Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

Benjamin J. Raphael; Ralph H. Hruban; Andrew J. Aguirre; Richard A. Moffitt; Jen Jen Yeh; Chip Stewart; A. Gordon Robertson; Andrew D. Cherniack; Manaswi Gupta; Gad Getz; Stacey B. Gabriel; Matthew Meyerson; Carrie Cibulskis; Suzanne S. Fei; Toshinori Hinoue; Hui Shen; Peter W. Laird; Shiyun Ling; Yiling Lu; Gordon B. Mills; Rehan Akbani; Phillipe Loher; Eric R. Londin; Isidore Rigoutsos; Aristeidis G. Telonis; Ewan A. Gibb; Anna Goldenberg; Aziz M. Mezlini; Katherine A. Hoadley; Eric Collisson; Eric Lander; Bradley A. Murray; Julian Hess; Mara Rosenberg; Louis Bergelson; Hailei Zhang; Juok Cho; Grace Tiao; Jaegil Kim; Dimitri Livitz; Ignaty Leshchiner; Brendan Reardon; Eliezer Van Allen; Atanas Kamburov; Rameen Beroukhim; Gordon Saksena; Steven E. Schumacher; Michael S. Noble; David I. Heiman; Nils Gehlenborg; Jaegil Kim; Michael S. Lawrence; Volkan Adsay; Gloria Petersen; David Klimstra; Nabeel Bardeesy; Mark D.M. Leiserson; Reanne Bowlby; Katayoon Kasaian; Inanc Birol; Karen L. Mungall; Sara Sadeghi; John N. Weinstein; Paul T. Spellman; Yuexin Liu; Laufey T. Amundadottir; Joel Tepper; Aatur D. Singhi; Rajiv Dhir; Drwiega Paul; Thomas Smyrk; Lizhi Zhang; Paula Kim; Jay Bowen; Jessica Frick; Julie M. Gastier-Foster; Mark Gerken; Kevin Lau; Kristen M. Leraas; Tara M. Lichtenberg; Nilsa C. Ramirez; Jeremy Renkel; Mark Sherman; Lisa Wise; Peggy Yena; Erik Zmuda; Juliann Shih; Adrian Ally; Miruna Balasundaram; Rebecca Carlsen; Andy Chu; Eric Chuah; Amanda Clarke; Noreen Dhalla; Robert A. Holt; Steven J.M. Jones; Darlene Lee; Yussanne Ma; Marco A. Marra; Michael Mayo; Richard A. Moore; Andrew J. Mungall; Jacqueline E. Schein; Payal Sipahimalani; Angela Tam; Nina Thiessen; Kane Tse; Tina Wong; Denise Brooks; J. Todd Auman; Saianand Balu; Tom Bodenheimer; D. Neil Hayes; Alan P. Hoyle; Stuart R. Jefferys; Corbin D. Jones; Shaowu Meng; Piotr A. Mieczkowski; Lisle E. Mose; Charles M. Perou; Amy H. Perou; Jeffrey Roach; Yan Shi; Janae V. Simons; Tara Skelly; Matthew G. Soloway; Donghui Tan; Umadevi Veluvolu; Joel S. Parker; Matthew D. Wilkerson; Anil Korkut; Yasin Senbabaoglu; Patrick Burch; Robert McWilliams; Kari Chaffee; Ann