Molecular Characterization and Therapeutic Targeting of Colorectal Cancers Harboring Receptor Tyrosine Kinase Fusions
- 7 January 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 27 (6), 1695-1705
- https://doi.org/10.1158/1078-0432.ccr-20-4073
Abstract
Introduction: Receptor tyrosine kinase (RTK) fusions in colorectal cancers (CRC) are rare but potentially therapeutically relevant. We describe clinical, molecular and pathologic attributes of RTK fusion-associated CRC. Methods: We identified all cases with RTK fusions in colorectal cancer patients seen at Dana-Farber Cancer Institute who underwent OncoPanel testing between 2013-2018. Clinical, histological and molecular features were extracted from the patient charts and molecular testing results. Results: We identified 12 driver oncogenic fusions in various RTKs. These fusions occurred exclusively in BRAF and RAS wild-type tumors and were enriched in right-sided and mismatch repair-deficient (MMR-D) CRC. All of the MMR-D CRCs with RTK fusions were found in tumors with acquired MMR-D due to MLH1 promoter hypermethylation and one was associated with a sessile serrated polyp. Molecular profiles of MMR-D CRC with RTK fusions largely resembled BRAF V600E-mutated MMR-D CRC rather than those secondary to Lynch syndrome. We describe two patients with fusion-associated microsatellite stable (MSS) CRC patients who derived clinical benefit from therapeautic targeting of their translocation. The first harbored an ALK-CAD fusion and received sequential crizotinib and alectinib therapy for a total of 7.5 months until developing an ALK L1196Q gatekeeper mutation. The second patient, whose tumor contained a ROS1-GOPC fusion, continues to benefit from entrectinib after 9 months of therapy. Conclusions: RTK fusions in CRC are a rare but important disease subgroup that occur in RAS and BRAF wild-type tumors. Despite enrichment in acquired MMR-D tumors, RTK fusions also occur in microsatellite-stable CRC and provide an important therapeutic target.Keywords
Other Versions
Funding Information
- NIH (P50CA127003)
- Damon Runyon Cancer Research Foundation (PST-15-18)
This publication has 49 references indexed in Scilit:
- Signatures of mutational processes in human cancerNature, 2013
- A Genetic Progression Model of BrafV600E-Induced Intestinal Tumorigenesis Reveals Targets for Therapeutic InterventionCancer Cell, 2013
- Crizotinib versus Chemotherapy in AdvancedALK-Positive Lung CancerThe New England Journal of Medicine, 2013
- Sensitive detection of somatic point mutations in impure and heterogeneous cancer samplesNature Biotechnology, 2013
- Recurrent R-spondin fusions in colon cancerNature, 2012
- The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing dataGenome Research, 2010
- Pathologic Predictors of Microsatellite Instability in Colorectal CancerThe American Journal of Surgical Pathology, 2009
- Cetuximab for the Treatment of Colorectal CancerThe New England Journal of Medicine, 2007
- BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testingJournal of Medical Genetics, 2004
- A genetic model for colorectal tumorigenesisCell, 1990