188 results on '"Brais, Lauren"'
Search Results
152. A blood-based metabolomic signature predictive of risk for pancreatic cancer
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Irajizad, Ehsan, Kenney, Ana, Tang, Tiffany, Vykoukal, Jody, Wu, Ranran, Murage, Eunice, Dennison, Jennifer B., Sans, Marta, Long, James P., Loftus, Maureen, Chabot, John A., Kluger, Michael D., Kastrinos, Fay, Brais, Lauren, Babic, Ana, Jajoo, Kunal, Lee, Linda S., Clancy, Thomas E., Ng, Kimmie, Bullock, Andrea, Genkinger, Jeanine M., Maitra, Anirban, Do, Kim-Anh, Yu, Bin, Wolpin, Brian M., Hanash, Sam, and Fahrmann, Johannes F.
- Abstract
Emerging evidence implicates microbiome involvement in the development of pancreatic cancer (PaCa). Here, we investigate whether increases in circulating microbial-related metabolites associate with PaCa risk by applying metabolomics profiling to 172 sera collected within 5 years prior to PaCa diagnosis and 863 matched non-subject sera from participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cohort. We develop a three-marker microbial-related metabolite panel to assess 5-year risk of PaCa. The addition of five non-microbial metabolites further improves 5-year risk prediction of PaCa. The combined metabolite panel complements CA19-9, and individuals with a combined metabolite panel + CA19-9 score in the top 2.5th percentile have absolute 5-year risk estimates of >13%. The risk prediction model based on circulating microbial and non-microbial metabolites provides a potential tool to identify individuals at high risk of PaCa that would benefit from surveillance and/or from potential cancer interception strategies.
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- 2023
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153. Association of progression-free survival with overall survival (OS) in patients (pts) with neuroendocrine tumor (NET) treated with somatostatin analogs.
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Ter-Minassian, Monica, primary, Brooks, Nichole V, additional, Brais, Lauren K, additional, Chan, Jennifer A., additional, Christiani, David C., additional, Lin, Xihong, additional, Gabriel, Sylvie, additional, Dinet, Jerome, additional, and Kulke, Matthew H., additional
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- 2015
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154. Survival Among Patients With Pancreatic Cancer and Long-Standing or Recent-Onset Diabetes Mellitus
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Yuan, Chen, primary, Rubinson, Douglas A., additional, Qian, Zhi Rong, additional, Wu, Chen, additional, Kraft, Peter, additional, Bao, Ying, additional, Ogino, Shuji, additional, Ng, Kimmie, additional, Clancy, Thomas E., additional, Swanson, Richard S., additional, Gorman, Megan J., additional, Brais, Lauren K., additional, Li, Tingting, additional, Stampfer, Meir J., additional, Hu, Frank B., additional, Giovannucci, Edward L., additional, Kulke, Matthew H., additional, Fuchs, Charles S., additional, and Wolpin, Brian M., additional
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- 2015
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155. Cell Cycle Protein Expression in Neuroendocrine Tumors: Association of CDK4/CDK6, CCND1, and Phosphorylated Retinoblastoma Protein With Proliferative Index.
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Yan Shi, Zhi Rong Qian, Sui Zhang, Wanwan Li, Yohei Masugi, Tingting Li, Chan, Jennifer A., Juhong Yang, Da Silva, Annacarolina, Mancang Gu, Li Liu, Tsuyoshi Hamada, Keisuke Kosumi, Trevor Dutton, Brais, Lauren K., Reiko Nishihara, Fuchs, Charles S., Shuji Ogino, and Kulke, Matthew H.
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- 2017
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156. Clinical presentation and outcomes in patients with advanced pheochromcytoma/paraganglioma: Evidence of temozolomide efficacy.
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Halperin, Daniel M., primary, Brais, Lauren, additional, Ramaiya, Nikhil H., additional, and Kulke, Matthew, additional
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- 2014
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157. Somatic mutation of CDKN1B in small intestine neuroendocrine tumors
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Francis, Joshua M, primary, Kiezun, Adam, additional, Ramos, Alex H, additional, Serra, Stefano, additional, Pedamallu, Chandra Sekhar, additional, Qian, Zhi Rong, additional, Banck, Michaela S, additional, Kanwar, Rahul, additional, Kulkarni, Amit A, additional, Karpathakis, Anna, additional, Manzo, Veronica, additional, Contractor, Tanupriya, additional, Philips, Juliet, additional, Nickerson, Elizabeth, additional, Pho, Nam, additional, Hooshmand, Susanne M, additional, Brais, Lauren K, additional, Lawrence, Michael S, additional, Pugh, Trevor, additional, McKenna, Aaron, additional, Sivachenko, Andrey, additional, Cibulskis, Kristian, additional, Carter, Scott L, additional, Ojesina, Akinyemi I, additional, Freeman, Samuel, additional, Jones, Robert T, additional, Voet, Douglas, additional, Saksena, Gordon, additional, Auclair, Daniel, additional, Onofrio, Robert, additional, Shefler, Erica, additional, Sougnez, Carrie, additional, Grimsby, Jonna, additional, Green, Lisa, additional, Lennon, Niall, additional, Meyer, Tim, additional, Caplin, Martyn, additional, Chung, Daniel C, additional, Beutler, Andreas S, additional, Ogino, Shuji, additional, Thirlwell, Christina, additional, Shivdasani, Ramesh, additional, Asa, Sylvia L, additional, Harris, Chris R, additional, Getz, Gad, additional, Kulke, Matthew, additional, and Meyerson, Matthew, additional
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- 2013
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158. Prognostic Significance of MTOR Pathway Component Expression in Neuroendocrine Tumors
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Qian, Zhi Rong, primary, Ter-Minassian, Monica, additional, Chan, Jennifer A., additional, Imamura, Yu, additional, Hooshmand, Susanne M., additional, Kuchiba, Aya, additional, Morikawa, Teppei, additional, Brais, Lauren K., additional, Daskalova, Anastassia, additional, Heafield, Rachel, additional, Lin, Xihong, additional, Christiani, David C., additional, Fuchs, Charles S., additional, Ogino, Shuji, additional, and Kulke, Matthew H., additional
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- 2013
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159. Abstract 2199: Associations of genetic polymorphisms in VEGFR1 with progression-free and overall survival in patients with neuroendocrine tumors treated with the VEGFA inhibitor bevacizumab.
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Ter-Minassian, Monica, primary, Qian, ZhiRong R., additional, Chan, Jennifer A., additional, Hooshmand, Susanne M., additional, Brais, Lauren K., additional, Heafield, Rachel, additional, Lin, Xihong, additional, Liu, Geoffrey, additional, Christiani, David C., additional, and Kulke, Matthew H., additional
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- 2013
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160. Clinical presentation, recurrence, and survival in patients with neuroendocrine tumors: results from a prospective institutional database
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Ter-Minassian, Monica, primary, Chan, Jennifer A, additional, Hooshmand, Susanne M, additional, Brais, Lauren K, additional, Daskalova, Anastassia, additional, Heafield, Rachel, additional, Buchanan, Laurie, additional, Qian, Zhi Rong, additional, Fuchs, Charles S, additional, Lin, Xihong, additional, Christiani, David C, additional, and Kulke, Matthew H, additional
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- 2013
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161. Association Between Somatostatin Receptor Expression and Clinical Outcomes in Neuroendocrine Tumors.
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Zhi Rong Qian, Tingting Li, Ter-Minassian, Monica, Juhong Yang, Chan, Jennifer A., Brais, Lauren K., Yohei Masugi, Thiaglingam, Arunthathi, Brooks, Nichole, Reiko Nishihara, Bonnemarie, Mireille, Atsuhiro Masuda, Kentaro Inamura, Kim, Sun A., Kosuke Mima, Yasutaka Sukawa,, Ruoxu Dou, Xihong Lin, Christiani, David C., and Schmidlin, Fabien
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- 2016
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162. Abstract 3633: Prognostic value of chromogranin A and alkaline phosphatase in patients with advanced neuroendocrine tumor
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Ter-Minassian, Monica, primary, Chan, Jennifer A., additional, Hooshmand, Susanne M., additional, Brais, Lauren K., additional, Daskalova, Anastassia, additional, Heafield, Rachel, additional, Qian, Zhiron, additional, Lin, Xihong, additional, Christiani, David C., additional, and Kulke, Matthew H., additional
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- 2012
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163. Diagnostic TR-FRET assays for detection of antibodies in patient samples
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Yue, Hong, Nowak, Radosław P., Overwijn, Daan, Payne, N. Connor, Fischinger, Stephanie, Atyeo, Caroline, Lam, Evan C., St. Denis, Kerri, Brais, Lauren K., Konishi, Yoshinobu, Sklavenitis-Pistofidis, Romanos, Baden, Lindsey R., Nilles, Eric J., Karlson, Elizabeth W., Yu, Xu G., Li, Jonathan Z., Woolley, Ann E., Ghobrial, Irene M., Meyerhardt, Jeffrey A., Balazs, Alejandro B., Alter, Galit, Mazitschek, Ralph, and Fischer, Eric S.