Oberg; Wei Zhang; Marie Claude Gingras; David A. Wheeler; Liu Xi; Monique Albert; John Bartlett; Harman Sekhon; Yeager Stephen; Zaren Howard; Miller Judy; Anne Breggia; Rachna T. Shroff; Sudha Chudamani; Jia Liu; Laxmi Lolla; Rashi Naresh; Todd Pihl; Qiang Sun; Yunhu Wan; Ye Wu; Smith Jennifer; Kevin Roggin; Karl Friedrich Becker; Madhusmita Behera; Joseph Bennett; Lori Boice; Eric Burks; Carlos Gilberto Carlotti Junior; John Chabot; Daniela Pretti da Cunha Tirapelli; Jose Sebastião dos Santos; Michael Dubina; Jennifer Eschbacher; Mei Huang; Lori Huelsenbeck-Dill; Roger Jenkins; Alexey Karpov; Rafael Kemp; Vladimir Lyadov; Shishir Maithel; Georgy Manikhas; Eric Montgomery; Houtan Noushmehr; Adeboye Osunkoya; Taofeek Owonikoko; Oxana Paklina; Olga Potapova; Suresh Ramalingam; W. Kimryn Rathmell; Kimberly Rieger-Christ; Charles Saller; Galiya Setdikova; Alexey Shabunin; Gabriel Sica; Tao Su; Travis Sullivan; Pat Swanson; Katherine Tarvin; Michael Tavobilov; Leigh B. Thorne; Stefan Urbanski; Olga Voronina; Timothy Wang; Daniel Crain; Erin Curley; Johanna Gardner; David Mallery; Scott Morris; Joseph Paulauskis; Robert Penny; Candace Shelton; Troy Shelton; Klaus Peter Janssen; Oliver Bathe; Nathan Bahary; Julia Slotta-Huspenina; Amber Johns; Hanina Hibshoosh; Rosa F. Hwang; Antonia Sepulveda; Amie Radenbaugh; Stephen B. Baylin; Mario Berrios; Moiz S. Bootwalla; Andrea Holbrook; Phillip H. Lai; Dennis T. Maglinte; Swapna Mahurkar; Timothy J. Triche; David J. Van Den Berg; Daniel J. Weisenberger; Lynda Chin; Raju Kucherlapati; Melanie Kucherlapati; Angeliki Pantazi; Peter Park; Gordon Saksena; Doug Voet; Pei Lin; Scott Frazer; Timothy Defreitas; Sam Meier; Lynda Chin; Sun Young Kwon; Yong Hoon Kim; Sang Jae Park; Sung Sik Han; Seong Hoon Kim; Hark Kim; Emma Furth; Margaret Tempero; Chris Sander; Andrew Biankin; David Chang; Peter Bailey; Anthony Gill; James Kench; Sean Grimmond; Amber Johns; Australian Pancreatic Cancer Genome Initiative (APGI; Russell Postier; Rosemary Zuna; Hugues Sicotte; John A. Demchok; Martin L. Ferguson; Carolyn M. Hutter; Kenna R. Mills Shaw; Margi Sheth; Heidi J. Sofia; Roy Tarnuzzer; Zhining Wang; Liming Yang; Jiashan (Julia) Zhang; Ina Felau; Jean C. Zenklusen

