PT  - JOURNAL ARTICLE
AU  - Kiyozumi, Yoshimi
AU  - Matsubayashi, Hiroyuki
AU  - Higashigawa, Satomi
AU  - Horiuchi, Yasue
AU  - Kado, Nobuhiro
AU  - Hirashima, Yasuyuki
AU  - Shiomi, Akio
AU  - Oishi, Takuma
AU  - Ohnami, Sumiko
AU  - Ohshima, Keiichi
AU  - Urakami, Kenichi
AU  - Nagashima, Takeshi
AU  - Yamaguchi, Ken
TI  - Role of Tumor Mutation Burden Analysis in Detecting Lynch Syndrome in Precision Medicine: Analysis of 2,501 Japanese Cancer Patients
AID  - 10.1158/1055-9965.EPI-20-0694
DP  - 2020 Oct 12
TA  - Cancer Epidemiology Biomarkers & Prevention
4099  - http://cebp.aacrjournals.org/content/early/2020/11/12/1055-9965.EPI-20-0694.short
4100  - http://cebp.aacrjournals.org/content/early/2020/11/12/1055-9965.EPI-20-0694.full
AB  - 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.MMR) 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.MMR sequencing. MMR IHC was conducted when high TMB (≥10) was detected in LS-related cancers with an additional condition of wild-type BRAF in colorectal cancers. Target sequencing and multiplex ligation-dependent probe amplification (MLPA) were further performed for g.MMR genes in MMR-deficient cancers (TMB-based g.MMR 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.MMR target sequencing (81.3%) showed superior sensitivity for detecting LS than universal g.MMR sequencing (56.3%; P = 0.127) but missed 3 LS patients (1 with a low-TMB cancer, 1 with a BRAF-mutant colorectal cancer, and 1 with an MMR-proficient cancer). Ion-semiconductor sequencing could detect single-nucleotide substitutions but not large deletions. POL-mutated cancers showed extremely high TMBs (48.4–749.2).Conclusions: g.MMR target sequencing, combined with TMB, somatic BRAF mutation, and MMR IHC is an effective strategy for detecting LS.Impact: TMB can be a biomarker for detecting LS in precision medicine.