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

被引：116

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

来源：

CANCER RESEARCH | 2019年 / 79卷 / 06期

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.

引用

页码：1047 / 1053

页数：7

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