doi:10.1016/j.ccell.2017.07.007

Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

Benjamin J. Raphael, Ralph H. Hruban, Andrew J. Aguirre, Richard A. Moffitt, Jen Jen Yeh, Chip Stewart, A. Gordon Robertson, Andrew D. Cherniack, Manaswi Gupta, Gad Getz, Stacey B. Gabriel, Matthew Meyerson, Carrie Cibulskis, Suzanne S. Fei, Toshinori Hinoue, Hui Shen, Peter W. Laird, Shiyun Ling, Yiling Lu, Gordon B. MillsRehan Akbani, Phillipe Loher, Eric R. Londin, Isidore Rigoutsos, Aristeidis G. Telonis, Ewan A. Gibb, Anna Goldenberg, Aziz M. Mezlini, Katherine A. Hoadley, Eric Collisson, Eric Lander, Bradley A. Murray, Julian Hess, Mara Rosenberg, Louis Bergelson, Hailei Zhang, Juok Cho, Grace Tiao, Jaegil Kim, Dimitri Livitz, Ignaty Leshchiner, Brendan Reardon, Eliezer Van Allen, Atanas Kamburov, Rameen Beroukhim, Gordon Saksena, Steven E. Schumacher, Michael S. Noble, David I. Heiman, Nils Gehlenborg, Jaegil Kim, Michael S. Lawrence, Volkan Adsay, Gloria Petersen, David Klimstra, Nabeel Bardeesy, Mark D.M. Leiserson, Reanne Bowlby, Katayoon Kasaian, Inanc Birol, Karen L. Mungall, Sara Sadeghi, John N. Weinstein, Paul T. Spellman, Yuexin Liu, Laufey T. Amundadottir, Joel Tepper, Aatur D. Singhi, Rajiv Dhir, Drwiega Paul, Thomas Smyrk, Lizhi Zhang, Paula Kim, Jay Bowen, Jessica Frick, Julie M. Gastier-Foster, Mark Gerken, Kevin Lau, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Jeremy Renkel, Mark Sherman, Lisa Wise, Peggy Yena, Erik Zmuda, Juliann Shih, Adrian Ally, Miruna Balasundaram, Rebecca Carlsen, Andy Chu, Eric Chuah, Amanda Clarke, Noreen Dhalla, Robert A. Holt, Steven J.M. Jones, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Denise Brooks, J. Todd Auman, Saianand Balu, Tom Bodenheimer, D. Neil Hayes, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Charles M. Perou, Amy H. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Joel S. Parker, Matthew D. Wilkerson, Anil Korkut, Yasin Senbabaoglu, Patrick Burch, Robert McWilliams, Kari Chaffee, Ann Oberg, Wei Zhang, Marie Claude Gingras, David A. Wheeler, Liu Xi, Monique Albert, John Bartlett, Harman Sekhon, Yeager Stephen, Zaren Howard, Miller Judy, Anne Breggia, Rachna T. Shroff, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Smith Jennifer, Kevin Roggin, Karl Friedrich Becker, Madhusmita Behera, Joseph Bennett, Lori Boice, Eric Burks, Carlos Gilberto Carlotti Junior, John Chabot, Daniela Pretti da Cunha Tirapelli, Jose Sebastião dos Santos, Michael Dubina, Jennifer Eschbacher, Mei Huang, Lori Huelsenbeck-Dill, Roger Jenkins, Alexey Karpov, Rafael Kemp, Vladimir Lyadov, Shishir Maithel, Georgy Manikhas, Eric Montgomery, Houtan Noushmehr, Adeboye Osunkoya, Taofeek Owonikoko, Oxana Paklina, Olga Potapova, Suresh Ramalingam, W. Kimryn Rathmell, Kimberly Rieger-Christ, Charles Saller, Galiya Setdikova, Alexey Shabunin, Gabriel Sica, Tao Su, Travis Sullivan, Pat Swanson, Katherine Tarvin, Michael Tavobilov, Leigh B. Thorne, Stefan Urbanski, Olga Voronina, Timothy Wang, Daniel Crain, Erin Curley, Johanna Gardner, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Klaus Peter Janssen, Oliver Bathe, Nathan Bahary, Julia Slotta-Huspenina, Amber Johns, Hanina Hibshoosh, Rosa F. Hwang, Antonia Sepulveda, Amie Radenbaugh, Stephen B. Baylin, Mario Berrios, Moiz S. Bootwalla, Andrea Holbrook, Phillip H. Lai, Dennis T. Maglinte, Swapna Mahurkar, Timothy J. Triche, David J. Van Den Berg, Daniel J. Weisenberger, Lynda Chin, Raju Kucherlapati, Melanie Kucherlapati, Angeliki Pantazi, Peter Park, Gordon Saksena, Doug Voet, Pei Lin, Scott Frazer, Timothy Defreitas, Sam Meier, Lynda Chin, Sun Young Kwon, Yong Hoon Kim, Sang Jae Park, Sung Sik Han, Seong Hoon Kim, Hark Kim, Emma Furth, Margaret Tempero, Chris Sander, Andrew Biankin, David Chang, Peter Bailey, Anthony Gill, James Kench, Sean Grimmond, Amber Johns, Australian Pancreatic Cancer Genome Initiative (APGI, Russell Postier, Rosemary Zuna, Hugues Sicotte, John A. Demchok, Martin L. Ferguson, Carolyn M. Hutter, Kenna R. Mills Shaw, Margi Sheth, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jiashan (Julia) Zhang, Ina Felau, Jean C. Zenklusen

Surgery, Surgical Oncology Division

Research output: Contribution to journal › Article › peer-review

1354 Scopus citations

Abstract

We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.

