, H, Buchanan, DD, Caan, BJ, Campbell, PT, Carlson, CS, Chan, AT, Chang-Claude, J, Chen, S, Connolly, CM, Easton, DF, Feskens, EJM, Gallinger, S, Giles, GG, Gunter, MJ, Hampe, J, Huyghe, JR, Hoffmeister, M, Hudson, TJ, Jacobs, EJ, Jenkins, MA, Kampman, E, Kang, HM, Kuehn, T, Kury, S, Lejbkowicz, F, Le Marchand, L, Milne, RL, Li, L, Li, CI, Lindblom, A, Lindor, NM, Martin, V, McNeil, CE, Melas, M, Moreno, V, Newcomb, PA, Offit, K, Pharaoh, PDP, Potter, JD, Riboli, E, Rennert, G, Sala, N, Schafmayer, C, Scacheri, PC, Schmit, SL, Severi, G, Slattery, ML, Smith, JD, Trichopoulou, A, Tumino, R, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Abecasis, GR, Casey, G, Nickerson, DA, Gruber, SB, Hsu, L, Zheng, W, and Peters, U

Abstract

Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n = 169) and whole blood (n = 922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR ≤ 0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P = 2.2 × 10- 4, replication P = 0.01), and PYGL (discovery P = 2.3 × 10- 4, replication P = 6.7 × 10- 4). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P < 0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight in

Published
2019

12. Discovery of common and rare genetic risk variants for colorectal cancer

Author

Huyghe, JR, Bien, SA, Harrison, TA, Kang, HM, Chen, S, Schmit, SL, Conti, DV, Qu, C, Jeon, J, Edlund, CK, Greenside, P, Wainberg, M, Schumacher, FR, Smith, JD, Levine, DM, Nelson, SC, Sinnott-Armstrong, NA, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Bamia, C, Banbury, BL, Baron, JA, Berndt, SI, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Chirlaque, M-D, Cho, SH, Connolly, CM, Cross, AJ, Cuk, K, Curtis, KR, de la Chapelle, A, Doheny, KF, Duggan, D, Easton, DF, Elias, SG, Elliott, F, English, DR, Feskens, EJM, Figueiredo, JC, Fischer, R, FitzGerald, LM, Forman, D, Gala, M, Gallinger, S, Gauderman, WJ, Giles, GG, Gillanders, E, Gong, J, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hampel, H, Harlid, S, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Hunter, DJ, Ibanez-Sanz, G, Idos, GE, Ingersoll, R, Jackson, RD, Jacobs, EJ, Jenkins, MA, Joshi, AD, Joshu, CE, Keku, TO, Key, TJ, Kim, HR, Kobayashi, E, Kolonel, LN, Kooperberg, C, Kuehn, T, Kury, S, Kweon, S-S, Larsson, SC, Laurie, CA, Le Marchand, L, Leal, SM, Lee, SC, Lejbkowicz, F, Lemire, M, Li, CI, Li, L, Lieb, W, Lin, Y, Lindblom, A, Lindor, NM, Ling, H, Louie, TL, Mannisto, S, Markowitz, SD, Martin, V, Masala, G, McNeil, CE, Melas, M, Milne, RL, Moreno, L, Murphy, N, Myte, R, Naccarati, A, Newcomb, PA, Offit, K, Ogino, S, Onland-Moret, NC, Pardini, B, Parfrey, PS, Pearlman, R, Perduca, V, Pharoah, PDP, Pinchev, M, Platz, EA, Prentice, RL, Pugh, E, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Rodriguez-Barranco, M, Romm, J, Sakoda, LC, Schafmayer, C, Schoen, RE, Seminara, D, Shah, M, Shelford, T, Shin, M-H, Shulman, K, Sieri, S, Slattery, ML, Southey, MC, Stadler, ZK, Stegmaier, C, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Thomas, SS, Toland, AE, Trichopoulou, A, Ulrich, CM, Van den Berg, DJ, van Duijnhoven, FJB, Van Guelpen, B, van Kranen, H, Vijai, J, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Win, AK, Wolf, CR, Wolk, A, Woods, MO, Wu, AH, Zaidi, SH, Zanke, BW, Zhang, Q, Zheng, W, Scacheri, PC, Potter, JD, Bassik, MC, Kundaje, A, Casey, G, Moreno, V, Abecasis, GR, Nickerson, DA, Gruber, SB, Hsu, L, Peters, U, Huyghe, JR, Bien, SA, Harrison, TA, Kang, HM, Chen, S, Schmit, SL, Conti, DV, Qu, C, Jeon, J, Edlund, CK, Greenside, P, Wainberg, M, Schumacher, FR, Smith, JD, Levine, DM, Nelson, SC, Sinnott-Armstrong, NA, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Bamia, C, Banbury, BL, Baron, JA, Berndt, SI, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Chirlaque, M-D, Cho, SH, Connolly, CM, Cross, AJ, Cuk, K, Curtis, KR, de la Chapelle, A, Doheny, KF, Duggan, D, Easton, DF, Elias, SG, Elliott, F, English, DR, Feskens, EJM, Figueiredo, JC, Fischer, R, FitzGerald, LM, Forman, D, Gala, M, Gallinger, S, Gauderman, WJ, Giles, GG, Gillanders, E, Gong, J, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hampel, H, Harlid, S, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Hunter, DJ, Ibanez-Sanz, G, Idos, GE, Ingersoll, R, Jackson, RD, Jacobs, EJ, Jenkins, MA, Joshi, AD, Joshu, CE, Keku, TO, Key, TJ, Kim, HR, Kobayashi, E, Kolonel, LN, Kooperberg, C, Kuehn, T, Kury, S, Kweon, S-S, Larsson, SC, Laurie, CA, Le Marchand, L, Leal, SM, Lee, SC, Lejbkowicz, F, Lemire, M, Li, CI, Li, L, Lieb, W, Lin, Y, Lindblom, A, Lindor, NM, Ling, H, Louie, TL, Mannisto, S, Markowitz, SD, Martin, V, Masala, G, McNeil, CE, Melas, M, Milne, RL, Moreno, L, Murphy, N, Myte, R, Naccarati, A, Newcomb, PA, Offit, K, Ogino, S, Onland-Moret, NC, Pardini, B, Parfrey, PS, Pearlman, R, Perduca, V, Pharoah, PDP, Pinchev, M, Platz, EA, Prentice, RL, Pugh, E, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Rodriguez-Barranco, M, Romm, J, Sakoda, LC, Schafmayer, C, Schoen, RE, Seminara, D, Shah, M, Shelford, T, Shin, M-H, Shulman, K, Sieri, S, Slattery, ML, Southey, MC, Stadler, ZK, Stegmaier, C, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Thomas, SS, Toland, AE, Trichopoulou, A, Ulrich, CM, Van den Berg, DJ, van Duijnhoven, FJB, Van Guelpen, B, van Kranen, H, Vijai, J, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Win, AK, Wolf, CR, Wolk, A, Woods, MO, Wu, AH, Zaidi, SH, Zanke, BW, Zhang, Q, Zheng, W, Scacheri, PC, Potter, JD, Bassik, MC, Kundaje, A, Casey, G, Moreno, V, Abecasis, GR, Nickerson, DA, Gruber, SB, Hsu, L, and Peters, U

Abstract

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

Published
2019

13. 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

14. Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Author

Fang, J, Jia, J, Makowski, M, Xu, M, Wang, Z, Zhang, T, Hoskins, Jw, Choi, J, Han, Y, Zhang, M, Thomas, J, Kovacs, M, Collins, I, Dzyadyk, M, Thompson, A, O'Neill, M, Das, S, Lan, Q, Koster, R, Solomon, Rs, Kraft, P, Wolpin, Bm, Jansen, Pwtc, Olson, S, Mcglynn, Ka, Kanetsky, Pa, Chatterjee, N, Barrett, Jh, Dunning, Am, Taylor, Jc, Newton Bishop, Ja, Bishop, Dt, Andresson, T, Petersen, Gm, Amos, Ci, Iles, Mm, Nathanson, Kl, Landi, Mt, Vermeulen, M, Brown, Km, Amundadottir, Lt, Canzian, F, Kooperberg, C, Arslan, Aa, Bracci, Pm, Buring, J, Duell, Ej, Gallinger, S, Jacobs, Ej, Kamineni, A, Van Den Eeden, S, Klein, Ap, Kolonel, Ln, Li, D, Olson, Sh, Risch, Ha, Sesso, Hd, Visvanathan, K, Zheng, W, Albanes, D, Austin, Ma, Boutron Ruault, Mc, Bueno de Mesquita, Hb, Cotterchio, M, Gaziano, Jm, Giovannucci, El, Goggins, M, Gross, M, Hassan, M, Helzlsouer, Kj, Holly, Ea, Hunter, Dj, Jenab, M, Kaaks, R, Key, Tj, Khaw, Kt, Krogh, V, Kurtz, Rc, Lacroix, A, Le Marchand, L, Mannisto, S, Patel, Av, Peeters, Phm, Riboli, E, Shu, Xo, Sund, M, Thornquist, M, Tjønneland, A, Tobias, Gs, Trichopoulos, D, Wactawski Wende, J, Yu, H, Yu, K, Zeleniuch Jacquotte, A, Hoover, R, Hartge, P, Fuchs, C, Chanock, Sj, Stevens, V, Caporaso, Ne, Brennan, P, Mckay, J, Wu, X, Hung, Rj, Mclaughlin, Jr, Bickeboller, H, Risch, A, Wichmann, E, Houlston, R, Mann, G, Hopper, J, Aitken, J, Armstrong, B, Giles, G, Holland, E, Kefford, R, Cust, A, Jenkins, M, Schmid, H, Puig, S, Aguilera, P, Badenas, C, Barreiro, A, Carrera, C, Gabriel, D, Xavier, Pg, Iglesias Garcia, P, Malvehy, J, Mila, M, Pigem, R, Potrony, M, Batille, Ja, Marti, Gt, Hayward, N, Martin, N, Montgomery, G, Duffy, D, Whiteman, D, Gregor, Sm, Calista, D, Landi, G, Minghetti, P, Arcangeli, F, Bertazzi, Pa, Ghiorzo, Paola, Bianchi, Giovanna, Pastorino, Lorenza, Bruno, William, Andreotti, Virginia, Queirolo, P, Spagnolo, Francesco, Mackie, R, Lang, J, Gruis, N, van Nieuwpoort, Fa, Out, C, Bergman, W, Kukutsch, N, Bavinck, Jnb, Bakker, B, van der Stoep, N, Ter Huurne, J, van der Rhee, H, Bekkenk, M, Snels, D, van Praag, M, Brochez, L, Gerritsen, R, Crijns, M, Vasen, H, Janssen, B, Ingvar, C, Olsson, H, Jonsson, G, Borg, A, Harbst, K, Nielsen, K, Zander, As, Molvern, A, Helsing, P, Andresen, Pa, Rootwelt, H, Akslen, La, Bressac de Paillerets, B, Demenais, F, Avril, Mf, Chaudru, V, Jeannin, P, Lesueur, F, Maubec, E, Mohamdi, H, Bossard, M, Vaysse, A, Boitier, F, Caron, O, Caux, F, Dalle, S, Dereure, O, Leroux, D, Martin, L, Mateus, C, Robert, C, Stoppa Lyonnet, D, Thomas, L, Wierzbicka, E, Elder, D, Ming, M, Mitra, N, Debniak, T, Lubinski, J, Hocevar, M, Novakovic, S, Peric, B, Skerl, P, Hansson, J, Hoiom, V, Freidman, E, Azizi, E, Baron Epel, O, Scope, A, Pavlotsky, F, Cohen Manheim, I, Laitman, Y, Harland, M, Randerson Moor, J, Laye, J, Davies, J, Nsengimana, J, O'Shea, S, Chan, M, Gascoyne, J, Tucker, Ma, Goldstein, Am, and Yang, X. r.