- Abstract
Serological assays are important diagnostic tools for surveying exposure to the pathogen, monitoring immune response post vaccination, and managing spread of the infectious agent among the population. Current serological laboratory assays are often limited because they require the use of specialized laboratory technology and/or work with a limited number of sample types. Here, we evaluate an alternative by developing time-resolved Förster resonance energy transfer (TR-FRET) homogeneous assays that exhibited exceptional versatility, scalability, and sensitivity and outperformed or matched currently used strategies in terms of sensitivity, specificity, and precision. We validated the performance of the assays measuring total immunoglobulin G (IgG) levels; antibodies against severe acute respiratory syndrome coronavirus (SARS-CoV) or Middle Eastern respiratory syndrome (MERS)-CoV spike (S) protein; and SARS-CoV-2 S and nucleocapsid (N) proteins and applied it to several large sample sets and real-world applications. We further established a TR-FRET-based ACE2-S competition assay to assess the neutralization propensity of the antibodies. Overall, these TR-FRET-based serological assays can be rapidly extended to other antigens and are compatible with commonly used plate readers.
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- 2023
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164. Survival Among Patients With Pancreatic Cancer and Long-Standing or Recent-Onset Diabetes Mellitus.
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Chen Yuan, Rubinson, Douglas A., Zhi Rong Qian, Chen Wu, Kraft, Peter, Ying Bao, Shuji Ogino, Ng, Kimmie, Clancy, Thomas E., Swanson, Richard S., Gorman, Megan J., Brais, Lauren K., Li, Tingting, Stampfer, Meir J., Hu, Frank B., Giovannucci, Edward L., Kulke, Matthew H., Fuchs, Charles S., and Wolpin, Brian M.
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- 2015
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165. Association Between Tumor Progression Endpoints and Overall Survival in Patients with Advanced Neuroendocrine Tumors
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Ter‐Minassian, Monica, Zhang, Sui, Brooks, Nichole V., Brais, Lauren K., Chan, Jennifer A., Christiani, David C., Lin, Xihong, Gabriel, Sylvie, Dinet, Jérôme, and Kulke, Matthew H.
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Neuroendocrine tumors ,Somatostatin analogs ,Progression‐free survival ,Overall survival ,Landmark analysis - Abstract
Endpoints related to tumor progression are commonly used in clinical trials of novel therapeutic agents for neuroendocrine tumors (NETs). Whether improved tumor control translates into improved overall survival (OS), however, is uncertain. We assessed associations between tumor progression endpoints and OS in observational cohorts of patients with advanced neuroendocrine tumors treated with somatostatin analogs or with everolimus. We identified 440 patients with advanced NET who had received treatment with single‐agent somatostatin analogs and 109 patients treated with everolimus, all of whom were treated at our institution and were evaluable for both tumor progression and survival. We assessed associations between progression‐free survival (PFS) and OS by using the Kendall tau test, and we assessed associations between tumor progression and OS by using a landmark analysis. In the 440 patients treated with somatostatin analogs, we observed a significant correlation between PFS and OS by using the Kendall tau test (0.31; p < .0001). Additionally, the development of progressive disease was associated with OS in a landmark analysis, at landmark times of 6, 12, 18, and 24 months. In the 109 patients treated with everolimus, we similarly observed a significant correlation between PFS and OS by using the Kendall tau test (0.44; p < .0001) and associations between progressive disease and OS by using a landmark analysis at 3, 6, and 12 months. In these observational cohorts of patients with metastatic NET treated with single‐agent somatostatin analogs or everolimus, longer times to disease progression and longer PFS were both associated with improved OS. Our findings support the continued use of disease progression endpoints in NET clinical trials. Implications for Practice. Clinical trials in patients with advanced neuroendocrine tumors have used progression‐free survival as a primary endpoint. While there is a general assumption that slowing or halting tumor growth is beneficial, little direct evidence links improvements in progression endpoints to improvements in overall survival. This study assessed associations between tumor progression endpoints and overall survival in observational cohorts of patients with advanced neuroendocrine tumor treated with somatostatin analogs or everolimus. Longer times to disease progression and improved progression‐free survival were both associated with improved overall survival. The findings support the continued use of tumor progression endpoints in clinical trials for neuroendocrine tumors.
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- 2017
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166. Prognostic Significance of MTOR Pathway Component Expression in Neuroendocrine Tumors.
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Zhi Rong Qian, Ter-Minassian, Monica, Chan, Jennifer A., Yu Imamura, Hooshmand, Susanne M., Aya Kuchiba, Morikawa, Teppei, Brais, Lauren K., Daskalova, Anastassia, Heafield, Rachel, Xihong Lin, Christiani, David C., Fuchs, Charles S., Shuji Ogino, and Kulke, Matthew H.
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- 2013
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167. Lead-Time Trajectory of CA19-9 as an Anchor Marker for Pancreatic Cancer Early Detection.
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Fahrmann, Johannes F., Schmidt, C. Max, Mao, Xiangying, Irajizad, Ehsan, Loftus, Maureen, Zhang, Jinming, Patel, Nikul, Vykoukal, Jody, Dennison, Jennifer B., Long, James P., Do, Kim-Anh, Zhang, Jianjun, Chabot, John A., Kluger, Michael D., Kastrinos, Fay, Brais, Lauren, Babic, Ana, Jajoo, Kunal, Lee, Linda S., and Clancy, Thomas E.
- Abstract
There is substantial interest in liquid biopsy approaches for cancer early detection among subjects at risk, using multi-marker panels. CA19-9 is an established circulating biomarker for pancreatic cancer; however, its relevance for pancreatic cancer early detection or for monitoring subjects at risk has not been established. CA19-9 levels were assessed in blinded sera from 175 subjects collected up to 5 years before diagnosis of pancreatic cancer and from 875 matched controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. For comparison of performance, CA19-9 was assayed in blinded independent sets of samples collected at diagnosis from 129 subjects with resectable pancreatic cancer and 275 controls (100 healthy subjects; 50 with chronic pancreatitis; and 125 with noncancerous pancreatic cysts). The complementary value of 2 additional protein markers, TIMP1 and LRG1, was determined. In the PLCO cohort, levels of CA19-9 increased exponentially starting at 2 years before diagnosis with sensitivities reaching 60% at 99% specificity within 0 to 6 months before diagnosis for all cases and 50% at 99% specificity for cases diagnosed with early-stage disease. Performance was comparable for distinguishing newly diagnosed cases with resectable pancreatic cancer from healthy controls (64% sensitivity at 99% specificity). Comparison of resectable pancreatic cancer cases to subjects with chronic pancreatitis yielded 46% sensitivity at 99% specificity and for subjects with noncancerous cysts, 30% sensitivity at 99% specificity. For prediagnostic cases below cutoff value for CA19-9, the combination with LRG1 and TIMP1 yielded an increment of 13.2% in sensitivity at 99% specificity (P =.031) in identifying cases diagnosed within 1 year of blood collection. CA19-9 can serve as an anchor marker for pancreatic cancer early detection applications. [ABSTRACT FROM AUTHOR]
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- 2021
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168. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer
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Klein, Alison P, Wolpin, Brian M, Risch, Harvey A, Stolzenberg-Solomon, Rachael Z, Mocci, Evelina, Zhang, Mingfeng, Canzian, Federico, Childs, Erica J, Hoskins, Jason W, Jermusyk, Ashley, Zhong, Jun, Chen, Fei, Albanes, Demetrius, Andreotti, Gabriella, Arslan, Alan A, Babic, Ana, Bamlet, William R, Beane-Freeman, Laura, Berndt, Sonja I, Blackford, Amanda, Borges, Michael, Borgida, Ayelet, Bracci, Paige M, Brais, Lauren, Brennan, Paul, Brenner, Hermann, Bueno-De-Mesquita, Bas, Buring, Julie, Campa, Daniele, Capurso, Gabriele, Cavestro, Giulia Martina, Chaffee, Kari G, Chung, Charles C, Cleary, Sean, Cotterchio, Michelle, Dijk, Frederike, Duell, Eric J, Foretova, Lenka, Fuchs, Charles, Funel, Niccola, Gallinger, Steven, M Gaziano, J Michael, Gazouli, Maria, Giles, Graham G, Giovannucci, Edward, Goggins, Michael, Goodman, Gary E, Goodman, Phyllis J, Hackert, Thilo, Haiman, Christopher, Hartge, Patricia, Hasan, Manal, Hegyi, Peter, Helzlsouer, Kathy J, Herman, Joseph, Holcatova, Ivana, Holly, Elizabeth A, Hoover, Robert, Hung, Rayjean J, Jacobs, Eric J, Jamroziak, Krzysztof, Janout, Vladimir, Kaaks, Rudolf, Khaw, Kay-Tee, Klein, Eric A, Kogevinas, Manolis, Kooperberg, Charles, Kulke, Matthew H, Kupcinskas, Juozas, Kurtz, Robert J, Laheru, Daniel, Landi, Stefano, Lawlor, Rita T, Lee, I-Min, LeMarchand, Loic, Lu, Lingeng, Malats, Núria, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L, Mohelníková-Duchoňová, Beatrice, Neale, Rachel E, Neoptolemos, John P, Oberg, Ann L, Olson, Sara H, Orlow, Irene, Pasquali, Claudio, Patel, Alpa V, Peters, Ulrike, Pezzilli, Raffaele, Porta, Miquel, Real, Francisco X, Rothman, Nathaniel, Scelo, Ghislaine, Sesso, Howard D, Severi, Gianluca, Shu, Xiao-Ou, Silverman, Debra, Smith, Jill P, Soucek, Pavel, Sund, Malin, Talar-Wojnarowska, Renata, Tavano, Francesca, Thornquist, Mark D, Tobias, Geoffrey S, Van Den Eeden, Stephen K, Vashist, Yogesh, Visvanathan, Kala, Vodicka, Pavel, Wactawski-Wende, Jean, Wang, Zhaoming, Wentzensen, Nicolas, White, Emily, Yu, Herbert, Yu, Kai, Zeleniuch-Jacquotte, Anne, Zheng, Wei, Kraft, Peter, Li, Donghui, Chanock, Stephen, Obazee, Ofure, Petersen, Gloria M, and Amundadottir, Laufey T
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Intracellular Signaling Peptides and Proteins ,Proteins ,Polymorphism, Single Nucleotide ,3. Good health ,Pancreatic Neoplasms ,Repressor Proteins ,Hepatocyte Nuclear Factor 4 ,Tensins ,Databases, Genetic ,Humans ,Intercellular Signaling Peptides and Proteins ,Genetic Predisposition to Disease ,Carcinoma, Pancreatic Ductal ,Genome-Wide Association Study ,Hepatocyte Nuclear Factor 1-beta - 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.
169. Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer
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Walsh, Naomi, Zhang, Han, Hyland, Paula L, Yang, Qi, Mocci, Evelina, Zhang, Mingfeng, Childs, Erica J, Collins, Irene, Wang, Zhaoming, Arslan, Alan A, Beane-Freeman, Laura, Bracci, Paige M, Brennan, Paul, Canzian, Federico, Duell, Eric J, Gallinger, Steven, Giles, Graham G, Goggins, Michael, Goodman, Gary E, Goodman, Phyllis J, Hung, Rayjean J, Kooperberg, Charles, Kurtz, Robert C, Malats, Núria, LeMarchand, Loic, Neale, Rachel E, Olson, Sara H, Scelo, Ghislaine, Shu, Xiao O, Van Den Eeden, Stephen K, Visvanathan, Kala, White, Emily, Zheng, Wei, PanScan And PanC4 Consortia, Albanes, Demetrius, Andreotti, Gabriella, Babic, Ana, Bamlet, William R, Berndt, Sonja I, Borgida, Ayelet, Boutron-Ruault, Marie-Christine, Brais, Lauren, Bueno-De-Mesquita, Bas, Buring, Julie, Chaffee, Kari G, Chanock, Stephen, Cleary, Sean, Cotterchio, Michelle, Foretova, Lenka, Fuchs, Charles, M Gaziano, J Michael, Giovannucci, Edward, Hackert, Thilo, Haiman, Christopher, Hartge, Patricia, Hasan, Manal, Helzlsouer, Kathy J, Herman, Joseph, Holcatova, Ivana, Holly, Elizabeth A, Hoover, Robert, Janout, Vladimir, Klein, Eric A, Laheru, Daniel, Lee, I-Min, Lu, Lingeng, Mannisto, Satu, Milne, Roger L, Oberg, Ann L, Orlow, Irene, Patel, Alpa V, Peters, Ulrike, Porta, Miquel, Real, Francisco X, Rothman, Nathaniel, Sesso, Howard D, Severi, Gianluca, Silverman, Debra, Strobel, Oliver, Sund, Malin, Thornquist, Mark D, Tobias, Geoffrey S, Wactawski-Wende, Jean, Wareham, Nick, Weiderpass, Elisabete, Wentzensen, Nicolas, Wheeler, William, Yu, Herbert, Zeleniuch-Jacquotte, Anne, Kraft, Peter, Li, Donghui, Jacobs, Eric J, Petersen, Gloria M, Wolpin, Brian M, Risch, Harvey A, Amundadottir, Laufey T, Yu, Kai, Klein, Alison P, and Stolzenberg-Solomon, Rachael Z
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Pancreatic Neoplasms ,Models, Statistical ,Case-Control Studies ,Humans ,Genetic Predisposition to Disease ,Polymorphism, Single Nucleotide ,3. Good health ,Carcinoma, Pancreatic Ductal ,Genome-Wide Association Study - Abstract
Background: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. Methods: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. Results: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. Conclusion: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified., This work was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. This publication has emanated from research supported in part by a Grant from Science Foundation Ireland under Grant number [15/SIRG/3482](NW) and Health Research Board/Irish Cancer Society (CPFPR-2012–2)(NW). This work was also supported by RO1 CA154823 and federal funds from the National Cancer Institute (NCI), US National Institutes of Health, under contract number HHSN261200800001E. Please see the Supplementary Materials (available online) for a complete list of funding acknowledgments
170. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21
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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, Demetrius, Andreotti, Gabriella, Brais, Lauren, Bueno-De-Mesquita, H Bas, 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, Manolis, Krogh, Vittorio, Kupcinskas, Juozas, 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 HM, 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, Dimitrios, Vashist, Yogesh, Vodicka, Pavel, Wactawski-Wende, Jean, Wentzensen, Nicolas, Yu, Herbert, Yu, Kai, Zeleniuch-Jacquotte, Anne, Kooperberg, Charles, Risch, Harvey A, Jacobs, Eric J, Li, Donghui, Fuchs, Charles, Hoover, Robert, Hartge, Patricia, Chanock, Stephen J, Petersen, Gloria M, Stolzenberg-Solomon, Rachael S, Wolpin, Brian M, Kraft, Peter, Klein, Alison P, Canzian, Federico, and Amundadottir, Laufey T
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Genotype ,NR5A2 ,pancreatic cancer ,Datasets as Topic ,imputation ,Polymorphism, Single Nucleotide ,3. Good health ,Pancreatic Neoplasms ,fine-mapping ,Chromosomes, Human, Pair 1 ,GWAS ,Chromosomes, Human, Pair 5 ,Humans ,Genetic Predisposition to Disease ,Chromosomes, Human, Pair 8 ,Genome-Wide Association Study - 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.
171. Highly Sensitive Circulating Tumor DNA Assay Aids Clinical Management of Radiographically Occult Isolated Peritoneal Metastases in Patients With GI Cancer.
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Singh, Harshabad, Klempner, Samuel J., Melnitchouk, Nelya, Chander, Deepak P., Negrea, Ovidiu George, Patel, Anuj K., Schlechter, Benjamin L., Rubinson, Douglas A., Huffman, Brandon M., Nambiar, Chetan, Remland, Joshua, Andrews, Elizabeth, Leahy, Megan E., Brais, Lauren K., Enzinger, Peter C., Mamon, Harvey J., Giannakis, Marios, Meyerhardt, Jeffrey A., Ng, Kimmie, and Perez, Kimberly J.
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CIRCULATING tumor DNA , *CANCER patients , *PERITONEUM diseases , *CROSS-sectional imaging , *METASTASIS , *PERITONEUM - Abstract
PURPOSE: GI cancers commonly spread to the peritoneal cavity, particularly from primary adenocarcinomas of the stomach and appendix. Peritoneal metastases are difficult to visualize on cross-sectional imaging and cause substantial morbidity and mortality. The purpose of this study was to determine whether serial highly sensitive tumor-informed circulating tumor DNA (ctDNA) measurements could longitudinally track changes in disease burden and inform clinical care. METHODS: This was a retrospective case series of patients with gastric or appendiceal adenocarcinoma and isolated peritoneal disease that was radiographically occult. Patients underwent quantitative tumor-informed ctDNA testing (Signatera) as part of routine clinical care. No interventions were prespecified based on ctDNA results. RESULTS: Of 13 patients studied, the median age was 65 (range, 45-75) years, with 7 (54%) women, 5 (38%) patients with gastric, and 8 (62%) patients with appendiceal adenocarcinoma. Eight (62%) patients had detectable ctDNA at baseline measurement, with median value 0.13 MTM/mL (range, 0.06-11.68), and assay was technically unsuccessful in two cases with appendiceal cancer because of limited tumor tissue. Five (100%) patients with gastric cancer and 3 (50%) patients with appendiceal cancer had detectable ctDNA at baseline. Although baseline levels of ctDNA were low, longitudinal assessment tracked with changes in disease burden among patients undergoing chemotherapy for metastatic disease. In two patients undergoing surveillance after definitive surgical management of gastric adenocarcinoma, detection of ctDNA prompted diagnosis of isolated peritoneal disease. CONCLUSION: Quantitative tumor-informed serial ctDNA testing aids clinical management of patients with isolated peritoneal disease. Low levels of baseline ctDNA suggest a role for highly sensitive ctDNA approaches over panel-based testing. Further exploration of this approach should be considered in patients with isolated peritoneal malignant disease. Tumor-informed ctDNA assay tracks disease burden in radiographically occult GI cancer peritoneal metastases [ABSTRACT FROM AUTHOR]
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- 2023
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172. Programmatic Precision Oncology Decision Support for Patients With Gastrointestinal Cancer.
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Keller, Rachel B., Mazor, Tali, Sholl, Lynette, Aguirre, Andrew J., Singh, Harshabad, Sethi, Nilay, Bass, Adam, Nagaraja, Ankur K., Brais, Lauren K., Hill, Emma, Hennessey, Connor, Cusick, Margaret, Del Vecchio Fitz, Catherine, Zwiesler, Zachary, Siegel, Ethan, Ovalle, Andrea, Trukhanov, Pavel, Hansel, Jason, Shapiro, Geoffrey I., and Abrams, Thomas A.