Original language	English (US)
Pages (from-to)	185-203.e13
Journal	Cancer cell
Volume	32
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2017.07.007
State	Published - Aug 14 2017

Funding

We are grateful to all patients and families who contributed to this study. This work was supported by the following grants from the NIH: U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, U24 CA211000, SPORE CA62924, P50 CA127003, and P30 CA016672. B.J. Raphael is a co-founder and consultant of Medley Genomics. R. Hruban receives royalty payments from Myriad Genetics for the PalB2 invention and is on the board of MiDiagnostics in a relationship overseen by Johns Hopkins University. M. Meyerson and A. Cherniack receive research funding from Bayer A.G. D.J. Weisenberger is a consultant for Zymo Research Corporation. E.A.G is an employee of GenomeDX Biosciences.

Keywords

genomics
heterogeneity
KRAS
miRNA
molecular subtypes
pancreatic cancer
PDAC
RPPA
TCGA
tumor cellularity

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ccell.2017.07.007

Cite this

Raphael, B. J., Hruban, R. H., Aguirre, A. J., Moffitt, R. A., Yeh, J. J., Stewart, C., Robertson, A. G., Cherniack, A. D., Gupta, M., Getz, G., Gabriel, S. B., Meyerson, M., Cibulskis, C., Fei, S. S., Hinoue, T., Shen, H., Laird, P. W., Ling, S., Lu, Y., ... Zenklusen, J. C. (2017). Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer cell, 32(2), 185-203.e13. https://doi.org/10.1016/j.ccell.2017.07.007

@article{6652027d61eb4471b2c1b7d4cfc35594,

title = "Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma",

abstract = "We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.",

keywords = "genomics, heterogeneity, KRAS, miRNA, molecular subtypes, pancreatic cancer, PDAC, RPPA, TCGA, tumor cellularity",