Subjects
0301 basic medicine, Male, Lung Neoplasms, Skin Neoplasms, General Physics and Astronomy, Genome-wide association study, VARIANTS, Histones, Skin cancer, RNA, Small Interfering, Melanoma, Telomerase, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Pancreas cancer, Regulation of gene expression, Genetics, Zinc finger, Gene knockdown, Multidisciplinary, Proteomics and Chromatin Biology, TRICL Consortium, Chromosome Mapping, GenoMEL Consortium, PANCREATIC-CANCER, Multidisciplinary Sciences, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Science & Technology - Other Topics, Chromosomes, Human, Pair 5, Female, Lung cancer, Signal Transduction, SUSCEPTIBILITY LOCI, Science, Locus (genetics), Single-nucleotide polymorphism, PROMOTES GROWTH, Biology, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, LUNG-CANCER, Testicular Neoplasms, Cell Line, Tumor, MD Multidisciplinary, Humans, Genetic Predisposition to Disease, QUANTITATIVE PROTEOMICS, GENOME-WIDE ASSOCIATION, Gene, PanScan Consortium, Càncer de pell, Càncer de pàncrees, Alleles, Science & Technology, Kirurgi, HUMAN-CELLS, Telomere Homeostasis, Correction, General Chemistry, Molecular biology, TERT-CLPTM1L LOCUS, Telomere, Pancreatic Neoplasms, 030104 developmental biology, Genetic Loci, TELOMERE LENGTH, Càncer de pulmó, Surgery, Genètica, Genome-Wide Association Study, Transcription Factors
Abstract

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele., Genetic variants at multiple loci of chr5p15.33 have been associated with susceptibility to numerous cancers. Here the authors show that the association of one of these loci may be explained by a variant, rs36115365, influencing telomerase reverse transcriptase (TERT) expression via ZNF148.

Published
2017

15. 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

16. Genome-wide association study identifies multiple loci associated with bladder cancer risk

Author

Figueroa, JD, Ye, Y, Siddiq, A, Garcia-Closas, M, Chatterjee, N, Prokunina-Olsson, L, Cortessis, VK, Kooperberg, C, Cussenot, O, Benhamou, S, Prescott, J, Porru, S, Dinney, CP, Malats, N, Baris, D, Purdue, M, Jacobs, EJ, Albanes, D, Wang, Z, Deng, X, Chung, CC, Tang, W, Bueno-De-Mesquita, HB, Trichopoulos, D, Ljungberg, B, Clavel-Chapelon, F, Weiderpass, E, Krogh, V, Dorronsoro, M, Travis, R, Tjonneland, A, Brenan, P, Chang-Claude, J, Riboli, E, Conti, D, Gago Dominguez, Manuela, Stern, MC, Pike, MC, Van den Berg, D, Yuan, JM, Hohensee, C, Rodabough, R, Cancel-Tassin, G, Roupret, M, Comperat, E, Chen, C, De Vivo, I, Giovannucci, E, Hunter, DJ, Kraft, P, Lindstrom, S, Carta, A, Pavanello, S, Arici, C, Mastrangelo, G, Kamat, AM, Lerner, SP, Grossman, HB, Lin, J, Gu, J, Pu, X, Hutchinson, A, Burdette, L, Wheeler, W, Kogevinas, M, Tardon, A, Serra, C, Carrato, A, Garcia-Closas, R, Lloreta, J, Schwenn, M, Karagas, MR, Johnson, A, Schned, A, Armenti, KR, Hosain, GM, Andriole, G, Grubb, R, Black, A, Diver, WR, Gapstur, SM, Weinstein, SJ, Virtamo, J, Haiman, CA, Landi, MT, Caporaso, N, Fraumeni, JF, Vineis, P, Wu, X, Silverman, DT, Chanock, S, and Rothman, N

Subjects
Risk, Genotype, Meta-Analysis as Topic, Urinary Bladder Neoplasms, Genetic Loci, Case-Control Studies, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Genome-Wide Association Study
Abstract

Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 x 10(-5) was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 x 10(-9)) and rs907611 on 11p15.5 (P = 4.11 x 10(-8)). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 x 10(-7)) and rs4510656 on 6p22.3 (P = 6.98 x 10(-7)); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.

Published
2014

17. Vitamin D Metabolic Pathway Genes and Pancreatic Cancer Risk

Author

Chang, JS, Arem, H, Yu, K, Xiong, X, Moy, K, Freedman, ND, Mayne, ST, Albanes, D, Arslan, AA, Austin, M, Bamlet, WR, Beane-Freeman, L, Bracci, P, Canzian, F, Cotterchio, M, Duell, EJ, Gallinger, S, Giles, GG, Goggins, M, Goodman, PJ, Hartge, P, Hassan, M, Helzlsouer, K, Henderson, B, Holly, EA, Hoover, R, Jacobs, EJ, Kamineni, A, Klein, A, Klein, E, Kolonel, LN, Li, D, Malats, N, Mannisto, S, McCullough, ML, Olson, SH, Orlow, I, Peters, U, Petersen, GM, Porta, M, Severi, G, Shu, X-O, Visvanathan, K, White, E, Yu, H, Zeleniuch-Jacquotte, A, Zheng, W, Tobias, GS, Maeder, D, Brotzman, M, Risch, H, Sampson, JN, Stolzenberg-Solomon, RZ, Chang, JS, Arem, H, Yu, K, Xiong, X, Moy, K, Freedman, ND, Mayne, ST, Albanes, D, Arslan, AA, Austin, M, Bamlet, WR, Beane-Freeman, L, Bracci, P, Canzian, F, Cotterchio, M, Duell, EJ, Gallinger, S, Giles, GG, Goggins, M, Goodman, PJ, Hartge, P, Hassan, M, Helzlsouer, K, Henderson, B, Holly, EA, Hoover, R, Jacobs, EJ, Kamineni, A, Klein, A, Klein, E, Kolonel, LN, Li, D, Malats, N, Mannisto, S, McCullough, ML, Olson, SH, Orlow, I, Peters, U, Petersen, GM, Porta, M, Severi, G, Shu, X-O, Visvanathan, K, White, E, Yu, H, Zeleniuch-Jacquotte, A, Zheng, W, Tobias, GS, Maeder, D, Brotzman, M, Risch, H, Sampson, JN, and Stolzenberg-Solomon, RZ

Abstract

Evidence on the association between vitamin D status and pancreatic cancer risk is inconsistent. This inconsistency may be partially attributable to variation in vitamin D regulating genes. We selected 11 vitamin D-related genes (GC, DHCR7, CYP2R1, VDR, CYP27B1, CYP24A1, CYP27A1, RXRA, CRP2, CASR and CUBN) totaling 213 single nucleotide polymorphisms (SNPs), and examined associations with pancreatic adenocarcinoma. Our study included 3,583 pancreatic cancer cases and 7,053 controls from the genome-wide association studies of pancreatic cancer PanScans-I-III. We used the Adaptive Joint Test and the Adaptive Rank Truncated Product statistic for pathway and gene analyses, and unconditional logistic regression for SNP analyses, adjusting for age, sex, study and population stratification. We examined effect modification by circulating vitamin D concentration (≤50, >50 nmol/L) for the most significant SNPs using a subset of cohort cases (n = 713) and controls (n = 878). The vitamin D metabolic pathway was not associated with pancreatic cancer risk (p = 0.830). Of the individual genes, none were associated with pancreatic cancer risk at a significance level of p<0.05. SNPs near the VDR (rs2239186), LRP2 (rs4668123), CYP24A1 (rs2762932), GC (rs2282679), and CUBN (rs1810205) genes were the top SNPs associated with pancreatic cancer (p-values 0.008-0.037), but none were statistically significant after adjusting for multiple comparisons. Associations between these SNPs and pancreatic cancer were not modified by circulating concentrations of vitamin D. These findings do not support an association between vitamin D-related genes and pancreatic cancer risk. Future research should explore other pathways through which vitamin D status might be associated with pancreatic cancer risk.

Published
2015

18. Vitamin D Metabolic Pathway Genes and Pancreatic Cancer Risk (vol 10, e0117574, 2015)

Author

Arem, H, Yu, K, Xiong, X, Moy, K, Freedman, ND, Mayne, ST, Albanes, D, Amundadottir, LT, Arslan, AA, Austin, M, Bamlet, WR, Beane-Freeman, L, Bracci, P, Canzian, F, Chanock, SJ, Cotterchio, M, Duell, EJ, Gallinger, S, Giles, GG, Goggins, M, Goodman, PJ, Hartge, P, Hassan, M, Helzlsouer, K, Henderson, B, Holly, EA, Hoover, R, Jacobs, EJ, Kamineni, A, Klein, A, Klein, E, Kolonel, LN, Li, D, Malats, N, Maennistoe, S, McCullough, ML, Olson, SH, Orlow, I, Peters, U, Petersen, GM, Porta, M, Severi, G, Shu, X-O, Van den Eeden, S, Visvanathan, K, White, E, Yu, H, Zeleniuch-Jacquotte, A, Zheng, W, Tobias, GS, Maeder, D, Brotzman, M, Risch, H, Sampson, JN, Stolzenberg-Solomon, RZ, Arem, H, Yu, K, Xiong, X, Moy, K, Freedman, ND, Mayne, ST, Albanes, D, Amundadottir, LT, Arslan, AA, Austin, M, Bamlet, WR, Beane-Freeman, L, Bracci, P, Canzian, F, Chanock, SJ, Cotterchio, M, Duell, EJ, Gallinger, S, Giles, GG, Goggins, M, Goodman, PJ, Hartge, P, Hassan, M, Helzlsouer, K, Henderson, B, Holly, EA, Hoover, R, Jacobs, EJ, Kamineni, A, Klein, A, Klein, E, Kolonel, LN, Li, D, Malats, N, Maennistoe, S, McCullough, ML, Olson, SH, Orlow, I, Peters, U, Petersen, GM, Porta, M, Severi, G, Shu, X-O, Van den Eeden, S, Visvanathan, K, White, E, Yu, H, Zeleniuch-Jacquotte, A, Zheng, W, Tobias, GS, Maeder, D, Brotzman, M, Risch, H, Sampson, JN, and Stolzenberg-Solomon, RZ