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GASTROINTESTINAL cancer , *CANCER patients , *DECISION support systems , *CANCER patient care , *ELECTRONIC health records - Abstract
PURPOSE: With the growing number of available targeted therapeutics and molecular biomarkers, the optimal care of patients with cancer now depends on a comprehensive understanding of the rapidly evolving landscape of precision oncology, which can be challenging for oncologists to navigate alone. METHODS: We developed and implemented a precision oncology decision support system, GI TARGET, (Gastrointestinal Treatment Assistance Regarding Genomic Evaluation of Tumors) within the Gastrointestinal Cancer Center at the Dana-Farber Cancer Institute. With a multidisciplinary team, we systematically reviewed tumor molecular profiling for GI tumors and provided molecularly informed clinical recommendations, which included identifying appropriate clinical trials aided by the computational matching platform MatchMiner, suggesting targeted therapy options on or off the US Food and Drug Administration–approved label, and consideration of additional or orthogonal molecular testing. RESULTS: We reviewed genomic data and provided clinical recommendations for 506 patients with GI cancer who underwent tumor molecular profiling between January and June 2019 and determined follow-up using the electronic health record. Summary reports were provided to 19 medical oncologists for patients with colorectal (n = 198, 39%), pancreatic (n = 124, 24%), esophagogastric (n = 67, 13%), biliary (n = 40, 8%), and other GI cancers. We recommended ≥ 1 precision medicine clinical trial for 80% (406 of 506) of patients, leading to 24 enrollments. We recommended on-label and off-label targeted therapies for 6% (28 of 506) and 25% (125 of 506) of patients, respectively. Recommendations for additional or orthogonal testing were made for 42% (211 of 506) of patients. CONCLUSION: The integration of precision medicine in routine cancer care through a dedicated multidisciplinary molecular tumor board is scalable and sustainable, and implementation of precision oncology recommendations has clinical utility for patients with cancer. [ABSTRACT FROM AUTHOR]
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- 2023
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173. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21
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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.
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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.
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- 2016
174. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer
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Christopher A. Haiman, Herbert Yu, Lauren K. Brais, Gabriele Capurso, Eric J. Duell, Michelle Cotterchio, Núria Malats, Beatrice Mohelníková-Duchoňová, Claudio Pasquali, Gary E. Goodman, Giulia Martina Cavestro, Kala Visvanathan, Sean P. Cleary, Jill P. Smith, Jean Wactawski-Wende, Rita T. Lawlor, Gianluca Severi, J. Michael Gaziano, Kathy J. Helzlsouer, Charles C. Chung, Harvey A. Risch, Stephen K. Van Den Eeden, Elizabeth A. Holly, Bas Bueno-de-Mesquita, Patricia Hartge, Fei Chen, Mark D. Thornquist, Hermann Brenner, Ulrike Peters, Ghislaine Scelo, Steven Gallinger, Sonja I. Berndt, Howard D. Sesso, Lenka Foretova, Laufey T. Amundadottir, Mingfeng Zhang, Federico Canzian, Rudolf Kaaks, Stephen J. Chanock, Nicolas Wentzensen, Ann L. Oberg, Eric J. Jacobs, Peter Kraft, Rayjean J. Hung, Evelina Mocci, Maria Gazouli, Francesca Tavano, Michael Borges, Zhaoming Wang, Alan A. Arslan, Wei Zheng, Ayelet Borgida, Paige M. Bracci, Jason W. Hoskins, William R. Bamlet, Juozas Kupcinskas, Joseph M. Herman, Demetrius Albanes, Charles S. Fuchs, Nathaniel Rothman, Niccola Funel, Pavel Soucek, Edward Giovannucci, Paul Brennan, Thilo Hackert, Jun Zhong, Manolis Kogevinas, Robert N. Hoover, Michael Goggins, Amanda L. Blackford, Robert J. Kurtz, Malin Sund, Roger L. Milne, Stefano Landi, Francisco X. Real, Emily White, Miquel Porta, Ivana Holcatova, Kari G. Chaffee, Vladimir Janout, Charles Kooperberg, Péter Hegyi, Frederike Dijk, Yogesh K. Vashist, Andrea Mambrini, Matthew H. Kulke, I. Min Lee, Kai Yu, Alison P. Klein, Phyllis J. Goodman, Donghui Li, Julie E. Buring, Debra T. Silverman, Ana Babic, John P. Neoptolemos, Erica J. Childs, Alpa V. Patel, Sara H. Olson, Brian M. Wolpin, Krzysztof Jamroziak, Gloria M. Petersen, Xiao-Ou Shu, Renata Talar-Wojnarowska, Rachel E. Neale, Daniel A. Laheru, Kay-Tee Khaw, Eric A. Klein, Ashley Jermusyk, Graham G. Giles, Daniele Campa, Laura Beane-Freeman, Rachael Z. Stolzenberg-Solomon, Raffaele Pezzilli, Geoffrey S. Tobias, Pavel Vodicka, Irene Orlow, Anne Zeleniuch-Jacquotte, Ofure Obazee, Satu Männistö, Lingeng Lu, Manal Hasan, Loic LeMarchand, Gabriella Andreotti, CCA - Cancer biology and immunology, Pathology, Lung Cancer Research Foundation, Sol Goldman Pancreas Cancer Research Center, Geoffrey Beene Foundation, Arnold and Arlene Goldstein Family Foundation, National Health and Medical Research Council (Australia), Czech Science Foundation, Joan Rombauer Pancreatic Cancer Foundation, NIH - National Cancer Institute (NCI) (Estados Unidos), Instituto de Salud Carlos III, Ministerio de Ciencia y Tecnología (España), Red Temática de Investigación Cooperativa en Cáncer (España), Centro de Investigación Biomédica en Red - CIBERESP (Epidemiología y Salud Pública), Mocci, Evelina [0000-0002-7101-9556], Canzian, Federico [0000-0002-4261-4583], Chaffee, Kari G [0000-0002-7313-1875], Dijk, Frederike [0000-0003-3970-6601], Gazouli, Maria [0000-0002-3295-6811], Jacobs, Eric J [0000-0002-8458-7659], Klein, Eric A [0000-0002-1783-0698], Lu, Lingeng [0000-0001-9871-0809], Malats, Núria [0000-0003-2538-3784], Milne, Roger L [0000-0001-5764-7268], Neoptolemos, John P [0000-0002-6201-7399], Oberg, Ann L [0000-0003-2539-9807], Pezzilli, Raffaele [0000-0001-9827-7451], Porta, Miquel [0000-0003-1684-7428], Real, Francisco X [0000-0001-9501-498X], Sund, Malin [0000-0002-7516-9543], Tobias, Geoffrey S [0000-0002-2878-8253], Van Den Eeden, Stephen K [0000-0002-5599-8387], Yu, Herbert [0000-0003-3950-4815], Zheng, Wei [0000-0003-1226-070X], Obazee, Ofure [0000-0001-8791-5008], Amundadottir, Laufey T [0000-0003-1859-8971], Apollo - University of Cambridge Repository, Klein, Alison P., Wolpin, Brian M., Risch, Harvey A., Stolzenberg-Solomon, Rachael Z., Mocci, Evelina, Zhang, Mingfeng, Canzian, Federico, Childs, Erica J., Hoskins, Jason W., Jermusyk, Ashley, Zhong, Jun, Chen, Fei, Albanes, Demetriu, Andreotti, Gabriella, Arslan, Alan A., Babic, Ana, Bamlet, William R., Beane-Freeman, Laura, Berndt, Sonja I., Blackford, Amanda, Borges, Michael, Borgida, Ayelet, Bracci, Paige M., Brais, Lauren, Brennan, Paul, Brenner, Hermann, Bueno-De-Mesquita, Ba, Buring, Julie, Campa, Daniele, Capurso, Gabriele, Cavestro, Giulia Martina, Chaffee, Kari G., Chung, Charles C., Cleary, Sean, Cotterchio, Michelle, Dijk, Frederike, Duell, Eric J., Foretova, Lenka, Fuchs, Charle, Funel, Niccola, Gallinger, Steven, Gaziano, J. Michael M., Gazouli, Maria, Giles, Graham G., Giovannucci, Edward, Goggins, Michael, Goodman, Gary E., Goodman, Phyllis J., Hackert, Thilo, Haiman, Christopher, Hartge, Patricia, Hasan, Manal, Hegyi, Peter, Helzlsouer, Kathy J., Herman, Joseph, Holcatova, Ivana, Holly, Elizabeth A., Hoover, Robert, Hung, Rayjean J., Jacobs, Eric J., Jamroziak, Krzysztof, Janout, Vladimir, Kaaks, Rudolf, Khaw, Kay-Tee, Klein, Eric A., Kogevinas, Manoli, Kooperberg, Charle, Kulke, Matthew H., Kupcinskas, Juoza, Kurtz, Robert J., Laheru, Daniel, Landi, Stefano, Lawlor, Rita T., Lee, I. -Min, Lemarchand, Loic, Lu, Lingeng, Malats, Núria, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L., Mohelníková-Duchoňová, Beatrice, Neale, Rachel E., Neoptolemos, John P., Oberg, Ann L., Olson, Sara H., Orlow, Irene, Pasquali, Claudio, Patel, Alpa V., Peters, Ulrike, Pezzilli, Raffaele, Porta, Miquel, Real, Francisco X., Rothman, Nathaniel, Scelo, Ghislaine, Sesso, Howard D., Severi, Gianluca, Shu, Xiao-Ou, Silverman, Debra, Smith, Jill P., Soucek, Pavel, Sund, Malin, Talar-Wojnarowska, Renata, Tavano, Francesca, Thornquist, Mark D., Tobias, Geoffrey S., Van Den Eeden, Stephen K., Vashist, Yogesh, Visvanathan, Kala, Vodicka, Pavel, Wactawski-Wende, Jean, Wang, Zhaoming, Wentzensen, Nicola, White, Emily, Yu, Herbert, Yu, Kai, Zeleniuch-Jacquotte, Anne, Zheng, Wei, Kraft, Peter, Li, Donghui, Chanock, Stephen, Obazee, Ofure, Petersen, Gloria M., and Amundadottir, Laufey T.