author = "Raphael, {Benjamin J.} and Hruban, {Ralph H.} and Aguirre, {Andrew J.} and Moffitt, {Richard A.} and Yeh, {Jen Jen} and Chip Stewart and Robertson, {A. Gordon} and Cherniack, {Andrew D.} and Manaswi Gupta and Gad Getz and Gabriel, {Stacey B.} and Matthew Meyerson and Carrie Cibulskis and Fei, {Suzanne S.} and Toshinori Hinoue and Hui Shen and Laird, {Peter W.} and Shiyun Ling and Yiling Lu and Mills, {Gordon B.} and Rehan Akbani and Phillipe Loher and Londin, {Eric R.} and Isidore Rigoutsos and Telonis, {Aristeidis G.} and Gibb, {Ewan A.} and Anna Goldenberg and Mezlini, {Aziz M.} and Hoadley, {Katherine A.} and Eric Collisson and Eric Lander and Murray, {Bradley A.} and Julian Hess and Mara Rosenberg and Louis Bergelson and Hailei Zhang and Juok Cho and Grace Tiao and Jaegil Kim and Dimitri Livitz and Ignaty Leshchiner and Brendan Reardon and {Van Allen}, Eliezer and Atanas Kamburov and Rameen Beroukhim and Gordon Saksena and Schumacher, {Steven E.} and Noble, {Michael S.} and Heiman, {David I.} and Nils Gehlenborg and Jaegil Kim and Lawrence, {Michael S.} and Volkan Adsay and Gloria Petersen and David Klimstra and Nabeel Bardeesy and Leiserson, {Mark D.M.} and Reanne Bowlby and Katayoon Kasaian and Inanc Birol and Mungall, {Karen L.} and Sara Sadeghi and Weinstein, {John N.} and Spellman, {Paul T.} and Yuexin Liu and Amundadottir, {Laufey T.} and Joel Tepper and Singhi, {Aatur D.} and Rajiv Dhir and Drwiega Paul and Thomas Smyrk and Lizhi Zhang and Paula Kim and Jay Bowen and Jessica Frick and Gastier-Foster, {Julie M.} and Mark Gerken and Kevin Lau and Leraas, {Kristen M.} and Lichtenberg, {Tara M.} and Ramirez, {Nilsa C.} and Jeremy Renkel and Mark Sherman and Lisa Wise and Peggy Yena and Erik Zmuda and Juliann Shih and Adrian Ally and Miruna Balasundaram and Rebecca Carlsen and Andy Chu and Eric Chuah and Amanda Clarke and Noreen Dhalla and Holt, {Robert A.} and Jones, {Steven J.M.} and Darlene Lee and Yussanne Ma and Marra, {Marco A.} and Michael Mayo and Moore, {Richard A.} and Mungall, {Andrew J.} and Schein, {Jacqueline E.} and Payal Sipahimalani and Angela Tam and Nina Thiessen and Kane Tse and Tina Wong and Denise Brooks and Auman, {J. Todd} and Saianand Balu and Tom Bodenheimer and Hayes, {D. Neil} and Hoyle, {Alan P.} and Jefferys, {Stuart R.} and Jones, {Corbin D.} and Shaowu Meng and Mieczkowski, {Piotr A.} and Mose, {Lisle E.} and Perou, {Charles M.} and Perou, {Amy H.} and Jeffrey Roach and Yan Shi and Simons, {Janae V.} and Tara Skelly and Soloway, {Matthew G.} and Donghui Tan and Umadevi Veluvolu and Parker, {Joel S.} and Wilkerson, {Matthew D.} and Anil Korkut and Yasin Senbabaoglu and Patrick Burch and Robert McWilliams and Kari Chaffee and Ann Oberg and Wei Zhang and Gingras, {Marie Claude} and Wheeler, {David A.