Next-Generation Sequencing Assay May Permit Accurate Detection of Mismatch Repair Deficiency in Colorectal Cancer


Key Points

  • Of the 31 cases with higher mutational load, 3 had > 150 mutations and harbored the P286R hotspot POLE mutation.
  • Next-generation sequencing assay mutational load cutoffs of ≥ 20 and < 150 mutations yielded sensitivity and specificity of 1.0 for mismatch repair deficiency.

Use of a custom next-generation sequencing assay may accurately predict mismatch repair deficiency on the basis of mutational load in colorectal cancer, according to a report by Stadler et al in the Journal of Clinical Oncology.

Study Details

The study involved data from 224 patients with colorectal cancer who had undergone genomic mutation profiling with the custom 341-gene assay (MSK-IMPACT) at Memorial Sloan Kettering Cancer Center between March 2014 and July 2015. Tumor mutational load, excluding copy number alterations, was determined for each case and compared with mismatch repair status on immunohistochemistry.

Next-Generation Sequencing Assay Findings

Overall, 28 tumors (13%) exhibited mismatch repair deficiency on immunohistochemistry. With the next-generation sequencing assay, 100% of 193 tumors with < 20 mutations were mismatch repair–proficient (median, 6 mutations; range = 0–17). Of 31 with ≥ 20 mutations, 28 (90%) were mismatch repair deficient; in these cases, the median number of mutations was 50 (range = 20–90; P < .001, vs mismatch repair–proficient POLE wild-type tumors). The 3 remaining tumors were readily identified as distinct from the mismatch repair–deficient tumors, with each having > 150 mutations and exhibiting the P286R hotspot POLE mutation consistent with an ultramutator phenotype. Using next-generation sequencing assay mutational load cutoffs of ≥ 20 and < 150, sensitivity and specificity for mismatch repair deficiency detection were both 1.0 (95% confidence interval = 0.93­–1.0).

The investigators concluded: “A cutoff for mutational load can be identified via multigene next-generation sequencing tumor profiling, which provides a highly accurate means of screening for [mismatch repair deficiency] in the same assay that is used for tumor genotyping.”

The study was supported by the Romeo Milio Lynch Syndrome Foundation, the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, the Kate and Robert Niehaus Clinical Genetics Initiative, and the National Institutes of Health/National Cancer Institute.

Leonard B. Saltz, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author of the Journal of Clinical Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.