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

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. 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. 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). g. target sequencing, combined with TMB, somatic mutation, and MMR IHC is an effective strategy for detecting LS. TMB can be a biomarker for detecting LS in precision medicine.