Colorectal Carcinomas Containing Hypermethylated MLH1 Promoter and Wild-Type BRAF/KRAS Are Enriched for Targetable Kinase Fusions

被引:113
作者
Cocco, Emiliano [1 ]
Benhamida, Jamal [2 ]
Middha, Sumit [2 ]
Zehir, Ahmet [2 ]
Mullaney, Kerry [2 ]
Shia, Jinru [2 ]
Yaeger, Rona [3 ]
Zhang, Liying [2 ]
Wong, Donna [2 ]
Villafania, Liliana [2 ]
Nafa, Khedoudja [2 ]
Scaltriti, Maurizio [1 ,2 ]
Drilon, Alexander [3 ,4 ]
Saltz, Leonard [3 ]
Schram, Alison M. [3 ,4 ]
Stadler, Zsofia K. [3 ]
Hyman, David M. [3 ,4 ]
Benayed, Ryma [2 ]
Ladanyi, Marc [1 ,2 ]
Hechtman, Jaclyn F. [2 ]
机构
[1] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathol Program, 1275 York Ave, New York, NY 10021 USA
[2] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA
[3] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA
[4] Weill Cornell Med Coll, New York, NY USA
关键词
CANCER; BRAF;
D O I
10.1158/0008-5472.CAN-18-3126
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Kinase fusions are rare and poorly characterized in colorectal carcinoma, yet they present unique opportunities for targeted therapy. In this study, we characterized kinase fusions from patients with advanced colorectal carcinoma who had MSK-IMPACT testing of their tumors between January 2014 and June 2018. Patients were analyzed for the presence of fusions, microsatellite instability (MSI), and RAS/BRAF mutations. Mismatch repair (MMR), IHC, and promoter hypermethylation status of MLH1 (MLH1ph) in microsatellite instability-high (MSI-H) colorectal carcinoma with fusions were investigated. Fusion transcripts were confirmed using a targeted RNA-seq panel assay. Of 2,314 colorectal carcinomas with MSK-IMPACT testing, 21 harbored kinase fusions. Over-all 57% (12/21) of colorectal carcinoma fusions were MSI-H/MMR-D. Loss of MLH1 and MLH1ph was confirmed in all 12 and all 10 cases with available material, respectively. Fusions were present in 5% of MSI-H/MMR-D colorectal carcinoma compared with 0.4% of MSS/MMR-P colorectal carcinoma (P < 0.001) and 15% of MSI-H/MMR-D colorectal carcinoma with wild-type RAS/BRAF. Of 24 total MLH1-deficient colorectal carcinomas with MLH1ph and wild-type RAS/BRAF, 10 (42%) harbored kinase fusions. Kinase fusions in MSI-H colorectal carcinoma were associated with sporadic MLH1ph rather than with Lynch syndrome, and these patients may be eligible for kinase inhibitors, particularly following resistance or toxicity in response to immunotherapy. These findings identify a molecular subset of colorectal carcinoma with kinase fusions that may be responsive to kinase inhibitors.
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收藏
页码:1047 / 1053
页数:7
相关论文
共 16 条
[1]   Colon Cancer, Version 1.2017 Clinical Practice Guidelines in Oncology [J].
Benson, Al B., III ;
Venook, Alan P. ;
Cederquist, Lynette ;
Chan, Emily ;
Chen, Yi-Jen ;
Cooper, Harry S. ;
Deming, Dustin ;
Engstrom, Paul F. ;
Enzinger, Peter C. ;
Fichera, Alessandro ;
Grem, Jean L. ;
Grothey, Axel ;
Hochster, Howard S. ;
Hoffe, Sarah ;
Hunt, Steven ;
Kamel, Ahmed ;
Kirilcuk, Natalie ;
Krishnamurthi, Smitha ;
Messersmith, Wells A. ;
Mulcahy, Mary F. ;
Murphy, James D. ;
Nurkin, Steven ;
Saltz, Leonard ;
Sharma, Sunil ;
Shibata, David ;
Skibber, John M. ;
Sofocleous, Constantinos T. ;
Stoffel, Elena M. ;
Stotsky-Himelfarb, Eden ;
Willett, Christopher G. ;
Wu, Christina S. ;
Gregory, Kristina M. ;
Freedman-Cass, Deborah .
JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK, 2017, 15 (03) :370-398
[2]  
Bosman FT, 2010, WHO Classification of tumors of the digestive system
[3]   Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology [J].
Cheng, Donavan T. ;
Mitchell, Talia N. ;
Zehir, Ahmet ;
Shah, Ronak H. ;
Benayed, Ryma ;
Syed, Aijazuddin ;
Chandramohan, Raghu ;
Liu, Zhen Yu ;
Won, Helen H. ;
Scott, Sasinya N. ;
Brannon, A. Rose ;
O'Reilly, Catherine ;
Sadowska, Justyna ;
Casanova, Jacklyn ;
Yannes, Angela ;
Hechtman, Jaclyn F. ;
Yao, Jinjuan ;
Song, Wei ;
Ross, Dara S. ;
Oultache, Alifya ;
Dogan, Snjezana ;
Borsu, Laetitia ;
Hameed, Meera ;
Nafa, Khedoudja ;
Arcila, Maria E. ;
Ladanyi, Marc ;
Berger, Michael F. .
JOURNAL OF MOLECULAR DIAGNOSTICS, 2015, 17 (03) :251-264
[4]   Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma [J].