Published
2015

19. Association of Aspirin and NSAID Use With Risk of Colorectal Cancer According to Genetic Variants

Author

Nan, H, Hutter, CM, Lin, Y, Jacobs, EJ, Ulrich, CM, White, E, Baron, JA, Berndt, SI, Brenner, H, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Casey, G, Chang-Claude, J, Chanock, SJ, Cotterchio, M, Duggan, D, Figueiredo, JC, Fuchs, CS, Giovannucci, EL, Gong, J, Haile, RW, Harrison, TA, Hayes, RB, Hoffmeister, M, Hopper, JL, Hudson, TJ, Jenkins, MA, Jiao, S, Lindor, NM, Lemire, M, Le Marchand, L, Newcomb, PA, Ogino, S, Pflugeisen, BM, Potter, JD, Qu, C, Rosse, SA, Rudolph, A, Schoen, RE, Schumacher, FR, Seminara, D, Slattery, ML, Thibodeau, SN, Thomas, F, Thornquist, M, Warnick, GS, Zanke, BW, Gauderman, WJ, Peters, U, Hsu, L, Chan, AT, Nan, H, Hutter, CM, Lin, Y, Jacobs, EJ, Ulrich, CM, White, E, Baron, JA, Berndt, SI, Brenner, H, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Casey, G, Chang-Claude, J, Chanock, SJ, Cotterchio, M, Duggan, D, Figueiredo, JC, Fuchs, CS, Giovannucci, EL, Gong, J, Haile, RW, Harrison, TA, Hayes, RB, Hoffmeister, M, Hopper, JL, Hudson, TJ, Jenkins, MA, Jiao, S, Lindor, NM, Lemire, M, Le Marchand, L, Newcomb, PA, Ogino, S, Pflugeisen, BM, Potter, JD, Qu, C, Rosse, SA, Rudolph, A, Schoen, RE, Schumacher, FR, Seminara, D, Slattery, ML, Thibodeau, SN, Thomas, F, Thornquist, M, Warnick, GS, Zanke, BW, Gauderman, WJ, Peters, U, Hsu, L, and Chan, AT

Abstract

IMPORTANCE: Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer. OBJECTIVE: To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene × environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: Case-control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011. Participants were all of European descent. EXPOSURES: Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors. MAIN OUTCOMES AND MEASURES: Colorectal cancer. RESULTS: Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% CI, 0.64-0.74]; P = 6.2 × 10(-28)) compared with nonregular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P = 4.6 × 10(-9) for interaction). Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.61-0.70]; P = 7.7 × 10(-33)) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81]; P = .002). In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P = 8.2 × 10(-9) for interaction). Regular use was associated with a lower risk of colorectal cancer among individuals

Published
2015

20. A genome-wide association study for colorectal cancer identifies a risk locus in 14q23.1

Author

Lemire, M, Qu, C, Loo, LWM, Zaidi, SHE, Wang, H, Berndt, SI, Bezieau, S, Brenner, H, Campbell, PT, Chan, AT, Chang-Claude, J, Du, M, Edlund, CK, Gallinger, S, Haile, RW, Harrison, TA, Hoffmeister, M, Hopper, JL, Hou, L, Hsu, L, Jacobs, EJ, Jenkins, MA, Jeon, J, Kuery, S, Li, L, Lindor, NM, Newcomb, PA, Potter, JD, Rennert, G, Rudolph, A, Schoen, RE, Schumacher, FR, Seminara, D, Severi, G, Slattery, ML, White, E, Woods, MO, Cotterchio, M, Le Marchand, L, Casey, G, Gruber, SB, Peters, U, Hudson, TJ, Lemire, M, Qu, C, Loo, LWM, Zaidi, SHE, Wang, H, Berndt, SI, Bezieau, S, Brenner, H, Campbell, PT, Chan, AT, Chang-Claude, J, Du, M, Edlund, CK, Gallinger, S, Haile, RW, Harrison, TA, Hoffmeister, M, Hopper, JL, Hou, L, Hsu, L, Jacobs, EJ, Jenkins, MA, Jeon, J, Kuery, S, Li, L, Lindor, NM, Newcomb, PA, Potter, JD, Rennert, G, Rudolph, A, Schoen, RE, Schumacher, FR, Seminara, D, Severi, G, Slattery, ML, White, E, Woods, MO, Cotterchio, M, Le Marchand, L, Casey, G, Gruber, SB, Peters, U, and Hudson, TJ

Abstract

Over 50 loci associated with colorectal cancer (CRC) have been uncovered by genome-wide association studies (GWAS). Identifying additional loci has the potential to help elucidate aspects of the underlying biological processes leading to better understanding of the pathogenesis of the disease. We re-evaluated a GWAS by excluding controls that have family history of CRC or personal history of colorectal polyps, as we hypothesized that their inclusion reduces power to detect associations. This is supported empirically and through simulations. Two-phase GWAS analysis was performed in a total of 16,517 cases and 14,487 controls. We identified rs17094983, a SNP associated with risk of CRC [p = 2.5 × 10(-10); odds ratio estimated by re-including all controls (OR) = 0.87, 95% confidence interval (CI) 0.83-0.91; minor allele frequency (MAF) = 13%]. Results were replicated in samples of African descent (1894 cases and 4703 controls; p = 0.01; OR = 0.86, 95% CI 0.77-0.97; MAF = 16 %). Gene expression data in 195 colon adenocarcinomas and 59 normal colon tissues from two different studies revealed that this locus has genotypes that are associated with RTN1 (Reticulon 1) expression (p = 0.001), a protein-coding gene involved in survival and proliferation of cancer cells which is highly expressed in normal colon tissues but has significantly reduced expression in tumor cells (p = 1.3 × 10(-8)).

Published
2015

21. A Pooled Analysis of Waist Circumference and Mortality in 650,000 Adults

Author

Cerhan, JR, Moore, SC, Jacobs, EJ, Kitahara, CM, Rosenberg, PS, Adami, H-O, Ebbert, JO, English, DR, Gapstur, SM, Giles, GG, Horn-Ross, PL, Park, Y, Patel, AV, Robien, K, Weiderpass, E, Willett, WC, Wolk, A, Zeleniuch-Jacquotte, A, Hartge, P, Bernstein, L, de Gonzalez, AB, Cerhan, JR, Moore, SC, Jacobs, EJ, Kitahara, CM, Rosenberg, PS, Adami, H-O, Ebbert, JO, English, DR, Gapstur, SM, Giles, GG, Horn-Ross, PL, Park, Y, Patel, AV, Robien, K, Weiderpass, E, Willett, WC, Wolk, A, Zeleniuch-Jacquotte, A, Hartge, P, Bernstein, L, and de Gonzalez, AB

Abstract

OBJECTIVES: To assess the independent effect of waist circumference on mortality across the entire body mass index (BMI) range and to estimate the loss in life expectancy related to a higher waist circumference. PATIENTS AND METHODS: We pooled data from 11 prospective cohort studies with 650,386 white adults aged 20 to 83 years and enrolled from January 1, 1986, through December 31, 2000. We used proportional hazards regression to estimate hazard ratios (HRs) and 95% CIs for the association of waist circumference with mortality. RESULTS: During a median follow-up of 9 years (maximum, 21 years), 78,268 participants died. After accounting for age, study, BMI, smoking status, alcohol consumption, and physical activity, a strong positive linear association of waist circumference with all-cause mortality was observed for men (HR, 1.52 for waist circumferences of ≥110 vs <90 cm; 95% CI, 1.45-1.59; HR, 1.07 per 5-cm increment in waist circumference; 95% CI, 1.06-1.08) and women (HR, 1.80 for waist circumferences of ≥95 vs <70 cm; 95% CI, 1.70-1.89; HR, 1.09 per 5-cm increment in waist circumference; 95% CI, 1.08-1.09). The estimated decrease in life expectancy for highest vs lowest waist circumference was approximately 3 years for men and approximately 5 years for women. The HR per 5-cm increment in waist circumference was similar for both sexes at all BMI levels from 20 to 50 kg/m(2), but it was higher at younger ages, higher for longer follow-up, and lower among male current smokers. The associations were stronger for heart and respiratory disease mortality than for cancer. CONCLUSIONS: In white adults, higher waist circumference was positively associated with higher mortality at all levels of BMI from 20 to 50 kg/m(2). Waist circumference should be assessed in combination with BMI, even for those in the normal BMI range, as part of risk assessment for obesity-related premature mortality.

Published
2014

22. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer

Author

Wolpin, BM, Rizzato, C, Kraft, P, Kooperberg, C, Petersen, GM, Wang, Z, Arslan, AA, Beane-Freeman, L, Bracci, PM, Buring, J, Canzian, F, Duell, EJ, Gallinger, S, Giles, GG, Goodman, GE, Goodman, PJ, Jacobs, EJ, Kamineni, A, Klein, AP, Kolonel, LN, Kulke, MH, Li, D, Malats, N, Olson, SH, Risch, HA, Sesso, HD, Visvanathan, K, White, E, Zheng, W, Abnet, CC, Albanes, D, Andreotti, G, Austin, MA, Barfield, R, Basso, D, Berndt, SI, Boutron-Ruault, M-C, Brotzman, M, Buechler, MW, Bueno-de-Mesquita, HB, Bugert, P, Burdette, L, Campa, D, Caporaso, NE, Capurso, G, Chung, C, Cotterchio, M, Costello, E, Elena, J, Funel, N, Gaziano, JM, Giese, NA, Goggins, M, Gorman, MJ, Gross, M, Haiman, CA, Hassan, M, Helzlsouer, KJ, Henderson, BE, Holly, EA, Hu, N, Hunter, DJ, Innocenti, F, Jenab, M, Kaaks, R, Key, TJ, Khaw, K-T, Klein, EA, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, RC, LaCroix, A, Landi, MT, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, RL, Nakamura, Y, Oberg, AL, Owzar, K, Patel, AV, Peeters, PHM, Peters, U, Pezzilli, R, Piepoli, A, Porta, M, Real, FX, Riboli, E, Rothman, N, Scarpa, A, Shu, X-O, Silverman, DT, Soucek, P, Sund, M, Talar-Wojnarowska, R, Taylor, PR, Theodoropoulos, GE, Thornquist, M, Tjonneland, A, Tobias, GS, Trichopoulos, D, Vodicka, P, Wactawski-Wende, J, Wentzensen, N, Wu, C, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Hoover, R, Hartge, P, Fuchs, C, Chanock, SJ, Stolzenberg-Solomon, RS, Amundadottir, LT, Wolpin, BM, Rizzato, C, Kraft, P, Kooperberg, C, Petersen, GM, Wang, Z, Arslan, AA, Beane-Freeman, L, Bracci, PM, Buring, J, Canzian, F, Duell, EJ, Gallinger, S, Giles, GG, Goodman, GE, Goodman, PJ, Jacobs, EJ, Kamineni, A, Klein, AP, Kolonel, LN, Kulke, MH, Li, D, Malats, N, Olson, SH, Risch, HA, Sesso, HD, Visvanathan, K, White, E, Zheng, W, Abnet, CC, Albanes, D, Andreotti, G, Austin, MA, Barfield, R, Basso, D, Berndt, SI, Boutron-Ruault, M-C, Brotzman, M, Buechler, MW, Bueno-de-Mesquita, HB, Bugert, P, Burdette, L, Campa, D, Caporaso, NE, Capurso, G, Chung, C, Cotterchio, M, Costello, E, Elena, J, Funel, N, Gaziano, JM, Giese, NA, Goggins, M, Gorman, MJ, Gross, M, Haiman, CA, Hassan, M, Helzlsouer, KJ, Henderson, BE, Holly, EA, Hu, N, Hunter, DJ, Innocenti, F, Jenab, M, Kaaks, R, Key, TJ, Khaw, K-T, Klein, EA, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, RC, LaCroix, A, Landi, MT, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, RL, Nakamura, Y, Oberg, AL, Owzar, K, Patel, AV, Peeters, PHM, Peters, U, Pezzilli, R, Piepoli, A, Porta, M, Real, FX, Riboli, E, Rothman, N, Scarpa, A, Shu, X-O, Silverman, DT, Soucek, P, Sund, M, Talar-Wojnarowska, R, Taylor, PR, Theodoropoulos, GE, Thornquist, M, Tjonneland, A, Tobias, GS, Trichopoulos, D, Vodicka, P, Wactawski-Wende, J, Wentzensen, N, Wu, C, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Hoover, R, Hartge, P, Fuchs, C, Chanock, SJ, Stolzenberg-Solomon, RS, and Amundadottir, LT

Abstract

We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 × 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 × 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 × 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 × 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 × 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.