} and Liu Xi and Monique Albert and John Bartlett and Harman Sekhon and Yeager Stephen and Zaren Howard and Miller Judy and Anne Breggia and Shroff, {Rachna T.} and Sudha Chudamani and Jia Liu and Laxmi Lolla and Rashi Naresh and Todd Pihl and Qiang Sun and Yunhu Wan and Ye Wu and Smith Jennifer and Kevin Roggin and Becker, {Karl Friedrich} and Madhusmita Behera and Joseph Bennett and Lori Boice and Eric Burks and {Carlotti Junior}, {Carlos Gilberto} and John Chabot and {Pretti da Cunha Tirapelli}, Daniela and {Sebasti{\~a}o dos Santos}, Jose and Michael Dubina and Jennifer Eschbacher and Mei Huang and Lori Huelsenbeck-Dill and Roger Jenkins and Alexey Karpov and Rafael Kemp and Vladimir Lyadov and Shishir Maithel and Georgy Manikhas and Eric Montgomery and Houtan Noushmehr and Adeboye Osunkoya and Taofeek Owonikoko and Oxana Paklina and Olga Potapova and Suresh Ramalingam and Rathmell, {W. Kimryn} and Kimberly Rieger-Christ and Charles Saller and Galiya Setdikova and Alexey Shabunin and Gabriel Sica and Tao Su and Travis Sullivan and Pat Swanson and Katherine Tarvin and Michael Tavobilov and Thorne, {Leigh B.} and Stefan Urbanski and Olga Voronina and Timothy Wang and Daniel Crain and Erin Curley and Johanna Gardner and David Mallery and Scott Morris and Joseph Paulauskis and Robert Penny and Candace Shelton and Troy Shelton and Janssen, {Klaus Peter} and Oliver Bathe and Nathan Bahary and Julia Slotta-Huspenina and Amber Johns and Hanina Hibshoosh and Hwang, {Rosa F.} and Antonia Sepulveda and Amie Radenbaugh and Baylin, {Stephen B.} and Mario Berrios and Bootwalla, {Moiz S.} and Andrea Holbrook and Lai, {Phillip H.} and Maglinte, {Dennis T.} and Swapna Mahurkar and Triche, {Timothy J.} and {Van Den Berg}, {David J.} and Weisenberger, {Daniel J.} and Lynda Chin and Raju Kucherlapati and Melanie Kucherlapati and Angeliki Pantazi and Peter Park and Gordon Saksena and Doug Voet and Pei Lin and Scott Frazer and Timothy Defreitas and Sam Meier and Lynda Chin and Kwon, {Sun Young} and Kim, {Yong Hoon} and Park, {Sang Jae} and Han, {Sung Sik} and Kim, {Seong Hoon} and Hark Kim and Emma Furth and Margaret Tempero and Chris Sander and Andrew Biankin and David Chang and Peter Bailey and Anthony Gill and James Kench and Sean Grimmond and Amber Johns and {Cancer Genome Initiative (APGI}, {Australian Pancreatic} and Russell Postier and Rosemary Zuna and Hugues Sicotte and Demchok, {John A.} and Ferguson, {Martin L.} and Hutter, {Carolyn M.} and {Mills Shaw}, {Kenna R.} and Margi Sheth and Sofia, {Heidi J.} and Roy Tarnuzzer and Zhining Wang and Liming Yang and Zhang, {Jiashan (Julia)} and Ina Felau and Zenklusen, {Jean C.}",