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0301 basic medicine ,Oncology ,Genetics and Molecular Biology (all) ,Pancreatic disease ,Chemistry(all) ,General Physics and Astronomy ,Genome-wide association study ,Disease ,Biochemistry ,DISEASE ,Tensins ,Databases, Genetic ,IMPUTATION ,03.02. Klinikai orvostan ,lcsh:Science ,Càncer ,Pancreas cancer ,GENE-EXPRESSION ,Cancer ,RISK ,Multidisciplinary ,Chemistry (all) ,Pancreatic Neoplasm ,Intracellular Signaling Peptides and Proteins ,HNF1B ,3. Good health ,TRANSCRIPTION FACTORS ,Hepatocyte Nuclear Factor 4 ,Intercellular Signaling Peptides and Proteins ,Human ,Carcinoma, Pancreatic Ductal ,medicine.medical_specialty ,Science ,Physics and Astronomy(all) ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Physics and Astronomy (all) ,Cancer epidemiology ,Pancreatic cancer ,Internal medicine ,medicine ,Carcinoma ,Humans ,Genetic Predisposition to Disease ,Allele ,Càncer de pàncrees ,Hepatocyte Nuclear Factor 1-beta ,Cancer och onkologi ,Biochemistry, Genetics and Molecular Biology (all) ,business.industry ,Biochemistry, Genetics and Molecular Biology(all) ,Protein ,Proteins ,ADENOCARCINOMA ,General Chemistry ,Repressor Protein ,medicine.disease ,Pancreatic Neoplasms ,Repressor Proteins ,BODY-MASS INDEX ,030104 developmental biology ,Tensin ,Cancer and Oncology ,Expression quantitative trait loci ,lcsh:Q ,business ,ASSOCIATION ANALYSES ,Genetics and Molecular Biology(all) ,Genome-Wide Association Study - 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., Genetic variants associated with susceptibility to pancreatic cancer have been identified using genome wide association studies (GWAS). Here, the authors combine data from over 9000 patients and perform a meta-analysis to identify five novel loci linked to pancreatic cancer.
175. Blockade of IL1β and PD1 with Combination Chemotherapy Reduces Systemic Myeloid Suppression in Metastatic Pancreatic Cancer with Heterogeneous Effects in the Tumor.
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Oberstein PE, Dias Costa A, Kawaler EA, Cardot-Ruffino V, Rahma OE, Beri N, Singh H, Abrams TA, Biller LH, Cleary JM, Enzinger P, Huffman BM, McCleary NJ, Perez KJ, Rubinson DA, Schlechter BL, Surana R, Yurgelun MB, Wang SJ, Remland J, Brais LK, Bollenrucher N, Chang E, Ali LR, Lenehan PJ, Dolgalev I, Werba G, Lima C, Keheler CE, Sullivan KM, Dougan M, Hajdu C, Dajee M, Pelletier MR, Nazeer S, Squires M, Bar-Sagi D, Wolpin BM, Nowak JA, Simeone DM, and Dougan SK
- Subjects
- Humans, Male, Female, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized pharmacology, Aged, Deoxycytidine analogs & derivatives, Deoxycytidine pharmacology, Deoxycytidine therapeutic use, Deoxycytidine administration & dosage, Middle Aged, Gemcitabine, Tumor Microenvironment immunology, Tumor Microenvironment drug effects, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes drug effects, Paclitaxel therapeutic use, Paclitaxel administration & dosage, Paclitaxel pharmacology, Neoplasm Metastasis, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal immunology, Carcinoma, Pancreatic Ductal pathology, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms pathology, Pancreatic Neoplasms immunology, Interleukin-1beta antagonists & inhibitors, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols pharmacology, Myeloid-Derived Suppressor Cells immunology, Myeloid-Derived Suppressor Cells drug effects, Myeloid-Derived Suppressor Cells metabolism, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
Innate inflammation promotes tumor development, although the role of innate inflammatory cytokines in established human tumors is unclear. Herein, we report clinical and translational results from a phase Ib trial testing whether IL1β blockade in human pancreatic cancer would alleviate myeloid immunosuppression and reveal antitumor T-cell responses to PD1 blockade. Patients with treatment-naïve advanced pancreatic ductal adenocarcinoma (n = 10) were treated with canakinumab, a high-affinity monoclonal human antiinterleukin-1β (IL1β), the PD1 blocking antibody spartalizumab, and gemcitabine/n(ab)paclitaxel. Analysis of paired peripheral blood from patients in the trial versus patients receiving multiagent chemotherapy showed a modest increase in HLA-DR+CD38+ activated CD8+ T cells and a decrease in circulating monocytic myeloid-derived suppressor cells (MDSC) by flow cytometry for patients in the trial but not in controls. Similarly, we used patient serum to differentiate monocytic MDSCs in vitro and showed that functional inhibition of T-cell proliferation was reduced when using on-treatment serum samples from patients in the trial but not when using serum from patients treated with chemotherapy alone. Within the tumor, we observed few changes in suppressive myeloid-cell populations or activated T cells as assessed by single-cell transcriptional profiling or multiplex immunofluorescence, although increases in CD8+ T cells suggest that improvements in the tumor immune microenvironment might be revealed by a larger study. Overall, the data indicate that exposure to PD1 and IL1β blockade induced a modest reactivation of peripheral CD8+ T cells and decreased circulating monocytic MDSCs; however, these changes did not lead to similarly uniform alterations in the tumor microenvironment., (©2024 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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176. Epigenetic and oncogenic inhibitors cooperatively drive differentiation and kill KRAS-mutant colorectal cancers.
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Loi P, Schade AE, Rodriguez CL, Krishnan A, Perurena N, Nguyen VTM, Xu Y, Watanabe M, Davis RA, Gardner A, Pilla NF, Mattioli K, Popow O, Gunduz N, Lannagan TRM, Fitzgerald S, Sicinska ET, Lin JR, Tan W, Brais LK, Haigis KM, Giannakis M, Ng K, Santagata S, Helin K, Sansom OJ, and Cichowski K
- Abstract
Current treatments for KRAS-mutant colorectal cancers (CRCs) are often limited by cellular plasticity and rewiring responses. Here we describe a promising therapeutic strategy that simultaneously targets epigenetic and oncogenic signals. Specifically, we show that inhibitors of the histone methyltransferase, EZH2, synergize with various RAS pathway inhibitors and promote dramatic tumor regression in vivo. Together these agents cooperatively suppress WNT-driven transcription and drive CRCs into a more differentiated cell state by inducing the Groucho/TLE corepressor, TLE4, along with a network of WNT pathway inhibitors and intestinal differentiation proteins. However, these agents also induce the pro-apoptotic protein BMF, which subsequently kills these more differentiated cells. Accordingly, cell death can be prevented by activating β-catenin, blocking differentiation, or by ablating BMF expression. Collectively, these studies reveal a new therapeutic approach for treating KRAS-mutant CRCs and illustrate a critical convergence of EZH2 and RAS on oncogenic WNT signals, intestinal differentiation, and apoptosis.
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- 2024
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177. Clinical outcomes and ctDNA correlates for CAPOX BETR: a phase II trial of capecitabine, oxaliplatin, bevacizumab, trastuzumab in previously untreated advanced HER2+ gastroesophageal adenocarcinoma.
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Singh H, Lowder KE, Kapner K, Kelly RJ, Zheng H, McCleary NJ, Abrams TA, Chan JA, Regan EM, Klempner SJ, Hannigan AM, Remland J, Brais LK, Andrews E, Yurgelun M, Cleary JM, Rubinson DA, Ritterhouse LL, Maron G, Aguirre AJ, Meyerhardt JA, Gardecki E, Lennerz JK, Wolpin BM, and Enzinger PC
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- Humans, Female, Middle Aged, Aged, Male, Adult, Esophagogastric Junction pathology, Treatment Outcome, Progression-Free Survival, Trastuzumab therapeutic use, Trastuzumab administration & dosage, Capecitabine administration & dosage, Capecitabine therapeutic use, Bevacizumab therapeutic use, Bevacizumab administration & dosage, Adenocarcinoma drug therapy, Adenocarcinoma genetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Receptor, ErbB-2 metabolism, Receptor, ErbB-2 genetics, Stomach Neoplasms drug therapy, Stomach Neoplasms genetics, Stomach Neoplasms pathology, Oxaliplatin administration & dosage, Oxaliplatin therapeutic use, Esophageal Neoplasms drug therapy, Esophageal Neoplasms genetics, Esophageal Neoplasms pathology, Circulating Tumor DNA genetics, Circulating Tumor DNA blood
- Abstract
Preclinical studies suggest that simultaneous HER2/VEGF blockade may have cooperative effects in gastroesophageal adenocarcinomas. In a single-arm investigator initiated clinical trial for patients with untreated advanced HER2+ gastroesophageal adenocarcinoma, bevacizumab was added to standard of care capecitabine, oxaliplatin, and trastuzumab in 36 patients (NCT01191697). Primary endpoint was objective response rate and secondary endpoints included safety, duration of response, progression free survival, and overall survival. The study met its primary endpoint with an objective response rate of 81% (95% CI 65-92%). Median progression free and overall survival were 14.0 (95% CI, 11.3-36.4) and 23.2 months (95% CI, 16.6-36.4), respectively. The median duration of response was 14.9 months. The regimen was well tolerated without unexpected or severe toxicities. In post-hoc ctDNA analysis, baseline ctDNA features were prognostic: Higher tumor fraction and alternative MAPK drivers portended worse outcomes. ctDNA at resistance identified oncogenic mutations and these were detectable 2-8 cycles prior to radiographic progression. Capecitabine, oxaliplatin, trastuzumab and bevacizumab shows robust clinical activity in HER2+ gastroesophageal adenocarcinoma. Combination of VEGF inhibitors with chemoimmunotherapy and anti-PD1 regimens is warranted., (© 2024. The Author(s).)