Published
2014

23. The role of aspirin in cancer prevention

Author

Thun, Mj, Jacobs, Ej, Patrono, Carlo, Thun, Mj, Jacobs, Ej, and Patrono, Carlo

Abstract

Clinical guidelines for prophylactic aspirin use currently only consider the cardiovascular benefits of aspirin, weighed against the potential harm from aspirin-induced bleeding. Daily aspirin use has been convincingly shown to reduce the risk of colorectal cancer and recurrence of adenomatous polyps, but in average-risk populations, these benefits alone do not outweigh harms from aspirin-induced bleeding. Recently published secondary analyses of cardiovascular trials provide the first randomized evidence that daily aspirin use may also reduce the incidence of all cancers combined, even at low doses (75-100 mg daily). This Review considers the general mechanism of action that defines aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) as a class, the specific advantages of aspirin over other NSAIDs for prophylactic use, the current evidence concerning the main health outcomes affected by aspirin use, and the hypothesis that inhibition of platelet activation may mediate both the cardioprotective and cancer-preventive effects of low-dose aspirin. It also considers how even a 10% reduction in overall cancer incidence beginning during the first 10 years of treatment could tip the balance of benefits and risks favourably in average-risk populations.

Published
2012

24. Vitamin C and vitamin E supplement use and bladder cancer mortality in a large cohort of US men and women

Author

Jacobs, EJ and Henion, AK

Subjects
Vitamin E -- Health aspects, Bladder cancer -- Prevention, Vitamin C -- Health aspects, Health, Prevention, Health aspects
Abstract

Jacobs EJ, Henion AK, Briggs PJ, et al. Am J Epidemiol 2002;156:1002-1010. Some epidemiologic studies suggest that use of vitamin C or vitamin E supplements, both potent antioxidants, may reduce [...]

Published
2003

25. Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium.

Author

Elena JW, Steplowski E, Yu K, Hartge P, Tobias GS, Brotzman MJ, Chanock SJ, Stolzenberg-Solomon RZ, Arslan AA, Bueno-de-Mesquita HB, Helzlsouer K, Jacobs EJ, Lacroix A, Petersen G, Zheng W, Albanes D, Allen NE, Amundadottir L, Bao Y, and Boeing H

Abstract

Purpose: Diabetes is a suspected risk factor for pancreatic cancer, but questions remain about whether it is a risk factor or a result of the disease. This study prospectively examined the association between diabetes and the risk of pancreatic adenocarcinoma in pooled data from the NCI pancreatic cancer cohort consortium (PanScan).Methods: The pooled data included 1,621 pancreatic adenocarcinoma cases and 1,719 matched controls from twelve cohorts using a nested case-control study design. Subjects who were diagnosed with diabetes near the time (<2 years) of pancreatic cancer diagnosis were excluded from all analyses. All analyses were adjusted for age, race, gender, study, alcohol use, smoking, BMI, and family history of pancreatic cancer.Results: Self-reported diabetes was associated with a forty percent increased risk of pancreatic cancer (OR = 1.40, 95 % CI: 1.07, 1.84). The association differed by duration of diabetes; risk was highest for those with a duration of 2-8 years (OR = 1.79, 95 % CI: 1.25, 2.55); there was no association for those with 9+ years of diabetes (OR = 1.02, 95 % CI: 0.68, 1.52).Conclusions: These findings provide support for a relationship between diabetes and pancreatic cancer risk. The absence of association in those with the longest duration of diabetes may reflect hypoinsulinemia and warrants further investigation. [ABSTRACT FROM AUTHOR]

Published
2013
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30. Circulating 25-hydroxyvitamin D and risk of pancreatic cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers.

Author

Stolzenberg-Solomon RZ, Jacobs EJ, Arslan AA, Qi D, Patel AV, Helzlsouer KJ, Weinstein SJ, McCullough ML, Purdue MP, Shu X, Snyder K, Virtamo J, Wilkins LR, Yu K, Zeleniuch-Jacquotte A, Zheng W, Albanes D, Cai Q, Harvey C, and Hayes R

Abstract

Results from epidemiologic studies examining pancreatic cancer risk and vitamin D intake or 25-hydroxyvitamin D (25(OH)D) concentrations (the best indicator of vitamin D derived from diet and sun) have been inconsistent. Therefore, the authors conducted a pooled nested case-control study of participants from 8 cohorts within the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP) (1974-2006) to evaluate whether prediagnostic circulating 25(OH)D concentrations were associated with the development of pancreatic cancer. In total, 952 incident pancreatic adenocarcinoma cases occurred among participants (median follow-up, 6.5 years). Controls (n = 1,333) were matched to each case by cohort, age, sex, race/ethnicity, date of blood draw, and follow-up time. Conditional logistic regression analysis was used to calculate smoking-, body mass index-, and diabetes-adjusted odds ratios and 95% confidence intervals for pancreatic cancer. Clinically relevant 25(OH)D cutpoints were compared with a referent category of 50-<75 nmol/L. No significant associations were observed for participants with lower 25(OH)D status. However, a high 25(OH)D concentration (> or =100 nmol/L) was associated with a statistically significant 2-fold increase in pancreatic cancer risk overall (odds ratio = 2.12, 95% confidence interval: 1.23, 3.64). Given this result, recommendations to increase vitamin D concentrations in healthy persons for the prevention of cancer should be carefully considered. [ABSTRACT FROM AUTHOR]

Published
2010
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32. Case-control study of overweight, obesity, and colorectal cancer risk, overall and by tumor microsatellite instability status.

Author

Campbell PT, Jacobs ET, Ulrich CM, Figueiredo JC, Poynter JN, McLaughlin JR, Haile RW, Jacobs EJ, Newcomb PA, Potter JD, Le Marchand L, Green RC, Parfrey P, Younghusband HB, Cotterchio M, Gallinger S, Jenkins MA, Hopper JL, Baron JA, and Thibodeau SN

Abstract

Background: Being overweight or obese is an established risk factor for colorectal cancer, more so for men than for women. Approximately 10%-20% of colorectal tumors display microsatellite instability (MSI), defined as the expansion or contraction of small repeated sequences in the DNA of tumor tissue relative to nearby normal tissue. We evaluated associations between overweight or obesity and colorectal cancer risk, overall and by tumor MSI status.Methods: The study included 1794 case subjects with incident colorectal cancer who were identified through population-based cancer registries and 2684 of their unaffected sex-matched siblings as control subjects. Recent body mass index (BMI), BMI at age 20 years, and adult weight change were derived from self-reports of height and weight. Tumor MSI status, assessed at as many as 10 markers, was obtained for 69.7% of the case subjects and classified as microsatellite (MS)-stable (0% of markers unstable; n = 913), MSI-low (>0% but <30% of markers unstable; n = 149), or MSI-high (> or =30% of markers unstable; n = 188). Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). All statistical tests were two-sided.Results: Recent BMI, modeled in 5 kg/m(2) increments, was positively associated with risk of colorectal cancer for men and women combined (OR = 1.24; 95% CI = 1.15 to 1.34), for women only (OR = 1.20; 95% CI = 1.10 to 1.32), and for men only (OR = 1.30; 95% CI = 1.15 to 1.47). There was no interaction with sex (P = .22). Recent BMI, per 5 kg/m(2), was positively associated with the risk of MS-stable (OR = 1.38; 95% CI = 1.24 to 1.54) and MSI-low (OR = 1.33; 95% CI = 1.04 to 1.72) colorectal tumors, but not with the risk of MSI-high tumors (OR = 1.05; 95% CI = 0.84 to 1.31).Conclusion: The increased risk of colorectal cancer associated with a high BMI might be largely restricted to tumors that display the more common MS-stable phenotype, suggesting further that colorectal cancer etiology differs by tumor MSI status. [ABSTRACT FROM AUTHOR]

Published
2010
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34. Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33

Author

Hidemi Ito, Stephen K. Van Den Eeden, Abdisamad M. Ibrahim, Ching C. Lau, Preetha Rajaraman, Gloria M. Petersen, Judith Hoffman-Bolton, Colin P.N. Dinney, Chang Hyun Kang, Melinda C. Aldrich, Mark P. Purdue, Xiao-Ou Shu, William J. Blot, Sanjay Shete, Alpa V. Patel, Charles Kooperberg, Paolo Vineis, David Van Den Berg, Chao A. Hsiung, Anthony J. Swerdlow, Qing Lan, Wu Chou Su, Afshan Siddiq, Ulrike Peters, Katia Scotlandi, Sara H. Olson, Kendra Schwartz, Kelly L. Bolton, Chancellor Hohensee, Josep Lloreta, Kevin B. Jacobs, Debra T. Silverman, Rudolf Kaaks, Wei Zheng, Steven Gallinger, Junwen Wang, Angela Carta, Massimo Serra, Petra H.M. Peeters, Victoria L. Stevens, Yasushi Yatabe, Geraldine Cancel-Tassin, Joshua N. Sampson, Young Tae Kim, Graham A. Colditz, Pan-Chyr Yang, Baosen Zhou, Fredrick R. Schumacher, Nicolas Wentzensen, Evelyn Tay, Claudia Maria Hattinger, Chen Wu, Pilar Amiano, Mattias Johansson, Maxwell P. Lee, Christian P. Kratz, Michael B. Cook, Mingfeng Zhang, Kay-Tee Khaw, Jian-Min Yuan, Anne Zeleniuch-Jacquotte, Jinping Jia, Roberto Tirabosco, Jing Ma, Neil E. Caporaso, Christopher A. Haiman, Bu Tian Ji, Adrienne M. Flanagan, Neyssa Marina, Eric J. Jacobs, Sophia S. Wang, Chong-Jen Yu, Edward Giovannucci, Margaret Wrensch, Robert L. Grubb, Bin Zhu, Daniel O. Stram, Manolis Kogevinas, Margaret R. Karagas, Mazda Jenab, Alison M. Mondul, Jun Xu, Preethi S. Raj, Anders Ahlbom, Christine D. Berg, Shelley Niwa, Kala Visvanathan, Loic Le Marchand, Jorge R. Toro, Robert N. Hoover, Heather Spencer Feigelson, Michelle Brotzman, Laurence N. Kolonel, Krista A. Zanetti, Chengfeng Wang, Mary Ann Butler, Ann Truelove, Irene L. Andrulis, Hongbing Shen, H. Dean Hosgood, Ming Shyan Huang, Gee-Chen Chang, Jianjun Liu, John K. Wiencke, Stephanie J. Weinstein, Beatrice Melin, Kouya Shiraishi, Zhihua Yin, Lee E. Moore, Börje Ljungberg, Jolanta Lissowska, Elizabeth M. Gillanders, M. T. Landi, Cari M. Kitahara, Maria Feychting, Kuan-Yu Chen, Matthias Simon, Brian M. Wolpin, Hemang Parikh, Hannah P. Yang, Graham G. Giles, Alison Johnson, Demetrius Albanes, Carlos González, Brian E. Henderson, Xifeng Wu, Harvey A. Risch, Amy Hutchinson, Christopher Hautman, Constance Chen, Zhibin Hu, Donghui Li, Elio Riboli, Julie E. Buring, Curtis C. Harris, Xu Che, Núria Malats, Roger Henriksson, Rosario Tumino, Joanne S. Colt, Alfredo Carrato, Paolo Boffetta, Maria Pik Wong, Hideo Tanaka, Federico Canzian, Alan D. L. Sihoe, Chien-Jen Chen, Kenneth Muir, Chen Ying, Qincheng He, Melissa C. Southey, Marc Sanson, Victoria K. Cortessis, Sharon A. Savage, Wei Hu, Yao Tettey, Daniela S. Gerhard, Sofia Pavanello, Guangwen Cao, H. Barton Grossman, Michael Goggins, Hideo Kunitoh, Peter D. Inskip, Seth P. Lerner, Peter Kraft, David Thomas, Peng Guan, Chung Hsing Chen, I. Shou Chang, Christoffer Johansen, Roberta McKean-Cowdin, Lee J. 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Subjects
Male, SINGLE-NUCLEOTIDE POLYMORPHISM, Genome-wide association study, Epigenesis, Genetic, Gene Frequency, Molecular Biology, Genetics, Genetics (clinical), Neoplasms, Odds Ratio, Genome-wide association studies (GWAS), Telomerase, DNA METHYLATION Author Information, Association Studies Articles, General Medicine, PANCREATIC-CANCER, PROSTATE-CANCER, Neoplasm Proteins, POSTMENOPAUSAL BREAST-CANCER, TERT PROMOTER MUTATIONS, Gene Expression Regulation, Neoplastic, 2 SUSCEPTIBILITY LOCI, DNA methylation, Chromosomes, Human, Pair 5, Female, Risk, Locus (genetics), Single-nucleotide polymorphism, TERT and CLPTM1L gene, Biology, Polymorphism, Single Nucleotide, LUNG-CANCER, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Allele, Gene, Allele frequency, Alleles, Genetic association, chromosome 5p15.33, Computational Biology, Membrane Proteins, DNA Methylation, Genetic Loci, TELOMERE LENGTH, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 x 10(-39); Region 3: rs2853677, P = 3.30 x 10(-36) and PConditional = 2.36 x 10(-8); Region 4: rs2736098, P = 3.87 x 10(-12) and PConditional = 5.19 x 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 x 10(-6); and Region 6: rs10069690, P = 7.49 x 10(-15) and PConditional = 5.35 x 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 x 10(-18) and PConditional = 7.06 x 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