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = aug,

day = "14",

doi = "10.1016/j.ccell.2017.07.007",

language = "English (US)",

volume = "32",

pages = "185--203.e13",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "2",

}

Raphael, BJ, Hruban, RH, Aguirre, AJ, Moffitt, RA, Yeh, JJ, Stewart, C, Robertson, AG, Cherniack, AD, Gupta, M, Getz, G, Gabriel, SB, Meyerson, M, Cibulskis, C, Fei, SS, Hinoue, T, Shen, H, Laird, PW, Ling, S, Lu, Y, Mills, GB, Akbani, R, Loher, P, Londin, ER, Rigoutsos, I, Telonis, AG, Gibb, EA, Goldenberg, A, Mezlini, AM, Hoadley, KA, Collisson, E, Lander, E, Murray, BA, Hess, J, Rosenberg, M, Bergelson, L, Zhang, H, Cho, J, Tiao, G, Kim, J, Livitz, D, Leshchiner, I, Reardon, B, Van Allen, E, Kamburov, A, Beroukhim, R, Saksena, G, Schumacher, SE, Noble, MS, Heiman, DI, Gehlenborg, N, Kim, J, Lawrence, MS, Adsay, V, Petersen, G, Klimstra, D, Bardeesy, N, Leiserson, MDM, Bowlby, R, Kasaian, K, Birol, I, Mungall, KL, Sadeghi, S, Weinstein, JN, Spellman, PT, Liu, Y, Amundadottir, LT, Tepper, J, Singhi, AD, Dhir, R, Paul, D, Smyrk, T, Zhang, L, Kim, P, Bowen, J, Frick, J, Gastier-Foster, JM, Gerken, M, Lau, K, Leraas, KM, Lichtenberg, TM, Ramirez, NC, Renkel, J, Sherman, M, Wise, L, Yena, P, Zmuda, E, Shih, J, Ally, A, Balasundaram, M, Carlsen, R, Chu, A, Chuah, E, Clarke, A, Dhalla, N, Holt, RA, Jones, SJM, Lee, D, Ma, Y, Marra, MA, Mayo, M, Moore, RA, Mungall, AJ, Schein, JE, Sipahimalani, P, Tam, A, Thiessen, N, Tse, K, Wong, T, Brooks, D, Auman, JT, Balu, S, Bodenheimer, T, Hayes, DN, Hoyle, AP, Jefferys, SR, Jones, CD, Meng, S, Mieczkowski, PA, Mose, LE, Perou, CM, Perou, AH, Roach, J, Shi, Y, Simons, JV, Skelly, T, Soloway, MG, Tan, D, Veluvolu, U, Parker, JS, Wilkerson, MD, Korkut, A, Senbabaoglu, Y, Burch, P, McWilliams, R, Chaffee, K, Oberg, A, Zhang, W, Gingras, MC, Wheeler, DA, Xi, L, Albert, M, Bartlett, J, Sekhon, H, Stephen, Y, Howard, Z, Judy, M, Breggia, A, Shroff, RT, Chudamani, S, Liu, J, Lolla, L, Naresh, R, Pihl, T, Sun, Q, Wan, Y, Wu, Y, Jennifer, S, Roggin, K, Becker, KF, Behera, M, Bennett, J, Boice, L, Burks, E, Carlotti Junior, CG, Chabot, J, Pretti da Cunha Tirapelli, D, Sebastião dos Santos, J, Dubina, M, Eschbacher, J, Huang, M, Huelsenbeck-Dill, L, Jenkins, R, Karpov, A, Kemp, R, Lyadov, V, Maithel, S, Manikhas, G, Montgomery, E, Noushmehr, H, Osunkoya, A, Owonikoko, T, Paklina, O, Potapova, O, Ramalingam, S, Rathmell, WK, Rieger-Christ, K, Saller, C, Setdikova, G, Shabunin, A, Sica, G, Su, T, Sullivan, T, Swanson, P, Tarvin, K, Tavobilov, M, Thorne, LB, Urbanski, S, Voronina, O, Wang, T, Crain, D, Curley, E, Gardner, J, Mallery, D, Morris, S, Paulauskis, J, Penny, R, Shelton, C, Shelton, T, Janssen, KP, Bathe, O, Bahary, N, Slotta-Huspenina, J, Johns, A, Hibshoosh, H, Hwang, RF, Sepulveda, A, Radenbaugh, A, Baylin, SB, Berrios, M, Bootwalla, MS, Holbrook, A, Lai, PH, Maglinte, DT, Mahurkar, S, Triche, TJ, Van Den Berg, DJ, Weisenberger, DJ, Chin, L, Kucherlapati, R, Kucherlapati, M, Pantazi, A, Park, P, Saksena, G, Voet, D, Lin, P, Frazer, S, Defreitas, T, Meier, S, Chin, L, Kwon, SY, Kim, YH, Park, SJ, Han, SS, Kim, SH, Kim, H, Furth, E, Tempero, M, Sander, C, Biankin, A, Chang, D, Bailey, P, Gill, A, Kench, J, Grimmond, S, Johns, A, Cancer Genome Initiative (APGI, AP, Postier, R, Zuna, R, Sicotte, H, Demchok, JA, Ferguson, ML, Hutter, CM, Mills Shaw, KR, Sheth, M, Sofia, HJ, Tarnuzzer, R, Wang, Z, Yang, L, Zhang, J, Felau, I & Zenklusen, JC 2017, 'Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma', Cancer cell, vol. 32, no. 2, pp. 185-203.e13. https://doi.org/10.1016/j.ccell.2017.07.007

TY - JOUR

T1 - Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

AU - Raphael, Benjamin J.

AU - Hruban, Ralph H.

AU - Aguirre, Andrew J.

AU - Moffitt, Richard A.

AU - Yeh, Jen Jen

AU - Stewart, Chip

AU - Robertson, A. Gordon

AU - Cherniack, Andrew D.

AU - Gupta, Manaswi

AU - Getz, Gad

AU - Gabriel, Stacey B.