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- 2024
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178. Experience and Needs of Patients With Young-Onset Colorectal Cancer and Their Caregivers: A Qualitative Study.
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Fletcher KM, Revette A, Enzinger A, Biller L, MacDougall K, Brown MB, Brais L, Arsenault B, McCleary N, Chan J, Boyle K, Meyerhardt JA, and Ng K
- Abstract
Purpose: The incidence of young-onset colorectal cancer (YOCRC; defined as patients who are diagnosed with CRC before age 50 years) is rising rapidly, and CRC is predicted to be the leading cause of cancer death in this age group by 2030. Yet, there has been limited research into the experiences and needs of patients with YOCRC and their caregivers. The goal of this study was to better understand the experiences and needs of patients with YOCRC and their caregivers., Patients and Methods: Semistructured focus groups were conducted with patients with YOCRC, caregivers of patients with YOCRC, and bereaved caregivers of patients with YOCRC. Focus group discussion guides addressed the experience and impact of diagnosis and treatment of YOCRC. Results were analyzed using a thematic analysis informed by framework analysis., Results: Twenty patients and caregivers participated in three focus groups (eight patients, seven caregivers, and five bereaved caregivers). Four primary themes were identified: (1) feeling overwhelmed by the health care system and desiring patient navigation; (2) feeling isolated and wanting opportunities for peer support; (3) life disruption because of difficulty juggling multiple roles and desiring psychosocial support; and (4) enthusiasm about participation in research and genetic testing., Conclusion: This study identified and described the unique experiences and care needs of patients with YOCRC and their caregivers. The findings provide evidence that specialized models of care are needed. The results of this study informed the development of a center dedicated to the care of patients with YOCRC.
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- 2024
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179. Sotorasib Is a Pan-RASG12C Inhibitor Capable of Driving Clinical Response in NRASG12C Cancers.
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Rubinson DA, Tanaka N, Fece de la Cruz F, Kapner KS, Rosenthal MH, Norden BL, Barnes H, Ehnstrom S, Morales-Giron AA, Brais LK, Lemke CT, Aguirre AJ, and Corcoran RB
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- Humans, GTP Phosphohydrolases genetics, Mutation, Cell Line, Tumor, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, Antineoplastic Agents therapeutic use, Antineoplastic Agents pharmacology, Pyrimidines therapeutic use, Pyrimidines pharmacology, Piperazines pharmacology, Piperazines therapeutic use, Membrane Proteins genetics, Membrane Proteins antagonists & inhibitors, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) antagonists & inhibitors, Pyridines
- Abstract
KRASG12C inhibitors, like sotorasib and adagrasib, potently and selectively inhibit KRASG12C through a covalent interaction with the mutant cysteine, driving clinical efficacy in KRASG12C tumors. Because amino acid sequences of the three main RAS isoforms-KRAS, NRAS, and HRAS-are highly similar, we hypothesized that some KRASG12C inhibitors might also target NRASG12C and/or HRASG12C, which are less common but critical oncogenic driver mutations in some tumors. Although some inhibitors, like adagrasib, were highly selective for KRASG12C, others also potently inhibited NRASG12C and/or HRASG12C. Notably, sotorasib was five-fold more potent against NRASG12C compared with KRASG12C or HRASG12C. Structural and reciprocal mutagenesis studies suggested that differences in isoform-specific binding are mediated by a single amino acid: Histidine-95 in KRAS (Leucine-95 in NRAS). A patient with NRASG12C colorectal cancer treated with sotorasib and the anti-EGFR antibody panitumumab achieved a marked tumor response, demonstrating that sotorasib can be clinically effective in NRASG12C-mutated tumors., Significance: These studies demonstrate that certain KRASG12C inhibitors effectively target all RASG12C mutations and that sotorasib specifically is a potent NRASG12C inhibitor capable of driving clinical responses. These findings have important implications for the treatment of patients with NRASG12C or HRASG12C cancers and could guide design of NRAS or HRAS inhibitors. See related commentary by Seale and Misale, p. 698. This article is featured in Selected Articles from This Issue, p. 695., (©2024 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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180. RAS/RAF Comutation and ERBB2 Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer.
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Singh H, Sahgal P, Kapner K, Corsello SM, Gupta H, Gujrathi R, Li YY, Cherniack AD, El Alam R, Kerfoot J, Andrews E, Lee A, Nambiar C, Hannigan AM, Remland J, Brais L, Leahy ME, Rubinson DA, Schlechter BL, Meyerson M, Kuang Y, Paweletz CP, Lee JK, Quintanilha JCF, Aguirre AJ, Perez KJ, Huffman BM, Rossi H, Abrams TA, Kabraji S, Trusolino L, Bertotti A, Sicinska ET, Parikh AR, Wolpin BM, Schrock AB, Giannakis M, Ng K, Meyerhardt JA, Hornick JL, Sethi NS, and Cleary JM
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- Humans, Animals, Mice, Gene Amplification, Receptor, ErbB-2 metabolism, Trastuzumab pharmacology, Trastuzumab therapeutic use, Treatment Outcome, Mutation, DNA Copy Number Variations, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism
- Abstract
Purpose: ERBB2-amplified colorectal cancer is a distinct molecular subtype with expanding treatments. Implications of concurrent oncogenic RAS/RAF alterations are not known., Experimental Design: Dana-Farber and Foundation Medicine Inc. Colorectal cancer cohorts with genomic profiling were used to identify ERBB2-amplified cases [Dana-Farber, n = 47/2,729 (1.7%); FMI, n = 1857/49,839 (3.7%)]. Outcomes of patients receiving HER2-directed therapies are reported (Dana-Farber, n = 9; Flatiron Health-Foundation Medicine clinicogenomic database, FH-FMI CGDB, n = 38). Multisite HER2 IHC and genomic profiling were performed to understand HER2 intratumoral and interlesional heterogeneity. The impact of concurrent RAS comutations on the effectiveness of HER2-directed therapies were studied in isogenic colorectal cancer cell lines and xenografts., Results: ERBB2 amplifications are enriched in left-sided colorectal cancer. Twenty percent of ERBB2-amplified colorectal cancers have co-occurring oncogenic RAS/RAF alterations. While RAS/RAF WT colorectal cancers typically have clonal ERBB2 amplification, colorectal cancers with co-occurring RAS/RAF alterations have lower level ERRB2 amplification, higher intratumoral heterogeneity, and interlesional ERBB2 discordance. These distinct genomic patterns lead to differential responsiveness and patterns of resistance to HER2-directed therapy. ERBB2-amplified colorectal cancer with RAS/RAF alterations are resistant to trastuzumab-based combinations, such as trastuzumab/tucatinib, but retain sensitivity to trastuzumab deruxtecan in in vitro and murine models. Trastuzumab deruxtecan shows clinical efficacy in cases with high-level ERBB2-amplified RAS/RAF coaltered colorectal cancer., Conclusions: Co-occurring RAS/RAF alterations define a unique subtype of ERBB2-amplified colorectal cancer that has increased intratumoral heterogeneity, interlesional discordance, and resistance to trastuzumab-based combinations. Further examination of trastuzumab deruxtecan in this previously understudied cohort of ERBB2-amplified colorectal cancer is warranted., (©2024 American Association for Cancer Research.)
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- 2024
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181. Adipose tissue and skeletal muscle wasting precede clinical diagnosis of pancreatic cancer.
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Babic A, Rosenthal MH, Sundaresan TK, Khalaf N, Lee V, Brais LK, Loftus M, Caplan L, Denning S, Gurung A, Harrod J, Schawkat K, Yuan C, Wang QL, Lee AA, Biller LH, Yurgelun MB, Ng K, Nowak JA, Aguirre AJ, Bhatia SN, Vander Heiden MG, Van Den Eeden SK, Caan BJ, and Wolpin BM
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- Humans, Adipose Tissue metabolism, Muscular Atrophy pathology, Muscle, Skeletal metabolism, Cachexia diagnosis, Cachexia etiology, Cachexia metabolism, Body Composition, Pancreatic Neoplasms complications, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms metabolism
- Abstract
Patients with pancreatic cancer commonly develop weight loss and muscle wasting. Whether adipose tissue and skeletal muscle losses begin before diagnosis and the potential utility of such losses for earlier cancer detection are not well understood. We quantify skeletal muscle and adipose tissue areas from computed tomography (CT) imaging obtained 2 months to 5 years before cancer diagnosis in 714 pancreatic cancer cases and 1748 matched controls. Adipose tissue loss is identified up to 6 months, and skeletal muscle wasting is identified up to 18 months before the clinical diagnosis of pancreatic cancer and is not present in the matched control population. Tissue losses are of similar magnitude in cases diagnosed with localized compared with metastatic disease and are not correlated with at-diagnosis circulating levels of CA19-9. Skeletal muscle wasting occurs in the 1-2 years before pancreatic cancer diagnosis and may signal an upcoming diagnosis of pancreatic cancer., (© 2023. The Author(s).)
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- 2023
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182. A deep learning algorithm to predict risk of pancreatic cancer from disease trajectories.
