Case 3
A 65-year-old female was diagnosed with colorectal carcinoma of the ascending colon. Histopathology showed medullary differentiation, and mismatch repair IHC revealed loss of MLH1 and PMS2 expression with retained MSH2 and MSH6 expression. Personal and family history were negative for colorectal, endometrial, adrenal, and brain cancer.
Mutation testing revealed wild-type BRAF yet MLH1 promoter hypermethylation was identified by pyrosequencing as shown in the following figure.
MLH1 Pyrosequencing of Adult Patient with Colorectal Carcinoma
NTRK gene fusion testing
DNA-based NGS testing with MSK-IMPACT™ was performed, which identified a previously characterised fusion. Pan-TRK IHC was also performed and was positive.
H&E (Top Left-Hand Panel) and Pan-TRK IHC (Top Right-Hand Panel) and Identification of the LMNA-NTRK1 Fusion Via MSK-IMPACT™, a DNA-Based NGS Panel
Integrated genomics viewer (IGV) shows a structural variant involving LMNA exon 8 and NTRK1 exon 11 in the bottom panel.
Antibody for IHC: clone EPR17341 available from Abcam, Cambridge, MA, USA(www.abcam.com)
TRK inhibitor treatment
The patient received an immune checkpoint inhibitor as first-line treatment due to microsatellite instability-high status, and TRK inhibitors were saved as a future consideration for second-line therapy.
Clinical interpretation and impact of NTRK gene fusion testing
This patient has a history of MLH1-deficient colorectal carcinoma without family or personal history to suggest Lynch syndrome. While it is likely that this is a sporadic instance of mismatch repair deficient colon cancer due to MLH1 promoter hypermethylation, mutation testing is negative for BRAF p. V600E. It has recently been shown that colorectal cancer patients with sporadic MLH1 deficiency due to MLH1 promoter hypermethylation and wild-type BRAF have a high incidence of kinase fusions (40%–50%) [1].
Fusion testing with an assay that detects multiple kinase fusions may not only detect alternative treatments for patients with MLH1-deficient colorectal cancer with promoter hypermethylation and wild-type BRAF, but also suggests that a specific tumour is sporadic rather than associated with Lynch syndrome.
References
- Sato K, Kawazu M, Yamamoto Y et al. Fusion Kinases Identified by Genomic Analyses of Sporadic Microsatellite Instability-High Colorectal Cancers. Clin Cancer Res 2018.