AU - Meyerson, Matthew

AU - Cibulskis, Carrie

AU - Fei, Suzanne S.

AU - Hinoue, Toshinori

AU - Shen, Hui

AU - Laird, Peter W.

AU - Ling, Shiyun

AU - Lu, Yiling

AU - Mills, Gordon B.

AU - Akbani, Rehan

AU - Loher, Phillipe

AU - Londin, Eric R.

AU - Rigoutsos, Isidore

AU - Telonis, Aristeidis G.

AU - Gibb, Ewan A.

AU - Goldenberg, Anna

AU - Mezlini, Aziz M.

AU - Hoadley, Katherine A.

AU - Collisson, Eric

AU - Lander, Eric

AU - Murray, Bradley A.

AU - Hess, Julian

AU - Rosenberg, Mara

AU - Bergelson, Louis

AU - Zhang, Hailei

AU - Cho, Juok

AU - Tiao, Grace

AU - Kim, Jaegil

AU - Livitz, Dimitri

AU - Leshchiner, Ignaty

AU - Reardon, Brendan

AU - Van Allen, Eliezer

AU - Kamburov, Atanas

AU - Beroukhim, Rameen

AU - Saksena, Gordon

AU - Schumacher, Steven E.

AU - Noble, Michael S.

AU - Heiman, David I.

AU - Gehlenborg, Nils

AU - Kim, Jaegil

AU - Lawrence, Michael S.

AU - Adsay, Volkan

AU - Petersen, Gloria

AU - Klimstra, David

AU - Bardeesy, Nabeel

AU - Leiserson, Mark D.M.

AU - Bowlby, Reanne

AU - Kasaian, Katayoon

AU - Birol, Inanc

AU - Mungall, Karen L.

AU - Sadeghi, Sara

AU - Weinstein, John N.

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AU - Baylin, Stephen B.

AU - Berrios, Mario

AU - Bootwalla, Moiz S.

AU - Holbrook, Andrea

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AU - Maglinte, Dennis T.

AU - Mahurkar, Swapna

AU - Triche, Timothy J.

AU - Van Den Berg, David J.

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AU - Kucherlapati, Melanie

AU - Pantazi, Angeliki

AU - Park, Peter

AU - Saksena, Gordon

AU - Voet, Doug

AU - Lin, Pei

AU - Frazer, Scott

AU - Defreitas, Timothy

AU - Meier, Sam

AU - Chin, Lynda

AU - Kwon, Sun Young

AU - Kim, Yong Hoon

AU - Park, Sang Jae

AU - Han, Sung Sik

AU - Kim, Seong Hoon

AU - Kim, Hark

AU - Furth, Emma

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AU - Johns, Amber

AU - Cancer Genome Initiative (APGI, Australian Pancreatic

AU - Postier, Russell

AU - Zuna, Rosemary

AU - Sicotte, Hugues

AU - Demchok, John A.

AU - Ferguson, Martin L.

AU - Hutter, Carolyn M.

AU - Mills Shaw, Kenna R.

AU - Sheth, Margi

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AU - Wang, Zhining

AU - Yang, Liming

AU - Zhang, Jiashan (Julia)

AU - Felau, Ina

AU - Zenklusen, Jean C.

PY - 2017/8/14

Y1 - 2017/8/14

N2 - We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.

AB - We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.

KW - genomics

KW - heterogeneity

KW - KRAS

KW - miRNA

KW - molecular subtypes

KW - pancreatic cancer

KW - PDAC

KW - RPPA

KW - TCGA

KW - tumor cellularity

UR - http://www.scopus.com/inward/record.url?scp=85026888109&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85026888109&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2017.07.007

DO - 10.1016/j.ccell.2017.07.007

M3 - Article

C2 - 28810144

AN - SCOPUS:85026888109

SN - 1535-6108

VL - 32

SP - 185-203.e13

JO - Cancer cell

JF - Cancer cell

IS - 2

ER -

Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

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