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Placido D, Yuan B, Hjaltelin JX, Zheng C, Haue AD, Chmura PJ, Yuan C, Kim J, Umeton R, Antell G, Chowdhury A, Franz A, Brais L, Andrews E, Marks DS, Regev A, Ayandeh S, Brophy MT, Do NV, Kraft P, Wolpin BM, Rosenthal MH, Fillmore NR, Brunak S, and Sander C
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- Humans, Middle Aged, Artificial Intelligence, Quality of Life, Algorithms, Deep Learning, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms epidemiology
- Abstract
Pancreatic cancer is an aggressive disease that typically presents late with poor outcomes, indicating a pronounced need for early detection. In this study, we applied artificial intelligence methods to clinical data from 6 million patients (24,000 pancreatic cancer cases) in Denmark (Danish National Patient Registry (DNPR)) and from 3 million patients (3,900 cases) in the United States (US Veterans Affairs (US-VA)). We trained machine learning models on the sequence of disease codes in clinical histories and tested prediction of cancer occurrence within incremental time windows (CancerRiskNet). For cancer occurrence within 36 months, the performance of the best DNPR model has area under the receiver operating characteristic (AUROC) curve = 0.88 and decreases to AUROC (3m) = 0.83 when disease events within 3 months before cancer diagnosis are excluded from training, with an estimated relative risk of 59 for 1,000 highest-risk patients older than age 50 years. Cross-application of the Danish model to US-VA data had lower performance (AUROC = 0.71), and retraining was needed to improve performance (AUROC = 0.78, AUROC (3m) = 0.76). These results improve the ability to design realistic surveillance programs for patients at elevated risk, potentially benefiting lifespan and quality of life by early detection of this aggressive cancer., (© 2023. The Author(s).)
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- 2023
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183. Spatially Resolved Single-Cell Assessment of Pancreatic Cancer Expression Subtypes Reveals Co-expressor Phenotypes and Extensive Intratumoral Heterogeneity.
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Williams HL, Dias Costa A, Zhang J, Raghavan S, Winter PS, Kapner KS, Ginebaugh SP, Väyrynen SA, Väyrynen JP, Yuan C, Navia AW, Wang J, Yang A, Bosse TL, Kalekar RL, Lowder KE, Lau MC, Elganainy D, Morales-Oyarvide V, Rubinson DA, Singh H, Perez K, Cleary JM, Clancy TE, Wang J, Mancias JD, Brais LK, Hill ER, Kozak MM, Linehan DC, Dunne RF, Chang DT, Koong AC, Hezel AF, Hahn WC, Shalek AK, Aguirre AJ, Nowak JA, and Wolpin BM
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- Humans, Prognosis, Phenotype, RNA, Gene Expression Regulation, Neoplastic, Claudins, Pancreatic Neoplasms pathology, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal pathology
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) has been classified into classical and basal-like transcriptional subtypes by bulk RNA measurements. However, recent work has uncovered greater complexity to transcriptional subtypes than was initially appreciated using bulk RNA expression profiling. To provide a deeper understanding of PDAC subtypes, we developed a multiplex immunofluorescence (mIF) pipeline that quantifies protein expression of six PDAC subtype markers (CLDN18.2, TFF1, GATA6, KRT17, KRT5, and S100A2) and permits spatially resolved, single-cell interrogation of pancreatic tumors from resection specimens and core needle biopsies. Both primary and metastatic tumors displayed striking intratumoral subtype heterogeneity that was associated with patient outcomes, existed at the scale of individual glands, and was significantly reduced in patient-derived organoid cultures. Tumor cells co-expressing classical and basal markers were present in > 90% of tumors, existed on a basal-classical polarization continuum, and were enriched in tumors containing a greater admixture of basal and classical cell populations. Cell-cell neighbor analyses within tumor glands further suggested that co-expressor cells may represent an intermediate state between expression subtype poles. The extensive intratumoral heterogeneity identified through this clinically applicable mIF pipeline may inform prognosis and treatment selection for patients with PDAC., Significance: A high-throughput pipeline using multiplex immunofluorescence in pancreatic cancer reveals striking expression subtype intratumoral heterogeneity with implications for therapy selection and identifies co-expressor cells that may serve as intermediates during subtype switching., (©2022 American Association for Cancer Research.)
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- 2023
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184. Utility of Normalized Body Composition Areas, Derived From Outpatient Abdominal CT Using a Fully Automated Deep Learning Method, for Predicting Subsequent Cardiovascular Events.
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Magudia K, Bridge CP, Bay CP, Farah S, Babic A, Fintelmann FJ, Brais LK, Andriole KP, Wolpin BM, and Rosenthal MH
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- Male, Humans, Female, Middle Aged, Retrospective Studies, Risk Factors, Outpatients, Body Composition, Tomography, X-Ray Computed methods, Deep Learning, Cardiovascular Diseases diagnostic imaging, Stroke
- Abstract
BACKGROUND. CT-based body composition (BC) measurements have historically been too resource intensive to analyze for widespread use and have lacked robust comparison with traditional weight metrics for predicting cardiovascular risk. OBJECTIVE. The aim of this study was to determine whether BC measurements obtained from routine CT scans by use of a fully automated deep learning algorithm could predict subsequent cardiovascular events independently from weight, BMI, and additional cardiovascular risk factors. METHODS. This retrospective study included 9752 outpatients (5519 women and 4233 men; mean age, 53.2 years; 890 patients self-reported their race as Black and 8862 self-reported their race as White) who underwent routine abdominal CT at a single health system from January 2012 through December 2012 and who were given no major cardiovascular or oncologic diagnosis within 3 months of undergoing CT. Using publicly available code, fully automated deep learning BC analysis was performed at the L3 vertebral body level to determine three BC areas (skeletal muscle area [SMA], visceral fat area [VFA], and subcutaneous fat area [SFA]). Age-, sex-, and race-normalized reference curves were used to generate z scores for the three BC areas. Subsequent myocardial infarction (MI) or stroke was determined from the electronic medical record. Multivariable-adjusted Cox proportional hazards models were used to determine hazard ratios (HRs) for MI or stroke within 5 years after CT for the three BC area z scores, with adjustment for normalized weight, normalized BMI, and additional cardiovascular risk factors (smoking status, diabetes diagnosis, and systolic blood pressure). RESULTS. In multivariable models, age-, race-, and sex-normalized VFA was associated with subsequent MI risk (HR of highest quartile compared with lowest quartile, 1.31 [95% CI, 1.03-1.67], p = .04 for overall effect) and stroke risk (HR of highest compared with lowest quartile, 1.46 [95% CI, 1.07-2.00], p = .04 for overall effect). In multivariable models, normalized SMA, SFA, weight, and BMI were not associated with subsequent MI or stroke risk. CONCLUSION. VFA derived from fully automated and normalized analysis of abdominal CT examinations predicts subsequent MI or stroke in Black and White patients, independent of traditional weight metrics, and should be considered an adjunct to BMI in risk models. CLINICAL IMPACT. Fully automated and normalized BC analysis of abdominal CT has promise to augment traditional cardiovascular risk prediction models.
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- 2023
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185. FGFR2 Extracellular Domain In-Frame Deletions Are Therapeutically Targetable Genomic Alterations That Function as Oncogenic Drivers in Cholangiocarcinoma.
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Cleary JM, Raghavan S, Wu Q, Li YY, Spurr LF, Gupta HV, Rubinson DA, Fetter IJ, Hornick JL, Nowak JA, Siravegna G, Goyal L, Shi L, Brais LK, Loftus M, Shinagare AB, Abrams TA, Clancy TE, Wang J, Patel AK, Brichory F, Vaslin Chessex A, Sullivan RJ, Keller RB, Denning S, Hill ER, Shapiro GI, Pokorska-Bocci A, Zanna C, Ng K, Schrag D, Jänne PA, Hahn WC, Cherniack AD, Corcoran RB, Meyerson M, Daina A, Zoete V, Bardeesy N, and Wolpin BM
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- Adolescent, Adult, Aged, Aged, 80 and over, Bile Duct Neoplasms genetics, Bile Duct Neoplasms pathology, Cholangiocarcinoma genetics, Cholangiocarcinoma pathology, Female, Humans, Male, Middle Aged, Molecular Targeted Therapy, Receptor, Fibroblast Growth Factor, Type 2 antagonists & inhibitors, Young Adult, Bile Duct Neoplasms drug therapy, Cholangiocarcinoma drug therapy, Protein Kinase Inhibitors therapeutic use, Receptor, Fibroblast Growth Factor, Type 2 genetics
- Abstract
We conducted next-generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent FGFR2 fusions among patients with intrahepatic cholangiocarcinoma (IHCC), we identified FGFR2 extracellular domain in-frame deletions (EID) in 5 of 178 (2.8%) patients with IHCC, including two patients with FGFR2 p.H167_N173del. Expression of this FGFR2 EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with FGFR2 EIDs were treated with Debio 1347, an oral FGFR1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F FGFR2 kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal FGFR2 EIDs as an alternative mechanism of FGFR2 activation in IHCC that predicts sensitivity to FGFR inhibitors in the clinic. SIGNIFICANCE: FGFR2 EIDs are transforming genomic alterations that occur predominantly in patients with IHCC. These FGFR2 EIDs are sensitive to FGFR inhibition in vitro , and patients with these alterations benefited from treatment with FGFR inhibitors in the clinic. This article is highlighted in the In This Issue feature, p. 2355 ., (©2021 American Association for Cancer Research.)
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- 2021
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186. Spatially organized multicellular immune hubs in human colorectal cancer.
