The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.
Colorectal Carcinomas Containing Hypermethylated MLH1 Promoter and Wild-Type BRAF/KRAS Are Enriched for Targetable Kinase Fusions
Open accessAbstract
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
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Le, D. T., Durham, J. N., Smith, K. N., Wang, H., Bartlett, B. R., Aulakh, L. K., Lu, S., Kemberling, H., Wilt, C., Luber, B. S., et al. (2017) · Science · doi:10.1126/science.aan6733 · Cited by 6,645
Overman, M. J., McDermott, R., Leach, J. L., Lonardi, S., Lenz, H.-J., Morse, M. A., Desai, J., Hill, A., Axelson, M., Moss, R. A., et al. (2017) · The Lancet Oncology · doi:10.1016/s1470-2045(17)30422-9 · Cited by 2,836
Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children
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., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1714448 · Cited by 2,824
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Metadata
- 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.
- Venue
- Cancer Research
- Published
- 2019-03-15
- Volume
- 79
- Issue
- 6
- Pages
- 1047-1053
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2908564099
- Cited by
- 163
- References
- 3
- FWCI
- 15.81
- Type
- journal article
- Language
- en
- Open access
- green
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- The paper
- 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. (2019). Colorectal Carcinomas Containing Hypermethylated MLH1 Promoter and Wild-Type BRAF/KRAS Are Enriched for Targetable Kinase Fusions. Cancer Research. https://doi.org/10.1158/0008-5472.can-18-3126
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