Spontaneous mutations in the single TTN gene represent high tumor mutation burden

Abstract

Tumor mutation burden (TMB) is an emerging biomarker, whose calculation requires targeted sequencing of many genes. We investigated if the measurement of mutation counts within a single gene is representative of TMB. Whole-exome sequencing (WES) data from the pan-cancer cohort (n = 10,224) of TCGA, and targeted sequencing (tNGS) and TTN gene sequencing from 24 colorectal cancer samples (AMC cohort) were analyzed. TTN was identified as the most frequently mutated gene within the pan-cancer cohort, and its mutation number best correlated with TMB assessed by WES (rho = 0.917, p < 2.2e-16). Colorectal cancer was one of good candidates for the application of this diagnostic model of TTN-TMB, and the correlation coefficients were 0.936 and 0.92 for TMB by WES and TMB by tNGS, respectively. Higher than expected TTN mutation frequencies observed in other FLAGS (FrequentLy mutAted GeneS) are associated with late replication time. Diagnostic accuracy for high TMB group did not differ between TTN-TMB and TMB assessed by tNGS. Classification modeling by machine learning using TTN-TMB for MSI-H diagnosis was constructed, and the diagnostic accuracy was 0.873 by area under the curve in external validation. TTN mutation was enriched in samples possessing high immunostimulatory signatures. We suggest that the mutation load within TTN represents high TMB status.

Identification of the Prognostic Significance of Somatic Mutation-Derived LncRNA Signatures of Genomic Instability in Lung Adenocarcinoma

“…In addition, we observed a high rate of mutation of TTN in our LUAD cohort. Previous studies have reported that somatic mutations in TTN were frequently occur in many cancer types and reflect the status of the tumor mutation burden ( Kim et al, 2013 ; Oh et al, 2020 ). Therefore, we further assessed the association between the GInLncSig and TTN mutation status.…”

Differential Mutation Detection Capability Through Capture-Based Targeted Sequencing in Plasma Samples in Hepatocellular Carcinoma

“…We also found associations between mutations in TTN and DNAH family members in AHB and IHB patients, between mutations in TTN and RYR family members in LC patients, and between TTN and TP53 mutations in HCC patients. TTN encodes a giant protein (>30,000 amino acids) and is rarely recognized as a tumor-associated gene; however, recent studies have suggested that mutations in the highly mutated TTN gene are closely related with high TMB status, and the potential biological mechanisms have been elucidated (35). However, our spectral analysis identified distinct mutational spectra at the amino acid level in the development of HCC and significant combinatorial mutational patterns (TTN was likely to be co-mutational with other genes during the development of HCC), so its role in the development of HCC still needs to be evaluated.…”

Genomic Heterogeneity and Clonal Evolution in Gastroesophageal Junction Cancer Revealed by Single Cell DNA Sequencing

“…The average mutation frequency of TTN in solid tumors was 29.68% and the mutation frequency in gastric adenocarcinoma was as high as 60%~70% (42). The mutation frequencies of TTN gene could also be used to represent the tumor mutation burden (43). In a study of 12 patients with synchronous GEJ cancer and GC, the TTN mutation were found in 7 of 24 tumor tissues (6).…”