Increased Somatic Mutations with Large Panel Next Generation Sequencing (NGS) in Deficient MMR (dMMR) Tumors: An Illustrative Case Report

Large panel Next-Generation Sequencing (NGS) of tumors or circulating cellfree (cf) DNA is commonly used when cancer progression occurs after standard therapies. Such NGS is done in order to evaluate the tumor for the presence of somatic genomic alterations in one or more of hundreds of genes with the hope of identifying a targetable or actionable molecular abnormality.

For colorectal cancer, routinely testing for tumor deficiency of expression of one of several mismatch repair genes (dMMR) is recommended for nearly all cases and commonly done using immunohistochemistry (IHC). Recently the FDA granted accelerated approval for checkpoint inhibitor use in any solid tumors demonstrating dMMR and routine testing for MMR expression in non-colorectal cancers is therefore anticipated. Also, dMMR tumors typically show more potentially actionable somatic driver mutations than are seen for proficient MMR tumors (pMMR), when NGS of the tumor tissue or circulating cf DNA is preformed.

Here, a Lynch syndrome patient is reported whose colon cancer demonstrated 70 somatic alterations. After a prolonged response to PD1 inhibitor therapy, a liquid biopsy again showed many mutations in the tumor circulating cf DNA. The very high BRCA2 Mutation Allelic Frequency (MAF) reported suggested a potential benefit from PARP inhibitor therapy in this patient.

This case illustrates that because patients with dMMR tumors characteristically demonstrate many mutations currently identified by NGS, patients with dMMR (or MSI-H) tumors might particularly benefit from NGS of their tumors in order to identify molecular actionable abnormalities that might respond to a highly targeted therapy. As patients with dMMR tumors live longer through checkpoint inhibitor therapy use it might also be anticipated that real-time NGS of their tumors could identify actionable molecular abnormalities acquired during the time they receive the checkpoint inhibitor.


Steven Sorscher

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