Christensen, James G. ;
Zou, Helen Y. ;
Arango, Maria E. ;
Li, Qiuhua ;
Lee, Joseph H. ;
McDonnell, Scott R. ;
Yamazaki, Shinji ;
Alton, Gordon R. ;
Mroczkowski, Barbara ;
Los, Gerrit .
MOLECULAR CANCER THERAPEUTICS, 2007, 6 (12) :3314-3322
[5]   Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children [J].
Drilon, A. ;
Laetsch, T. W. ;
Kummar, S. ;
DuBois, S. G. ;
Lassen, U. N. ;
Demetri, G. D. ;
Nathenson, M. ;
Doebele, R. C. ;
Farago, A. F. ;
Pappo, A. S. ;
Turpin, B. ;
Dowlati, A. ;
Brose, M. S. ;
Mascarenhas, L. ;
Federman, N. ;
Berlin, J. ;
El-Deiry, W. S. ;
Baik, C. ;
Deeken, J. ;
Boni, V. ;
Nagasubramanian, R. ;
Taylor, M. ;
Rudzinski, E. R. ;
Meric-Bernstam, F. ;
Sohal, D. P. S. ;
Ma, P. C. ;
Raez, L. E. ;
Hechtman, J. F. ;
Benayed, R. ;
Ladanyi, M. ;
Tuch, B. B. ;
Ebata, K. ;
Cruickshank, S. ;
Ku, N. C. ;
Cox, M. C. ;
Hawkins, D. S. ;
Hong, D. S. ;
Hyman, D. M. .
NEW ENGLAND JOURNAL OF MEDICINE, 2018, 378 (08) :731-739
[6]   The BRAF Oncoprotein Functions through the Transcriptional Repressor MAFG to Mediate the CpG Island Methylator Phenotype [J].
Fang, Minggang ;
Ou, Jianhong ;
Hutchinson, Lloyd ;
Green, Michael R. .
MOLECULAR CELL, 2014, 55 (06) :904-915
[7]   MLH1-deficient Colorectal Carcinoma With Wild-type BRAF and MLH1 Promoter Hypermethylation Harbor KRAS Mutations and Arise From Conventional Adenomas [J].
Farchoukh, Lama ;
Kuan, Shih-Fan ;
Dudley, Beth ;
Brand, Randall ;
Nikiforova, Marina ;
Pai, Reetesh K. .
AMERICAN JOURNAL OF SURGICAL PATHOLOGY, 2016, 40 (10) :1390-1399
[8]   Pan-Trk Immunohistochemistry Is an Efficient and Reliable Screen for the Detection of NTRK Fusions [J].
Hechtman, Jaclyn F. ;
Benayed, Ryma ;
Hyman, David M. ;
Drilon, Alexander ;
Zehir, Ahmet ;
Frosina, Denise ;
Arcila, Maria E. ;
Dogan, Snjezana ;
Klimstra, David S. ;
Ladanyi, Marc ;
Jungbluth, Achim A. .
AMERICAN JOURNAL OF SURGICAL PATHOLOGY, 2017, 41 (11) :1547-1551
[9]   Identification of Targetable Kinase Alterations in Patients with Colorectal Carcinoma That are Preferentially Associated with Wild-Type RAS/RAF [J].
Hechtman, Jaclyn F. ;
Zehir, Ahmet ;
Yaeger, Rona ;
Wang, Lu ;
Middha, Sumit ;
Zheng, Tao ;
Hyman, David M. ;
Solit, David ;
Arcila, Maria E. ;
Borsu, Laetitia ;
Shia, Jinru ;
Vakiani, Efsevia ;
Saltz, Leonard ;
Ladanyi, Marc .
MOLECULAR CANCER RESEARCH, 2016, 14 (03) :296-301
[10]   Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade [J].
Le, Dung T. ;
Durham, Jennifer N. ;
Smith, Kellie N. ;
Wang, Hao ;
Bartlett, Bjarne R. ;
Aulakh, Laveet K. ;
Lu, Steve ;
Kemberling, Holly ;
Wilt, Cara ;
Luber, Brandon S. ;
Wong, Fay ;
Azad, Nilofer S. ;
Rucki, Agnieszka A. ;
Laheru, Dan ;
Donehower, Ross ;
Zaheer, Atif ;
Fisher, George A. ;
Crocenzi, Todd S. ;
Lee, James J. ;
Greten, Tim F. ;
Duffy, Austin G. ;
Ciombor, Kristen K. ;
Eyring, Aleksandra D. ;
Lam, Bao H. ;
Joe, Andrew ;
Kang, S. Peter ;
Holdhoff, Matthias ;
Danilova, Ludmila ;
Cope, Leslie ;
Meyer, Christian ;
Zhou, Shibin ;
Goldberg, Richard M. ;
Armstrong, Deborah K. ;
Bever, Katherine M. ;
Fader, Amanda N. ;
Taube, Janis ;
Housseau, Franck ;
Spetzler, David ;
Xiao, Nianqing ;
Pardoll, Drew M. ;
Papadopoulos, Nickolas ;
Kinzler, Kenneth W. ;
Eshleman, James R. ;
Vogelstein, Bert ;
Anders, Robert A. ;
Diaz, Luis A., Jr. .
SCIENCE, 2017, 357 (6349) :409-413