Role of Tumor Mutation Burden Analysis in Detecting Lynch Syndrome in Precision Medicine: Analysis of 2,501 Japanese Cancer Patients
| Autor: | Nobuhiro Kado, Yoshimi Kiyozumi, Ken Yamaguchi, Satomi Higashigawa, Takuma Oishi, Yasue Horiuchi, Keiichi Ohshima, Kenichi Urakami, Takeshi Nagashima, Hiroyuki Matsubayashi, Yasuyuki Hirashima, Sumiko Ohnami, Akio Shiomi |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Epidemiology Colorectal cancer Polymorphism Single Nucleotide Sensitivity and Specificity 03 medical and health sciences 0302 clinical medicine Japan Exome Sequencing Biomarkers Tumor medicine Humans Multiplex Multiplex ligation-dependent probe amplification Precision Medicine Germ-Line Mutation Aged Aged 80 and over business.industry Endometrial cancer Cancer Middle Aged medicine.disease Colorectal Neoplasms Hereditary Nonpolyposis digestive system diseases Lynch syndrome Tumor Burden 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research Biomarker (medicine) Female business Small intestine cancer |
| Zdroj: | Cancer Epidemiology, Biomarkers & Prevention. 30:166-174 |
| ISSN: | 1538-7755 1055-9965 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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