Coding and noncoding somatic mutations in candidate genes in basal cell carcinoma

Maria Giovanna Maturo,Ketty Peris,Celia Requena,Nalini Srinivas,Maria Concetta Fargnoli,Eduardo Nagore,Carlos Serra-Guillen,Cristina Pellegrini,Rajiv Kumar,Onofre Sanmartin,Beatriz Llombart,Carlos Guillen,Barbara Heidenreich,Lucia Di Nardo,Sivaramakrishna Rachakonda

doi:10.1038/s41598-020-65057-2

Abstract

Basal cell carcinoma (BCC) represents the most commonly diagnosed human cancer among persons of European ancestry with etiology mainly attributed to sun-exposure. In this study we investigated mutations in coding and flanking regions of PTCH1 and TP53 and noncoding alterations in the TERT and DPH3 promoters in 191 BCC tumors. In addition, we measured CpG methylation within the TERT hypermethylated oncological region (THOR) and transcription levels of the reverse transcriptase subunit. We observed mutations in PTCH1 in 58.6% and TP53 in 31.4% of the tumors. Noncoding mutations in TERT and DPH3 promoters were detected in 59.2% and 38.2% of the tumors, respectively. We observed a statistically significant co-occurrence of mutations at the four investigated loci. While PTCH1 mutations tended to associate with decreased patient age at diagnosis; TP53 mutations were associated with light skin color and increased number of nevi; TERT and DPH3 promoter with history of cutaneous neoplasms in BCC patients. Increased reverse transcriptase subunit expression was observed in tumors with TERT promoter mutations and not with THOR methylation. Our study signifies, in addition to the protein altering mutations in the PTCH1 and TP53 genes, the importance of noncoding mutations in BCC, particularly functional alterations in the TERT promoter.

Highlights

Due to the criticality of p53 mediated transcription in tumor suppression, mutations in TP53 mainly occur within the DNA binding domain that cluster at several hotspot amino-acid residues[15,16]
Other than confirming the high frequency of patched 1 (PTCH1) and TP53 mutations in Basal cell carcinoma (BCC) tumors, we showed recurrent noncoding mutations within the telomerase reverse transcriptase (TERT) and DPH3 promoters
TERT promoter mutations were the most frequent alterations followed by PTCH1 mutations; the simultaneous occurrence of mutations in the four investigated loci was more frequent than per chance

Summary

Introduction

Due to the criticality of p53 mediated transcription in tumor suppression, mutations in TP53 mainly occur within the DNA binding domain that cluster at several hotspot amino-acid residues[15,16]. The TERT promoter mutations are frequent in multiple cancers, with some exceptions, arising from tissues with low rates of self-renewal[22,26,27,28]. Those promoter mutations create de novo sites where binding of ETS transcription factors leads to increased transcription through epigenetic histone modification[26,29]. Noncoding mutations in a bidirectional DPH3 promoter region with unknown functional consequences are frequent in different skin cancers including BCC31. We investigated the correlation between TERT promoter mutations and telomere length in BCC tumors

Methods

Results

Conclusion