Published
2014

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

Author

Anne Tjønneland, Jason W. Hoskins, Kala Visvanathan, Yogesh K. Vashist, Dimitrios Trichopoulos, Matthew H. Kulke, Ruth C. Travis, Charles S. Fuchs, Herbert Yu, Kai Yu, Phyllis J. Goodman, Michael Goggins, Jean Wactawski-Wende, Laurie Burdette, Joanne W. Elena, Andrea Mambrini, Petra H.M. Peeters, H. Bas Bueno-de-Mesquita, Maria Teresa Landi, Ulrike Peters, Mingfeng Zhang, Laurence N. Kolonel, Hermann Brenner, Elżbieta Iskierka-Jażdżewska, Robert C. Kurtz, Stephen J. Chanock, Marie-Christine Boutron-Ruault, Ann L. Oberg, Elio Riboli, Maarten F. Bijlsma, Eric J. Jacobs, Manolis Kogevinas, Evelina Mocci, Steven Gallinger, Jinping Jia, Mark P. Purdue, Raffaele Pezzilli, Harvey A. Risch, Demetrius Albanes, Irene Collins, Maria Gazouli, Michelle Cotterchio, Oliver Strobel, Erica J. Childs, Charles C. Chung, Geoffrey S. Tobias, J. Ramón Quirós, Núria Malats, Robert N. Hoover, Pavel Vodicka, Brian M. Wolpin, Ugo Boggi, Patricia Hartge, Gloria M. Petersen, Peter Kraft, Christopher Hautman, Gary E. Goodman, Manal Hassan, Donghui Li, Howard D. Sesso, Malin Sund, Julie E. Buring, Loic Le Marchand, Wei Zheng, Xiao-Ou Shu, Ewa Małecka-Panas, Pavel Soucek, Salvatore Panico, Nicolas Wentzensen, Graham G. Giles, Alpa V. Patel, Daniele Campa, Myron D. Gross, Ghislaine Scelo, J. Michael Gaziano, Juozas Kupcinskas, Debra T. Silverman, Laufey T. Amundadottir, Rachael S. Stolzenberg-Solomon, Neil E. Caporaso, Mazda Jenab, Sara H. Olson, Stefano Landi, Giulia Martina Cavestro, Aruna Kamineni, Laura Beane-Freeman, Roger L. Milne, Rachel E. Neale, Aldo Scarpa, Kathy J. Helzlsouer, Miquel Porta, Emily White, Eric J. Duell, Paige M. Bracci, Nan Hu, Federico Canzian, Eric A. Klein, Gabriele Capurso, Anne Zeleniuch-Jacquotte, Eithne Costello, David J. Hunter, Rudolf Kaaks, Sonja I. Berndt, Kay-Tee Khaw, Nathaniel Rothman, Christian C. Abnet, Francesca Tavano, Christopher A. Haiman, Zhaoming Wang, Ofure Obazee, Alan A. Arslan, Edward Giovannucci, Alison P. Klein, Daniela Basso, Charles Kooperberg, Philip R. Taylor, Satu Männistö, Timothy J. Key, Mark D. Thornquist, Gabriella Andreotti, Lauren K. Brais, Gisella Figlioli, Vittorio Krogh, University Medical Center Utrecht, Imperial College Trust, Cancer Research UK, Medical Research Council UK (MRC), National Institute for Health Research (NIHR), Cancer Research UK (Reino Unido), Medical Research Council (Reino Unido), National Institute for Health Research (Reino Unido), Zhang, Mingfeng, Wang, Zhaoming, Obazee, Ofure, Jia, Jinping, Childs, Erica J, Hoskins, Jason, Figlioli, Gisella, Mocci, Evelina, Collins, Irene, Chung, Charles C, Hautman, Christopher, Arslan, Alan A, Beane Freeman, Laura, Bracci, Paige M, Buring, Julie, Duell, Eric J, Gallinger, Steven, Giles, Graham G, Goodman, Gary E, Goodman, Phyllis J, Kamineni, Aruna, Kolonel, Laurence N, Kulke, Matthew H, Malats, Núria, Olson, Sara H, Sesso, Howard D, Visvanathan, Kala, White, Emily, Zheng, Wei, Abnet, Christian C, Albanes, Demetriu, Andreotti, Gabriella, Brais, Lauren, Bueno de Mesquita, H. Ba, Basso, Daniela, Berndt, Sonja I, Boutron Ruault, Marie Christine, Bijlsma, Maarten F, Brenner, Hermann, Burdette, Laurie, Campa, Daniele, Caporaso, Neil E, Capurso, Gabriele, Cavestro, Giulia Martina, Cotterchio, Michelle, Costello, Eithne, Elena, Joanne, Boggi, Ugo, Gaziano, J. Michael, Gazouli, Maria, Giovannucci, Edward L, Goggins, Michael, Gross, Myron, Haiman, Christopher A, Hassan, Manal, Helzlsouer, Kathy J, Hu, Nan, Hunter, David J, Iskierka Jazdzewska, Elzbieta, Jenab, Mazda, Kaaks, Rudolf, Key, Timothy J, Khaw, Kay Tee, Klein, Eric A, Kogevinas, Manoli, Krogh, Vittorio, Kupcinskas, Juoza, Kurtz, Robert C, Landi, Maria T, Landi, Stefano, Le Marchand, Loic, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L, Neale, Rachel E, Oberg, Ann L, Panico, Salvatore, Patel, Alpa V, Peeters, Petra H. M, Peters, Ulrike, Pezzilli, Raffaele, Porta, Miquel, Purdue, Mark, Quiros, J. Ramón, Riboli, Elio, Rothman, Nathaniel, Scarpa, Aldo, Scelo, Ghislaine, Shu, Xiao Ou, Silverman, Debra T, Soucek, Pavel, Strobel, Oliver, Sund, Malin, Małecka Panas, Ewa, Taylor, Philip R, Tavano, Francesca, Travis, Ruth C, Thornquist, Mark, Tjønneland, Anne, Tobias, Geoffrey S, Trichopoulos, Dimitrio, Vashist, Yogesh, Vodicka, Pavel, Wactawski Wende, Jean, Wentzensen, Nicola, Yu, Herbert, Yu, Kai, Zeleniuch Jacquotte, Anne, Kooperberg, Charle, Risch, Harvey A, Jacobs, Eric J, Li, Donghui, Fuchs, Charle, Hoover, Robert, Hartge, Patricia, Chanock, Stephen J, Petersen, Gloria M, Stolzenberg Solomon, Rachael S, Wolpin, Brian M, Kraft, Peter, Klein, Alison P, Canzian, Federico, Amundadottir, Laufey T., Khaw, Kay-Tee [0000-0002-8802-2903], Apollo - University of Cambridge Repository, CCA -Cancer Center Amsterdam, Center of Experimental and Molecular Medicine, Radiotherapy, 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, Mc, Bijlsma, Mf, Brenner, H, Burdette, L, Campa, D, Caporaso, Ne, Capurso, G, Cavestro, GIULIA MARTINA, 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, Kt, 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, Ph, Peters, U, Pezzilli, R, Porta, M, Purdue, M, Quiros, Jr, Riboli, E, Rothman, N, Scarpa, A, Scelo, G, Shu, Xo, Silverman, Dt, Soucek, P, Strobel, O, Sund, M, Małecka Panas, E, Taylor, Pr, Tavano, F, Travis, Rc, Thornquist, M, Tjønneland, A, Tobias, G, 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, R, Wolpin, Bm, Kraft, P, Klein, Ap, Canzian, F, and Amundadottir, L. T.

