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

Abstract

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.

Microsatellite instability is biased in Amsterdam II-defined Lynch-related cancer cases with family history but is rare in other cancers: a summary of 1000 analyses

“…For pancreaticobiliary cancers, the higher indication of ICI was expected because of their aggressive biological behavior and poor prognosis but much improved in cases with MSI-H and treated by ICI [ 37 ]. However, the current cases, including 25 familial pancreatic cancers and 2 familial biliary cancers, showed a very low MSI-H incidence (0.6–1.6%), similar to the low level of tumor mutation burden (0.5–2.2/Mb) demonstrated in our previous study [ 34 ]. In pancreatic and ovarian cancers, PARP inhibitors are effective when the patients harbor germline variants in the genes associated with homologous recombination pathways.…”

“…Generally, MSI in LS-related cancers has been reported in lower frequencies in Asian countries; for example, 17.3–25.7% [ 26 – 28 ] in EC, 4.3–10.0% in CRC [ 26 , 29 – 31 ], and 2.3–9.3% in gastric cancer [ 26 , 29 , 32 ], suggesting an ethnic deviation. This is also reflected in the lower incidences of LS in Asian countries (2.9% [ 33 ]–4.4% [ 28 ] in EC and 0.6% [ 34 ]–0.7% [ 35 ] in CRC).…”

“…Generally, MSI in LSrelated cancers has been reported in lower frequencies in Asian countries; for example, 17.3-25.7% [26][27][28] in EC, 4.3-10.0% in CRC [26,[29][30][31], and 2.3-9.3% in gastric cancer [26,29,32], suggesting an ethnic deviation. This is also reflected in the lower incidences of LS in Asian countries (2.9% [33]-4.4% [28] in EC and 0.6% [34]-0.7% [35] in CRC). Non-LS-related cancers, such as cervical and skin cancer and NEC, showed a significantly lower incidence of MSI-H (3.8%) compared with the LS (rB)-related cancer groups (10.9%)(P = 0.005) and the LS (AII)-related cancer group (15.6%)(P < 0.0001) (Table 2).…”

“…Of the 1000 cancers, 778 were analyzed for MSI to examine the indication of ICI via companion diagnostics and 222 were analyzed to detect LS in genetic counseling. These cancers included CRCs (466 cancers), pancreatic cancers (162), endometrial cancers (ECs)(75), biliary tract cancers (64), gastric cancers (36), uterine cervical cancers (34), laryngeal-pharyngeal and esophagus cancers (30), skin cancers (27), ovarian cancers (24), neuroendocrine carcinomas (NEC) (22), small intestine cancers (15), thymic cancers (10), breast cancers (7), hepatic cancers (6), brain tumors (2), and others (20) (Table 1). Age and incidence of smoking was not significantly different between the LS-related and non-LS-related cancers, however incidence of smoking was significantly higher in the non-LS-related cancer group (57.1%, 89/156) than LS-related cancer group (47.0%, 397/844) (P = 0.02) (Table 1).…”

Prognosis prediction of stage IV colorectal cancer patients by mRNA transcriptional profile

“…Immunotherapy may have better control of hereditary CRC than other systematic strategies. 25,26 In contrast to genetic alterations at DNA level, transcriptional alterations, and expression alterations showed a large variety of observations with little consensus. For example, some studies identified the expression of single markers for prognosis prediction, such as CD133, 27 HSF4, 28 and PLAC1, 29 etc., while other studies identified panels of genes with significant efficacy in prognosis prediction at protein expression levels, mRNA levels or miRNA levels of multiple genes.…”