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Cancer Cell. 2017 Aug 14;32(2):185-203.e13. doi: 10.1016/j.ccell.2017.07.007.

Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma.

Collaborators (271)

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 Jr, 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 JJ, Felau I, Zenklusen JC.

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:

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

PMID:
28810144
PMCID:
PMC5964983
DOI:
10.1016/j.ccell.2017.07.007
[Indexed for MEDLINE]
Free PMC Article

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