Colorectal carcinomas containing hypermethylated MLH1 promoter and wild-type BRAF/KRAS are enriched for targetable kinase fusions Journal Article


Authors: Cocco, E.; Benhamida, J.; Middha, S.; Zehir, A.; Mullaney, K.; Shia, J.; Yaeger, R.; Zhang, L.; Wong, D.; Villafania, L.; Nafa, K.; Scaltriti, M.; Drilon, A.; Saltz, L.; Schram, A. M.; Stadler, Z. K.; Hyman, D. M.; Benayed, R.; Ladanyi, M.; Hechtman, J. F.
Article Title: Colorectal carcinomas containing hypermethylated MLH1 promoter and wild-type BRAF/KRAS are enriched for targetable kinase fusions
Abstract: 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. Overall 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.Significance: A high frequency of targetable kinase fusions in BRAF/RAS wild-type, MSI-H colorectal carcinoma offers a rationale for routine screening to identify patients with colorectal carcinoma with kinase fusions that may be responsive to kinase inhibitors.See related commentary by Valeri, p. 1041. ©2019 American Association for Cancer Research.
Journal Title: Cancer Research
Volume: 79
Issue: 6
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2019-03-15
Start Page: 1047
End Page: 1053
Language: English
DOI: 10.1158/0008-5472.Can-18-3126
PUBMED: 30643016
PROVIDER: scopus
PMCID: PMC6420871
DOI/URL:
Notes: Source: Scopus
Altmetric Score
MSK Authors
  1. Leonard B Saltz
    599 Saltz
  2. Khedoudja Nafa
    184 Nafa
  3. Liying Zhang
    89 Zhang
  4. Zsofia Kinga Stadler
    152 Stadler
  5. Marc Ladanyi
    879 Ladanyi
  6. Jinru Shia
    465 Shia
  7. Rona Denit Yaeger
    75 Yaeger
  8. David Hyman
    194 Hyman
  9. Ahmet Zehir
    157 Zehir
  10. Alexander Edward Drilon
    146 Drilon
  11. Alison Michele Schram
    23 Schram
  12. Jaclyn Frances Hechtman
    108 Hechtman
  13. Rym Benayed
    76 Benayed
  14. Sumit   Middha
    56 Middha
  15. Emiliano Cocco
    12 Cocco
  16. Donna Wong
    2 Wong