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

Ji-Hye Oh,Eun Jeong Cho,Se Jin Jang,Insuk Sohn,Jihun Kim,Chang Ohk Sung,Sung-Min Chun,Ji-Young Lee

doi:10.1038/s41525-019-0107-6

Ji-Hye Oh, Eun Jeong Cho + Show 6 more

Open Access

https://doi.org/10.1038/s41525-019-0107-6

Copy DOI

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.

Highlights

Genomic instability is an important characteristic of cancers that results in an increased number of genetic alterations
Through computational analyses of 33 cancer types from pancancer databases and the AMC cohort, we demonstrated that the mutation count within the TTN gene can represent the tumor mutation burden (TMB) status within various tumor types and can be used to predict the microsatellite instability-high (MSI-H) status in colorectal cancer (CRC)
A high correlation was typically observed in the tumors known as hypermutated tumor types, such as SKCM, CRC, UCEC, LUAD, BLCA, that frequently possess more than 10 mutations per Mb.[21,30]

Summary

Introduction

Genomic instability is an important characteristic of cancers that results in an increased number of genetic alterations. In colorectal cancer (CRC), it has become apparent that genomic instability is related to tumorigenesis.[1,2] CRCs can be divided into two distinctive subgroups, the hypermutated group and the nonhypermutated group, at the genomic level.[3] Hypermutated tumors are characterized by an increased frequency of base substitutions, insertions, and deletions of one or several nucleotides These nucleotide alterations are often related to defective base excision repair system components, including defects in DNA polymerase δ and ε (POLD and POLE).[4,5] defects in the DNA mismatch repair (MMR) system components, including MSH2, MLH1, MSH6, PMS1, and PMS2, are another major contributor to hypermutated tumors.[3] A defect in the MMR system is characterized by an increase in random insertions or a reduction of the number of oligo-nucleotide repeats within microsatellite sequences, resulting in the microsatellite instability-high (MSI-H) phenotype.[1,6,7] tumors exhibiting a loss of these DNA repair systems are expected to possess an increased spontaneous mutation rate across the entire genome

Objectives

Methods

Results

Conclusion