Role of Tumor Mutation Burden Analysis in Detecting Lynch Syndrome in Precision Medicine: Analysis of 2,501 Japanese Cancer Patients.

Background: Tumor mutation burden (TMB) is the total exonic mutation count per megabase of tumor DNA. Recent advances in precision medicine occasionally detect Lynch syndrome (LS) by germline sequencing for mismatch-repair (g.) genes but not using TMB. The current study analyzes the utility of TMB in detecting LS.

Methods: Whole-exome sequencing (ion-semiconductor sequencing) was performed for somatic and germline DNA from 2,501 various cancer patients to detect TMB and g. sequencing. MMR IHC was conducted when high TMB (≥10) was detected in LS-related cancers with an additional condition of wild-type in colorectal cancers. Target sequencing and multiplex ligation-dependent probe amplification (MLPA) were further performed for g. genes in MMR-deficient cancers (TMB-based g. target sequencing). We compared universal sequencing and TMB-based target sequencing in their sensitivity for detecting LS.

Results: LS was detected in 16 (0.6%) of the 2,501 patients: 1.1% (9/826) of colorectal cancer patients, 16.2% (6/37) of endometrial cancer patients, and 14.3% (1/7) of small intestine cancer patients. TMB-based g. target sequencing (81.3%) showed superior sensitivity for detecting LS than universal g. sequencing (56.3%; = 0.127) but missed 3 LS patients (1 with a low-TMB cancer, 1 with a -mutant colorectal cancer, and 1 with an MMR-proficient cancer). Ion-semiconductor sequencing could detect single-nucleotide substitutions but not large deletions. -mutated cancers showed extremely high TMBs (48.4-749.2).

Conclusions: g. target sequencing, combined with TMB, somatic mutation, and MMR IHC is an effective strategy for detecting LS.

Impact: TMB can be a biomarker for detecting LS in precision medicine.