Subjects
0301 basic medicine, Candidate gene, Pancreatic disease, GENETIC SUSCEPTIBILITY, pancreatic cancer, Datasets as Topic, Genome-wide association study, imputation, TRET, 0302 clinical medicine, Fine-mapping, GWAS, Imputation, NR5A2, Pancreatic cancer, Oncology, Genotype, Genetics, 3. Good health, fine-mapping, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 8, 616.37-006.6 [udc], BLADDER-CANCER, Single-nucleotide polymorphism, GENOTYPE IMPUTATION, BREAST, Polymorphism, Single Nucleotide, 03 medical and health sciences, Journal Article, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Pàncrees -- Càncer, Cancer och onkologi, LONG-RANGE INTERACTION, business.industry, medicine.disease, Pancreatic neoplasms, genetics, Polymorphism, single nucleotide, RISK LOCI, Fold change, COMMON VARIANT, Cromosomes, Pancreatic Neoplasms, 030104 developmental biology, Cancer and Oncology, business, Imputation (genetics), LRH-1, Priority Research Paper, Genome-Wide Association Study
Abstract

Altres ajuts: The authors acknowledge the contribution of the staff of the Cancer Genomics Research Laboratory (CGR) at the National Cancer Institute, NIH, for their help throughout the project. This work was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Additional acknowledgements for individual participating studies are listed in the Supplemental Materials. 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 = 4.88×10 −15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22×10 −9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70×10 −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 = 5.7×10 −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 = 7.5×10 −4 -2.0×10 −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

36. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci

Author

Rajesh Kumar, Gerald L. Andriole, Robert L. Grubb, Monica McGrath, Amanda Black, Manuela Gago-Dominguez, Margaret A. Knowles, Francisco X. Real, Nilanjan Chatterjee, Thorunn Rafnar, Kevin B. Jacobs, Silvia Polidoro, Debra T. Silverman, Sita H. Vermeulen, Manuel Sanchez, Núria Malats, Salvatore Panico, Amy Hutchinson, William Wheeler, Carmen Navarro, Montserrat Garcia-Closas, Carlotta Sacerdote, Gabriel Valdivia, Yi-Ping Fu, Kari Stefansson, Michelle A.T. Hildebrandt, Alessandra Allione, Katja K.H. Aben, Alison Johnson, W. Ryan Diver, Laurie Burdett, Sophia C.E. Bolick, David J. Hunter, Jarmo Virtamo, Jack A. Taylor, Ludmila Prokunina-Olsson, José I Sanz-Velez, Mark P. Purdue, Fulvio Ricceri, Elio Riboli, Maria Teresa Landi, Susan M. Gapstur, Søren Besenbacher, Joseph F. Fraumeni, Olivier Cussenot, J. Alfred Witjes, Victoria K. Cortessis, Paul Brennan, Tony Fletcher, David Van Den Berg, Börje Ljungberg, Lambertus A. Kiemeney, Dalsu Baris, Mark Teo, Zongli Xu, Geraldine Cancel-Tassin, Holger Dietrich, Zhaoming Wang, Maria D. Garcia-Prats, Françoise Clavel-Chapelon, Adonina Tardón, Paolo Vineis, Peter Rudnai, Margaret R. Karagas, Naomi E. Allen, H. Bas Bueno-de-Mesquita, Molly Schwenn, Jose I. Mayordomo, Ashley C. Godfrey, Manolis Kogevinas, Silvia Selinski, Stephen J. Chanock, Jonine D. Figueroa, Alan R. Schned, Stefano Porru, Mariana C. Stern, Demetrius Albanes, Simonetta Guarrera, Patrick Sulem, Immaculata De Vivo, Hushan Yang, Robert N. Hoover, Kvetoslava Koppova, Michael J. Thun, Malcolm C. Pike, Giuseppe Matullo, D T Bishop, Neil E. Caporaso, Klaus Golka, Eugen Gurzau, Colin P.N. Dinney, Josep Lloreta, Nathaniel Rothman, Eric J. Jacobs, Simone Benhamou, Alfredo Carrato, Federico Canzian, Xifeng Wu, Consol Serra, Anne Tjønneland, Jian-Min Yuan, Meredith Yeager, Reina García-Closas, Stephanie J. Weinstein, Jan G. Hengstler, Dimitrios Trichopoulos, Remco R. R. Makkinje, Anne E. Kiltie, Bogdan Czerniak, Meng Chen, Rothman, N, Garcia Closas, M, Chatterjee, N, Malats, N, Wu, X, Figueroa, Jd, Real, Fx, Van Den Berg, D, Matullo, G, Baris, D, Thun, M, Kiemeney, La, Vineis, P, De Vivo, I, Albanes, D, Purdue, Mp, Rafnar, T, Hildebrandt, Ma, Kiltie, Ae, Cussenot, O, Golka, K, Kumar, R, Taylor, Ja, Mayordomo, Ji, Jacobs, Kb, Kogevinas, M, Hutchinson, A, Wang, Z, Fu, Yp, Prokunina Olsson, L, Burdett, L, Yeager, M, Wheeler, W, Tardón, A, Serra, C, Carrato, A, García Closas, R, Lloreta, J, Johnson, A, Schwenn, M, Karagas, Mr, Schned, A, Andriole G., Jr, Grubb R., 3rd, Black, A, Jacobs, Ej, Diver, Wr, Gapstur, Sm, Weinstein, Sj, Virtamo, J, Cortessis, Vk, Gago Dominguez, M, Pike, Mc, Stern, Mc, Yuan, Jm, Hunter, Dj, Mcgrath, M, Dinney, Cp, Czerniak, B, Chen, M, Yang, H, Vermeulen, Sh, Aben, Kk, Witjes, Ja, Makkinje, Rr, Sulem, P, Besenbacher, S, Stefansson, K, Riboli, E, Brennan, P, Panico, Salvatore, Navarro, C, Allen, Ne, Bueno de Mesquita, Hb, Trichopoulos, D, Caporaso, Nicola, Landi, Mt, Canzian, F, Ljungberg, B, Tjonneland, A, Clavel Chapelon, F, Bishop, Dt, Teo, Mt, Knowles, Ma, Guarrera, S, Polidoro, S, Ricceri, F, Sacerdote, C, Allione, A, Cancel Tassin, G, Selinski, S, Hengstler, Jg, Dietrich, H, Fletcher, T, Rudnai, P, Gurzau, E, Koppova, K, Bolick, Sc, Godfrey, A, Xu, Z, Sanz Velez, Ji, D., García Prats M, Sanchez, M, Valdivia, G, Porru, S, Benhamou, S, Hoover, Rn, Fraumeni JF, Jr, Silverman, Dt, and Chanock, Sj

Subjects
Male, Arylamine N-Acetyltransferase, Chromosomes, Human, Pair 22, Genome-wide association study, Aetiology, screening and detection [ONCOL 5], medicine.disease_cause, Genome-wide association studies, Risk Factors, genome-wide association, bladder cancer, Psychology, Genetics, Sex Characteristics, Incidence, Bladder cancer, Smoking, Chromosome Mapping, Single Nucleotide, Tag SNP, Europe, Chromosomes, Human, Pair 2, Pair 2, Female, Human, Locus (genetics), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Chromosomes, Article, Molecular epidemiology [NCEBP 1], Translational research [ONCOL 3], medicine, Humans, Family, Genetic Predisposition to Disease, Polymorphism, Pair 18, Pair 22, Genome-Wide Association Study, Neoplasm Staging, Spain, United States, Urinary Bladder Neoplasms, Cancer, Chromosome, medicine.disease, Evaluation of complex medical interventions [NCEBP 2], Carcinogenesis, Chromosomes, Human, Pair 18
Abstract

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.

Published
2010

37. Genome-wide Association Study Of Survival In Patients With Pancreatic Adenocarcinoma

Author

Kala Visvanathan, Jean Wactawski-Wende, Salvatore Panico, Andrea Z. LaCroix, Patricia Hartge, Charles S. Fuchs, Chen Wu, Mazda Jenab, Chengfeng Wang, Brian M. Wolpin, Poorva Mudgal, Anne Zeleniuch-Jacquotte, Kay-Tee Khaw, Laufey T. Amundadottir, Elio Riboli, Marie-Christine Boutron-Ruault, Edward Giovannucci, Wei Zheng, Federico Canzian, Guoliang Jiang, Emily Steplowski, Julie E. Buring, H. Bas Bueno-de-Mesquita, Myron D. Gross, Michelle Brotzman, Eric J. Jacobs, Joanne W. Elena, Demetrius Albanes, Eric J. Duell, Stephen J. Chanock, Dongxin Lin, Göran Hallmans, David J. Hunter, Charles Kooperberg, Geoffrey S. Tobias, Alan A. Arslan, Zhi Rong Qian, Guangwen Cao, Anne Tjønneland, Kathy J. Helzlsouer, Alpa V. Patel, Howard D. Sesso, Jarmo Virtamo, Rachael Z. Stolzenberg-Solomon, Robert N. Hoover, J. Michael Gaziano, Mousheng Xu, Hongbing Shen, Gloria M. Petersen, Kai Yu, Peter Kraft, Xiao-Ou Shu, Dimitrios Trichopoulos, Zhao-Shen Li, Julie B. Mendelsohn, Amy Hutchinson, Wu, C, Kraft, P, Stolzenberg Solomon, R, Steplowski, E, Brotzman, M, Xu, M, Mudgal, P, Amundadottir, L, Arslan, Aa, Bueno de Mesquita, Hb, Gross, M, Helzlsouer, K, Jacobs, Ej, Kooperberg, C, Petersen, Gm, Zheng, W, Albanes, D, Boutron Ruault, Mc, Buring, Je, Canzian, F, Cao, G, Duell, Ej, Elena, Jw, Gaziano, Jm, Giovannucci, El, Hallmans, G, Hutchinson, A, Hunter, Dj, Jenab, M, Jiang, G, Khaw, Kt, Lacroix, A, Li, Z, Mendelsohn, Jb, Panico, Salvatore, Patel, Av, Qian, Zr, Riboli, E, Sesso, H, Shen, H, Shu, Xo, Tjonneland, A, Tobias, G, Trichopoulos, D, Virtamo, J, Visvanathan, K, Wactawski Wende, J, Wang, C, Yu, K, Zeleniuch Jacquotte, A, Chanock, S, Hoover, R, Hartge, P, Fuchs, C, Lin, D, and Wolpin, Bm

Subjects
Oncology, Male, Genome-wide association study, Kaplan-Meier Estimate, Gastroenterology, 0302 clinical medicine, Models, 80 and over, 2.1 Biological and endogenous factors, Non-Receptor, Pancreas cancer, Cancer, Aged, 80 and over, 0303 health sciences, Principal Component Analysis, Molecular Epidemiology, Tumor, Single Nucleotide, Middle Aged, Protein Tyrosine Phosphatases, Non-Receptor, 3. Good health, Survival Rate, Europe, 030220 oncology & carcinogenesis, Adenocarcinoma, Female, Adult, Asian Continental Ancestry Group, medicine.medical_specialty, China, European Continental Ancestry Group, Clinical Sciences, and over, Biology, Genetic polymorphisms, Polymorphism, Single Nucleotide, White People, Article, Paediatrics and Reproductive Medicine, 03 medical and health sciences, Pancreatic Cancer, Rare Diseases, Asian People, Genetic, Internal medicine, Pancreatic cancer, Biomarkers, Tumor, medicine, Cancer Genetics, Genetics, Humans, In patient, Polymorphism, Càncer de pàncrees, 030304 developmental biology, Proportional Hazards Models, Aged, Models, Genetic, Molecular epidemiology, Gastroenterology & Hepatology, Prevention, Polimorfisme genètic, Human Genome, medicine.disease, Pancreatic Neoplasms, Cancer genetics, Protein Tyrosine Phosphatases, Digestive Diseases, Biomarkers, Follow-Up Studies, Genome-Wide Association Study
Abstract

Background and objective: Survival of patients with pancreatic adenocarcinoma is limited and few prognostic factors are known. We conducted a two-stage genome-wide association study (GWAS) to identify germline variants associated with survival in patients with pancreatic adenocarcinoma. Methods: We analysed overall survival in relation to single nucleotide polymorphisms (SNPs) among 1005 patients from two large GWAS datasets, PanScan I and ChinaPC. Cox proportional hazards regression was used in an additive genetic model with adjustment for age, sex, clinical stage and the top four principal components of population stratification. The first stage included 642 cases of European ancestry (PanScan), from which the top SNPs (p10(-5)) were advanced to a joint analysis with 363 additional patients from China (ChinaPC). Results: In the first stage of cases of European descent, the top-ranked loci were at chromosomes 11p15.4, 18p11.21 and 1p36.13, tagged by rs12362504 (p=1.63x10(-7)), rs981621 (p=1.65x10(-7)) and rs16861827 (p=3.75x10(-7)), respectively. 131 SNPs with p10(-5) were advanced to a joint analysis with cases from the ChinaPC study. In the joint analysis, the top-ranked SNP was rs10500715 (minor allele frequency, 0.37; p=1.72x10(-7)) on chromosome 11p15.4, which is intronic to the SET binding factor 2 (SBF2) gene. The HR (95% CI) for death was 0.74 (0.66 to 0.84) in PanScan I, 0.79 (0.65 to 0.97) in ChinaPC and 0.76 (0.68 to 0.84) in the joint analysis. Conclusions: Germline genetic variation in the SBF2 locus was associated with overall survival in patients with pancreatic adenocarcinoma of European and Asian ancestry. This association should be investigated in additional large patient cohorts.