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Pelka K, Hofree M, Chen JH, Sarkizova S, Pirl JD, Jorgji V, Bejnood A, Dionne D, Ge WH, Xu KH, Chao SX, Zollinger DR, Lieb DJ, Reeves JW, Fuhrman CA, Hoang ML, Delorey T, Nguyen LT, Waldman J, Klapholz M, Wakiro I, Cohen O, Albers J, Smillie CS, Cuoco MS, Wu J, Su MJ, Yeung J, Vijaykumar B, Magnuson AM, Asinovski N, Moll T, Goder-Reiser MN, Applebaum AS, Brais LK, DelloStritto LK, Denning SL, Phillips ST, Hill EK, Meehan JK, Frederick DT, Sharova T, Kanodia A, Todres EZ, Jané-Valbuena J, Biton M, Izar B, Lambden CD, Clancy TE, Bleday R, Melnitchouk N, Irani J, Kunitake H, Berger DL, Srivastava A, Hornick JL, Ogino S, Rotem A, Vigneau S, Johnson BE, Corcoran RB, Sharpe AH, Kuchroo VK, Ng K, Giannakis M, Nieman LT, Boland GM, Aguirre AJ, Anderson AC, Rozenblatt-Rosen O, Regev A, and Hacohen N
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- Bone Morphogenetic Proteins metabolism, Cancer-Associated Fibroblasts metabolism, Cancer-Associated Fibroblasts pathology, Cell Compartmentation, Cell Line, Tumor, Chemokines metabolism, Cohort Studies, Colorectal Neoplasms genetics, DNA Mismatch Repair genetics, Endothelial Cells metabolism, Gene Expression Regulation, Neoplastic, Humans, Immunity, Inflammation pathology, Monocytes pathology, Myeloid Cells pathology, Neutrophils pathology, Stromal Cells metabolism, T-Lymphocytes metabolism, Transcription, Genetic, Colorectal Neoplasms immunology, Colorectal Neoplasms pathology
- Abstract
Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks., Competing Interests: Declaration of interests K.P., M.H., J.H.C., V.K.K., A.J.A., O.R.-R., A. Regev., and N.H. are co-inventors on US Patent Application No. 16/995,425 relating to methods for predicting outcomes and treating colorectal cancer as described in the manuscript. A.J.A. is a Consultant for Oncorus, Arrakis Therapeutics, and Merck and receives research funding from Mirati Therapeutics, Deerfield, and Novo Ventures. R.B.C. receives consulting/speaking fees from Abbvie, Amgen, Array Biopharma/Pfizer, Asana Biosciences, Astex Pharmaceuticals, AstraZeneca, Avidity Biosciences, BMS, C4 Therapeutics, Chugai, Elicio, Fog Pharma, Fount Therapeutics/Kinnate Biopharma, Genentech, Guardant Health, Ipsen, LOXO, Merrimack, Mirati Therapeutics, Natera, N-of-one/QIAGEN, Novartis, nRichDx, Revolution Medicines, Roche, Roivant, Shionogi, Shire, Spectrum Pharmaceuticals, Symphogen, Tango Therapeutics, Taiho, Warp Drive Bio, and Zikani Therapeutics; holds equity in Avidity Biosciences, C4 Therapeutics, Fount Therapeutics/Kinnate Biopharma, nRichDx, and Revolution Medicines; and has received research funding from Asana, AstraZeneca, Lilly, and Sanofi. V.K.K. consults for Pfizer, GSK, Tizona Therapeutics, Celsius Therapeutics, Bicara Therapeutics, Compass Therapeutics, Biocon, and Syngene. G.M.B. has sponsored research agreements with Palleon Pharmaceuticals, Olink Proteomics, and Takeda Oncology; served on SABs for Novartis and Nektar Therapeutics; and received honoraria from Novartis. A.C.A. is a paid consultant for iTeos Therapeutics, and is an SAB member for Tizona Therapeutics, Compass Therapeutics, Zumutor Biologics, and ImmuneOncia, which have interests in cancer immunotherapy. A.C.A.’s interests were reviewed and managed by the BWH and Partners Healthcare in accordance with their conflict of interest policies. M.G. receives research funding from BMS, Merck, and Servier. J.W.R., C.A.F., and M.L.H. are employees of and stockholders for NanoString Technologies Inc. D.R.Z. is a former employee of NanoString Technologies Inc. B.I. is a consultant for Merck and Volastra Therapeutic. R.B. is an UptoDate Author. A. Rotem is an equity holder in Celsius Therapeutics and NucleAI. K.N. has research funding from Janssen, Revolution Medicines, Evergrande Group, Pharmavite; advisory board: Seattle Genetics, BiomX; consulting: X-Biotix Therapeutics; research funding: BMS, Merck, and Servier. B.E.J. is on the SAB for Checkpoint Therapeutics. O.R.-R. is a named inventor on patents and patent applications filed by the Broad Institute in single-cell genomics. From October 2020, O.R.-R. is an employee of Genentech. A. Regev. is a founder of and equity holder in Celsius Therapeutics, an equity holder in Immunitas Therapeutics, and was an SAB member for Thermo Fisher Scientific, Syros Pharmaceuticals, and Neogene Therapeutics until August 1, 2020. From August 1, 2020, A. Regev. is an employee of Genentech. A. Regev. is a named inventor on several patents and patent applications filed by the Broad Institute in single-cell and spatial genomics. N.H. holds equity in BioNTech and is an advisor for Related Sciences/Danger Bio., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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187. A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer.
- Author
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Zhong J, Jermusyk A, Wu L, Hoskins JW, Collins I, Mocci E, Zhang M, Song L, Chung CC, Zhang T, Xiao W, Albanes D, Andreotti G, Arslan AA, Babic A, Bamlet WR, Beane-Freeman L, Berndt S, Borgida A, Bracci PM, Brais L, Brennan P, Bueno-de-Mesquita B, Buring J, Canzian F, Childs EJ, Cotterchio M, Du M, Duell EJ, Fuchs C, Gallinger S, Gaziano JM, Giles GG, Giovannucci E, Goggins M, Goodman GE, Goodman PJ, Haiman C, Hartge P, Hasan M, Helzlsouer KJ, Holly EA, Klein EA, Kogevinas M, Kurtz RJ, LeMarchand L, Malats N, Männistö S, Milne R, Neale RE, Ng K, Obazee O, Oberg AL, Orlow I, Patel AV, Peters U, Porta M, Rothman N, Scelo G, Sesso HD, Severi G, Sieri S, Silverman D, Sund M, Tjønneland A, Thornquist MD, Tobias GS, Trichopoulou A, Van Den Eeden SK, Visvanathan K, Wactawski-Wende J, Wentzensen N, White E, Yu H, Yuan C, Zeleniuch-Jacquotte A, Hoover R, Brown K, Kooperberg C, Risch HA, Jacobs EJ, Li D, Yu K, Shu XO, Chanock SJ, Wolpin BM, Stolzenberg-Solomon RZ, Chatterjee N, Klein AP, Smith JP, Kraft P, Shi J, Petersen GM, Zheng W, and Amundadottir LT
- Subjects
- Databases, Genetic, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Transcriptome, Pancreatic Neoplasms genetics
- Abstract
Background: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown., Methods: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples)., Results: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction., Conclusions: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation., (Published by Oxford University Press 2020. This work is written by US Government employees and is in the public domain in the US.)
- Published
- 2020
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188. Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer.
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Walsh N, Zhang H, Hyland PL, Yang Q, Mocci E, Zhang M, Childs EJ, Collins I, Wang Z, Arslan AA, Beane-Freeman L, Bracci PM, Brennan P, Canzian F, Duell EJ, Gallinger S, Giles GG, Goggins M, Goodman GE, Goodman PJ, Hung RJ, Kooperberg C, Kurtz RC, Malats N, LeMarchand L, Neale RE, Olson SH, Scelo G, Shu XO, Van Den Eeden SK, Visvanathan K, White E, Zheng W, Albanes D, Andreotti G, Babic A, Bamlet WR, Berndt SI, Borgida A, Boutron-Ruault MC, Brais L, Brennan P, Bueno-de-Mesquita B, Buring J, Chaffee KG, Chanock S, Cleary S, Cotterchio M, Foretova L, Fuchs C, M Gaziano JM, Giovannucci E, Goggins M, Hackert T, Haiman C, Hartge P, Hasan M, Helzlsouer KJ, Herman J, Holcatova I, Holly EA, Hoover R, Hung RJ, Janout V, Klein EA, Kurtz RC, Laheru D, Lee IM, Lu L, Malats N, Mannisto S, Milne RL, Oberg AL, Orlow I, Patel AV, Peters U, Porta M, Real FX, Rothman N, Sesso HD, Severi G, Silverman D, Strobel O, Sund M, Thornquist MD, Tobias GS, Wactawski-Wende J, Wareham N, Weiderpass E, Wentzensen N, Wheeler W, Yu H, Zeleniuch-Jacquotte A, Kraft P, Li D, Jacobs EJ, Petersen GM, Wolpin BM, Risch HA, Amundadottir LT, Yu K, Klein AP, and Stolzenberg-Solomon RZ
- Subjects
- Case-Control Studies, Genetic Predisposition to Disease, Humans, Models, Statistical, Polymorphism, Single Nucleotide, Carcinoma, Pancreatic Ductal genetics, Genome-Wide Association Study methods, Pancreatic Neoplasms genetics
- Abstract
Background: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes., Methods: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided., Results: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets., Conclusion: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified., (Published by Oxford University Press 2018. This work is written by US Government employees and is in the public domain in the US.)
- Published
- 2019
- Full Text
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