Frameshift Mutations in the Mononucleotide Repeats of TAF1 and TAF1L Genes in Gastric and Colorectal Cancers with Regional Heterogeneity

Abstract

Initiation of transcription by RNA polymerase II requires TATA-box-binding protein (TBP)-associated factors (TAFs). TAF1 is a major scaffold by which TBP and TAFs interact in the basal transcription factor. TAF1L is a TAF1 homologue with 95 % amino acid identity with TAF1. TAF1 is involved in apoptosis induction and cell cycle regulation, but roles of TAF1 and TAF1L in tumorigenesis remain unknown. The aim of this study was to explore whether TAF1 and TAF1L genes were mutated in gastric (GC) and colorectal cancers (CRC). In a public database, we found that TAF1 and TAF1L genes had mononucleotide repeats in the coding sequences that might be mutation targets in the cancers with microsatellite instability (MSI). We analyzed the mutations in 79 GC and 124 CRC by single-strand conformation polymorphism analysis and DNA sequencing. In the present study, we found TAF1 frameshift mutations (3.8 % of CRC with MSI-H) and TAF1L frameshift mutations (2.9 % of GC and 3.8 % of CRC with MSI-H). These mutations were not found in stable MSI/low MSI (MSS/MSI-L) (0/90). In addition, we analyzed intratumoral heterogeneity (ITH) of TAF1 and TAF1L frameshift mutations in 16 CRC and found that two and one CRC harbored regional ITH of TAF1 and TAF1L frameshift mutations, respectively. Our data indicate that TAF1 and TAF1L genes harbored not only somatic mutations but also mutational ITH, which together might play a role in tumorigenesis of GC and CRC with MSI-H. Our results also suggest that ultra-regional mutation analysis is required for a comprehensive evaluation of mutation status in these tumors.

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