38. Rapid estimation of electroporation-dependent tissue properties in canine lung tumors using a deep neural network.

Author

Jacobs EJ 4th, Aycock KN, Santos PP, Tuohy JL, and Davalos RV

Subjects
Humans, Animals, Dogs, Electroporation, Electroporation Therapies, Electric Conductivity, Neural Networks, Computer, Biosensing Techniques, Lung Neoplasms
Abstract

The efficiency of electroporation treatments depends on the application of a critical electric field over the targeted tissue volume. Both the electric field and temperature distribution strongly depend on the tissue-specific electrical properties, which both differ between patients in healthy and malignant tissues and change in an electric field-dependent manner from the electroporation process itself. Therefore, tissue property estimations are paramount for treatment planning with electroporation therapies. Ex vivo methods to find electrical tissue properties often misrepresent the targeted tissue, especially when translating results to tumors. A voltage ramp is an in situ method that applies a series of increasing electric potentials across treatment electrodes and measures the resulting current. Here, we develop a robust deep neural network, trained on finite element model simulations, to directly predict tissue properties from a measured voltage ramp. There was minimal test error (R 2 >0.94;p<0.0001) in three important electric tissue properties. Further, our model was validated to correctly predict the complete dynamic conductivity curve in a previously characterized ex vivo liver model (R 2 >0.93;p<0.0001) within 100 s from probe insertion, showing great utility for a clinical application. Lastly, we characterize the first reported electrical tissue properties of lung tumors from five canine patients (R 2 >0.99;p<0.0001). We believe this platform can be incorporated prior to treatment to quickly ascertain patient-specific tissue properties required for electroporation treatment planning models or real-time treatment prediction algorithms. Further, this method can be used over traditional ex vivo methods for in situ tissue characterization with clinically relevant geometries., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors have patents related to the paper. R.V.D. has ownership interest in startup companies within the field of bioelectrics. In addition, R.V.D. also receives royalty income from technologies he has invented and serves as a consultant., (Copyright © 2023. Published by Elsevier B.V.)

Published
2024
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39. Mental health in undergraduate students several months into the COVID-19 pandemic compared to before the pandemic.

Author

Jacobs EJ, Spiker S, Newsome KB, Danielson ML, Bhupalam S, and Leeb RT

Abstract

Objective: To compare mental health indicators among undergraduates in Fall 2019, before the COVID-19 pandemic, and Fall 2020, when many students returned to campus amidst restrictions on in-person contact., Participants: Analyses included 26,881 undergraduate students, aged 18-24, from 70 U.S. institutions., Methods: Students completed the National College Health Assessment-III survey in Fall 2019 or Fall 2020., Results: The prevalences of high stress, loneliness, a low flourishing score, and serious psychological distress increased in 2020 compared to 2019. Serious psychological distress increased substantially in 2020 among students not living with family (adjusted prevalence ratio (aPR)=1.36, 95% CI 1.29-1.45) but not among students living with family (aPR = 1.09, 95% CI 0.95-1.26)., Conclusions: These results suggest prevalences of several indicators of poor mental health were elevated among U.S. undergraduates several months into the pandemic. The pandemic may have had greater impact on mental health among students not living with family.

Published
2023
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40. Ultra-thin and ultra-porous nanofiber networks as a basement-membrane mimic.

Author

Graybill PM, Jacobs EJ 4th, Jana A, Agashe A, Nain AS, and Davalos RV

Subjects
Porosity, Blood-Brain Barrier physiology, Coculture Techniques, Basement Membrane, Nanofibers
Abstract

Current basement membrane (BM) mimics used for modeling endothelial and epithelial barriers in vitro do not faithfully recapitulate key in vivo physiological properties such as BM thickness, porosity, stiffness, and fibrous composition. Here, we use networks of precisely arranged nanofibers to form ultra-thin (∼3 μm thick) and ultra-porous (∼90%) BM mimics for blood-brain barrier modeling. We show that these nanofiber networks enable close contact between endothelial monolayers and pericytes across the membrane, which are known to regulate barrier tightness. Cytoskeletal staining and transendothelial electrical resistance (TEER) measurements reveal barrier formation on nanofiber membranes integrated within microfluidic devices and transwell inserts. Further, significantly higher TEER values indicate a biological benefit for co-cultures formed on the ultra-thin nanofiber membranes. Our BM mimic overcomes critical technological challenges in forming co-cultures that are in proximity and facilitate cell-cell contact, while still being constrained to their respective sides. We anticipate that our nanofiber networks will find applications in drug discovery, cell migration, and barrier dysfunction studies.

Published
2023
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41. Spatiotemporal estimations of temperature rise during electroporation treatments using a deep neural network.

Author

Jacobs EJ 4th, Campelo SN, Aycock KN, Yao D, and Davalos RV

Subjects
Swine, Animals, Temperature, Electric Conductivity, Neural Networks, Computer, Electroporation methods, Electroporation Therapies
Abstract

The nonthermal mechanism for irreversible electroporation has been paramount for treating tumors and cardiac tissue in anatomically sensitive areas, where there is concern about damage to nearby bowels, ducts, blood vessels, or nerves. However, Joule heating still occurs as a secondary effect of applying current through a resistive tissue and must be minimized to maintain the benefits of electroporation at high voltages. Numerous thermal mitigation protocols have been proposed to minimize temperature rise, but intraoperative temperature monitoring is still needed. We show that an accurate and robust temperature prediction AI model can be developed using estimated tissue properties (bulk and dynamic conductivity), known geometric properties (probe spacing), and easily measurable treatment parameters (applied voltage, current, and pulse number). We develop the 2-layer neural network on realistic 2D finite element model simulations with conditions encompassing most electroporation applications. Calculating feature contributions, we found that temperature prediction is mostly dependent on current and pulse number and show that the model remains accurate when incorrect tissue properties are intentionally used as input parameters. Lastly, we show that the model can predict temperature rise within ex vivo perfused porcine livers, with error <0.5 °C. This model, using easily acquired parameters, is shown to predict temperature rise in over 1000 unique test conditions with <1 °C error and no observable outliers. We believe the use of simple, readily available input parameters would allow this model to be incorporated in many already available electroporation systems for real-time temperature estimations., Competing Interests: Declaration of competing interest The authors have patents related to the paper. R.V.D. has ownership interest for startup companies within the field of bioelectrics. In addition, R.V.D. also receives royalty income from technologies he has invented and serves as a consultant., (Copyright © 2023. Published by Elsevier Ltd.)

Published
2023
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43. A prospective case-cohort analysis of plasma metabolites and breast cancer risk.

Author

Stevens VL, Carter BD, Jacobs EJ, McCullough ML, Teras LR, and Wang Y

Subjects
Female, Humans, Cohort Studies, Prospective Studies, Risk Factors, Breast Neoplasms epidemiology, Breast Neoplasms etiology, Breast Neoplasms diagnosis
Abstract

Background: Breast cancer incidence rates have not declined despite an improvement in risk prediction and the identification of modifiable risk factors, suggesting the need to identify novel risk factors and etiological pathways involved in this cancer. Metabolomics has emerged as a promising tool to find circulating metabolites associated with breast cancer risk., Methods: Untargeted metabolomic analysis was done on prediagnostic plasma samples from a case-cohort study of 1695 incident breast cancer cases and a 1983 women subcohort drawn from Cancer Prevention Study 3. The associations of 868 named metabolites (per one standard deviation increase) with breast cancer were determined using Prentice-weighted Cox proportional hazards regression modeling., Results: A total of 11 metabolites were associated with breast cancer at false discovery rate (FDR) < 0.05 with the majority having inverse association [ranging from RR = 0.85 (95% CI 0.80-0.92) to RR = 0.88 (95% CI 0.82-0.94)] and one having a positive association [RR = 1.14 (95% CI 1.06-1.23)]. An additional 50 metabolites were associated at FDR < 0.20 with inverse associations ranging from RR = 0.88 (95% CI 0.81-0.94) to RR = 0.91 (95% CI 0.85-0.98) and positive associations ranging from RR = 1.13 (95% CI 1.05-1.22) to RR = 1.11 (95% CI 1.02-1.20). Several of these associations validated the findings of previous metabolomic studies. These included findings that several progestogen and androgen steroids were associated with increased risk of breast cancer in postmenopausal women and four phospholipids, and the amino acids glutamine and asparagine were associated with decreased risk of this cancer in pre- and postmenopausal women. Several novel associations were also identified, including a positive association for syringol sulfate, a biomarker for smoked meat, and 3-methylcatechol sulfate and 3-hydroxypyridine glucuronide, which are metabolites of xenobiotics used for the production of pesticides and other products., Conclusions: Our study validated previous metabolite findings and identified novel metabolites associated with breast cancer risk, demonstrating the utility of large metabolomic studies to provide new leads for understanding breast cancer etiology. Our novel findings suggest that consumption of smoked meats and exposure to catechol and pyridine should be investigated as potential risk factors for breast cancer., (© 2023. The Author(s).)

Published
2023
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44. Real-Time Temperature Rise Estimation during Irreversible Electroporation Treatment through State-Space Modeling.

Author

Campelo SN, Jacobs EJ 4th, Aycock KN, and Davalos RV

Abstract

To evaluate the feasibility of real-time temperature monitoring during an electroporation-based therapy procedure, a data-driven state-space model was developed. Agar phantoms mimicking low conductivity (LC) and high conductivity (HC) tissues were tested under the influences of high (HV) and low (LV) applied voltages. Real-time changes in impedance, measured by Fourier Analysis SpecTroscopy (FAST) along with the known tissue conductivity and applied voltages, were used to train the model. A theoretical finite element model was used for external validation of the model, producing model fits of 95.8, 88.4, 90.7, and 93.7% at 4 mm and 93.2, 58.9, 90.0, and 90.1% at 10 mm for the HV-HC, LV-LC, HV-LC, and LV-HC groups, respectively. The proposed model suggests that real-time temperature monitoring may be achieved with good accuracy through the use of real-time impedance monitoring.

Published
2022
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45. Microbial rhodoquinone biosynthesis proceeds via an atypical RquA-catalyzed amino transfer from S-adenosyl-L-methionine to ubiquinone.

Author

Neupane T, Chambers LR, Godfrey AJ, Monlux MM, Jacobs EJ, Whitworth S, Spawn JE, Clingman SHK, Vergunst KL, Niven FM, Townley JJ, Orion IW, Goodspeed CR, Cooper KA, Cronk JD, Shepherd JN, and Langelaan DN

Abstract

Rhodoquinone (RQ) is a close analogue of ubiquinone (UQ) that confers diverse bacterial and eukaryotic taxa the ability to utilize fumarate as an electron acceptor in hypoxic conditions. The RquA protein, identified in a Rhodospirillum rubrum RQ-deficient mutant, has been shown to be required for RQ biosynthesis in bacteria. In this report, we demonstrate that RquA, homologous to SAM-dependent methyltransferases, is necessary and sufficient to catalyze RQ biosynthesis from UQ in vitro. Remarkably, we show that RquA uses SAM as the amino group donor in a substitution reaction that converts UQ to RQ. In contrast to known aminotransferases, RquA does not use pyridoxal 5'-phosphate (PLP) as a coenzyme, but requires the presence of Mn 2+ as a cofactor. As these findings reveal, RquA provides an example of a non-canonical SAM-dependent enzyme that does not catalyze methyl transfer, instead it uses SAM in an atypical amino transfer mechanism., (© 2022. The Author(s).)

