Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants

Frontiers in Oncology

Laura Susok¹  Piotr Kozlowski²  Ilamathi M-Thirusenthilarasan²  Martyna Olga Urbanek-Trzeciak²  Paulina Maria Nawrocka²  Paulina Galka-Marciniak²  Michael Sand³  Natalia Szostak⁴  Anna Philips⁴ 

[1] Department of Dermatology, Venereology and Allergology, St. Josef Hospital, Ruhr-University Bochum, Bochum, Germany;Department of Molecular Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland;Department of Plastic Surgery, St. Josef Hospital, Catholic Clinics of the Ruhr Peninsula, Essen, Germany Department of Plastic, Reconstructive and Aesthetic Surgery, St. Josef Hospital, Essen, Germany;Laboratory of Bioinformatics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland;

关键词: basal cell carcinoma (BCC);    cancer somatic mutations;    noncoding mutations;    immune checkpoint;    copy number alterations;    cancer drivers;   

DOI  :  10.3389/fonc.2021.752579

来源: DOAJ

【 摘 要 】

Basal cell carcinoma (BCC) of the skin is the most common cancer in humans, characterized by the highest mutation rate among cancers, and is mostly driven by mutations in genes involved in the hedgehog pathway. To date, almost all BCC genetic studies have focused exclusively on protein-coding sequences; therefore, the impact of noncoding variants on the BCC genome is unrecognized. In this study, with the use of whole-exome sequencing of 27 tumor/normal pairs of BCC samples, we performed an analysis of somatic mutations in both protein-coding sequences and gene-associated noncoding regions, including 5’UTRs, 3’UTRs, and exon-adjacent intron sequences. Separately, in each region, we performed hotspot identification, mutation enrichment analysis, and cancer driver identification with OncodriveFML. Additionally, we performed a whole-genome copy number alteration analysis with GISTIC2. Of the >80,000 identified mutations, ~50% were localized in noncoding regions. The results of the analysis generally corroborated the previous findings regarding genes mutated in coding sequences, including PTCH1, TP53, and MYCN, but more importantly showed that mutations were also clustered in specific noncoding regions, including hotspots. Some of the genes specifically mutated in noncoding regions were identified as highly potent cancer drivers, of which BAD had a mutation hotspot in the 3’UTR, DHODH had a mutation hotspot in the Kozak sequence in the 5’UTR, and CHCHD2 frequently showed mutations in the 5’UTR. All of these genes are functionally implicated in cancer-related processes (e.g., apoptosis, mitochondrial metabolism, and de novo pyrimidine synthesis) or the pathogenesis of UV radiation-induced cancers. We also found that the identified BAD and CHCHD2 mutations frequently occur in melanoma but not in other cancers via The Cancer Genome Atlas analysis. Finally, we identified a frequent deletion of chr9q, encompassing PTCH1, and unreported frequent copy number gain of chr9p, encompassing the genes encoding the immune checkpoint ligands PD-L1 and PD-L2. In conclusion, this study is the first systematic analysis of coding and noncoding mutations in BCC and provides a strong basis for further analyses of the variants in BCC and cancer in general.

【 授权许可】

Unknown