Published
2022
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46. Prospective associations of hemoglobin A 1c and c-peptide with risk of diabetes-related cancers in the Cancer Prevention Study-II Nutrition Cohort.

Author

Campbell PT, Newton CC, Jacobs EJ, McCullough ML, Wang Y, Rees-Punia E, Guinter MA, Murphy N, Koshiol J, Dehal AN, Rohan T, Strickler H, Petrick J, Gunter M, Zhang X, McGlynn KA, Pollak M, Patel AV, and Gapstur SM

Subjects
Female, Humans, Male, C-Peptide, Cohort Studies, Glycated Hemoglobin, Hemoglobin A, Colorectal Neoplasms diagnosis, Diabetes Mellitus, Type 2 epidemiology, Liver Neoplasms complications
Abstract

Self-reported type 2 diabetes mellitus (T2DM) is a risk factor for many cancers, suggesting its pathology relates to carcinogenesis. We conducted a case-cohort study to examine associations of hemoglobin A 1c (HbA 1c ) and c-peptide with cancers associated with self-reported T2DM. This study was drawn from a prospective cohort of 32,383 women and men who provided blood specimens at baseline: c-peptide and HbA 1c were assessed in 3,000 randomly selected participants who were cancer-free-at-baseline and an additional 2,281 participants who were cancer-free-at-baseline and subsequently diagnosed with incident colorectal, liver, pancreatic, female breast, endometrial, ovarian, bladder, or kidney cancers. Weighted-Cox regression models estimated hazards ratios (HRs) and 95% confidence intervals (CI), adjusted for covariates. C-peptide was associated with higher risk of liver cancer (per standard deviation (SD) HR: 1.80; 95%CI: 1.32-2.46). HbA 1c was associated with higher risk of pancreatic cancer (per SD HR: 1.21 95%CI 1.05-1.40) and with some suggestion of higher risks for all-cancers-of-interest (per SD HR: 1.05; 95%CI: 0.99-1.11) and colorectal (per SD HR: 1.09; 95%CI: 0.98-1.20), ovarian (per SD HR: 1.18; 95%CI 0.96-1.45) and bladder (per SD HR: 1.08; 95%CI 0.96-1.21) cancers. Compared to no self-reported T2DM and HbA 1c <6.5% (reference group), self-reported T2DM and HbA 1c <6.5% (i.e., T2DM in good glycemic control) was not associated with risk of colorectal cancer, whereas it was associated with higher risks of all-cancers-of-interest combined (HR: 1.28; 95%CI: 1.01-1.62), especially for breast and endometrial cancers. Additional large, prospective studies are needed to further explore the roles of hyperglycemia, hyperinsulinemia, and related metabolic traits with T2DM-associated cancers to better understand the mechanisms underlying the self-reported T2DM-cancer association and to identify persons at higher cancer risk., Competing Interests: Conflict of interest statement The authors declare that they have no conflicts of interest. The authors declare no potential conflicts of interest.

Published
2022
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47. Experimental and Numerical Investigation of Parameters Affecting High-Frequency Irreversible Electroporation for Prostate Cancer Ablation.

Author

Aycock KN, Vadlamani RA, Jacobs EJ, Imran KM, Verbridge SS, Allen IC, Manuchehrabadi N, and Davalos RV

Subjects
Heart Rate, Humans, Male, Muscle Contraction, Quality of Life, Electroporation, Prostatic Neoplasms surgery
Abstract

While the primary goal of focal therapy for prostate cancer (PCa) is conserving patient quality of life by reducing oncological burden, available modalities use thermal energy or whole-gland radiation which can damage critical neurovascular structures within the prostate and increase risk of genitourinary dysfunction. High-frequency irreversible electroporation (H-FIRE) is a promising alternative ablation modality that utilizes bursts of pulsed electric fields (PEFs) to destroy aberrant cells via targeted membrane damage. Due to its nonthermal mechanism, H-FIRE offers several advantages over state-of-the-art treatments, but waveforms have not been optimized for treatment of PCa. In this study, we characterize lethal electric field thresholds (EFTs) for H-FIRE waveforms with three different pulse widths as well as three interpulse delays in vitro and compare them to conventional irreversible electroporation (IRE). Experiments were performed in non-neoplastic and malignant prostate cells to determine the effect of waveforms on both targeted (malignant) and adjacent (non-neoplastic) tissue. A numerical modeling approach was developed to estimate the clinical effects of each waveform including extent of nonthermal ablation, undesired thermal damage, and nerve excitation. Our findings indicate that H-FIRE waveforms with pulse durations of 5 and 10 μs provide large ablations comparable to IRE with tolerable levels of thermal damage and minimized muscle contractions. Lower duration (2 μs) H-FIRE waveforms exhibit the least amount of muscle contractions but require increased voltages which may be accompanied by unwanted thermal damage., (Copyright © 2022 by ASME.)

Published
2022
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48. The Applications of Focused Ultrasound (FUS) in Alzheimer's Disease Treatment: A Systematic Review on Both Animal and Human Studies.

Author

Liu X, Naomi SSM, Sharon WL, and Russell EJ

Abstract

Alzheimer's disease (AD) affects the basic ability to function and has imposed an immense burden on the community and health care system. Focused ultrasound (FUS) has recently been proposed as a novel noninvasive therapeutic approach for AD. However, systematic reviews on the FUS application in AD treatment have not been forthcoming. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria to summarize the techniques associated with safety and efficacy, as well as possible underlying mechanisms of FUS effects on AD in animal and human studies. Animal studies demonstrated FUS with microbubbles (FUS-MB) induced blood-brain-barrier (BBB) opening that could facilitate various therapeutic agents entering the brain. Repeated FUS-MB and FUS stimulation can relieve AD pathology and improve cognitive and memory function. Human studies showed repeated FUS-MB are well tolerated with few adverse events and FUS stimulation could enhance local perfusion and neural function, which correlated with cognitive improvement. We conclude that FUS is a feasible and safe therapeutic and drug delivery strategy for AD. However, FUS treatment on humans is still in the early stages and requires further optimization and standardization., (Copyright: © 2021 Liu et al.)

Published
2021
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49. A 584 bp deletion in CTRB2 inhibits chymotrypsin B2 activity and secretion and confers risk of pancreatic cancer.

Author

Jermusyk A, Zhong J, Connelly KE, Gordon N, Perera S, Abdolalizadeh E, Zhang T, O'Brien A, Hoskins JW, Collins I, Eiser D, Yuan C, Risch HA, Jacobs EJ, Li D, Du M, Stolzenberg-Solomon RZ, Klein AP, Smith JP, Wolpin BM, Chanock SJ, Shi J, Petersen GM, Westlake CJ, and Amundadottir LT

Subjects
Case-Control Studies, Chymotrypsin antagonists & inhibitors, Chymotrypsin metabolism, Genome-Wide Association Study, Genotype, Humans, Pancreatic Neoplasms etiology, Pancreatic Neoplasms metabolism, Chymotrypsin genetics, Pancreatic Neoplasms pathology, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Sequence Deletion
Abstract

Genome-wide association studies (GWASs) have discovered 20 risk loci in the human genome where germline variants associate with risk of pancreatic ductal adenocarcinoma (PDAC) in populations of European ancestry. Here, we fine-mapped one such locus on chr16q23.1 (rs72802365, p = 2.51 × 10 -17 , OR = 1.36, 95% CI = 1.31-1.40) and identified colocalization (PP = 0.87) with aberrant exon 5-7 CTRB2 splicing in pancreatic tissues (p GTEx = 1.40 × 10 -69 , β GTEx = 1.99; p LTG = 1.02 × 10 -30 , β LTG = 1.99). Imputation of a 584 bp structural variant overlapping exon 6 of CTRB2 into the GWAS datasets resulted in a highly significant association with pancreatic cancer risk (p = 2.83 × 10 -16 , OR = 1.36, 95% CI = 1.31-1.42), indicating that it may underlie this signal. Exon skipping attributable to the deletion (risk) allele introduces a premature stop codon in exon 7 of CTRB2, yielding a truncated chymotrypsinogen B2 protein that lacks chymotrypsin activity, is poorly secreted, and accumulates intracellularly in the endoplasmic reticulum (ER). We propose that intracellular accumulation of a nonfunctional chymotrypsinogen B2 protein leads to ER stress and pancreatic inflammation, which may explain the increased pancreatic cancer risk in carriers of CTRB2 exon 6 deletion alleles., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Published
2021
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50. Association between Smoking Cannabis and Quitting Cigarettes in a Large American Cancer Society Cohort.

Author

Westmaas JL, Strollo SE, Newton CC, Carter BD, Diver WR, Flanders WD, Stevens VL, Patel AV, Alcaraz KI, Thrul J, and Jacobs EJ

Subjects
Adult, Cross-Sectional Studies, Female, Follow-Up Studies, Humans, Intention, Longitudinal Studies, Male, Middle Aged, Smoking Cessation methods, Cigarette Smoking epidemiology, Marijuana Smoking epidemiology, Smoking Cessation statistics & numerical data
Abstract

Background: Cannabis use is increasing, including among smokers, an at-risk population for cancer. Research is equivocal on whether using cannabis inhibits quitting cigarettes. The current longitudinal study investigated associations between smoking cannabis and subsequently quitting cigarettes., Methods: Participants were 4,535 adult cigarette smokers from a cohort enrolled in the American Cancer Society's Cancer Prevention Study-3 in 2009-2013. Cigarette quitting was assessed on a follow-up survey in 2015-2017, an average of 3.1 years later. Rates of quitting cigarettes at follow-up were examined by retrospectively assessed baseline cannabis smoking status ( never, former, recent ), and by frequency of cannabis smoking among recent cannabis smokers ( low : ≤3 days/month; medium : 4-19 days/month; high : ≥20 days/month). Logistic regression models adjusted for sociodemographic factors, smoking- and health-related behaviors, and time between baseline and follow-up., Results: Adjusted cigarette quitting rates at follow-up did not differ significantly by baseline cannabis smoking status [never 36.2%, 95% confidence interval (CI), 34.5-37.8; former 34.1%, CI, 31.4-37.0; recent 33.6%, CI, 30.1-37.3], nor by frequency of cannabis smoking (low 31.4%, CI, 25.6-37.3; moderate 36.7%, CI, 30.7-42.3; high 34.4%, CI, 28.3-40.2) among recent baseline cannabis smokers. In cross-sectional analyses conducted at follow-up, the proportion of cigarette smokers intending to quit smoking cigarettes in the next 30 days did not differ by cannabis smoking status ( P = 0.83)., Conclusions: Results do not support the hypothesis that cannabis smoking inhibits quitting cigarette smoking among adults., Impact: Future longitudinal research should include follow-ups of >1 year, and assess effects of intensity/frequency of cannabis use and motivation to quit on smoking cessation., (©2021 The Authors; Published by the American Association for Cancer Research.)

Published
2021
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