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

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 sequen...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Paulina Maria Nawrocka, Paulina Galka-Marciniak, Martyna Olga Urbanek-Trzeciak, Ilamathi M-Thirusenthilarasan, Natalia Szostak, Anna Philips, Laura Susok, Michael Sand, Piotr Kozlowski
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	basal cell carcinoma (BCC) cancer somatic mutations noncoding mutations immune checkpoint copy number alterations cancer drivers Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/b95ea444c96542f2b8fe78b2d27006fa
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:b95ea444c96542f2b8fe78b2d27006fa
record_format	dspace
spelling	oai:doaj.org-article:b95ea444c96542f2b8fe78b2d27006fa2021-12-01T01:54:50ZProfile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants2234-943X10.3389/fonc.2021.752579https://doaj.org/article/b95ea444c96542f2b8fe78b2d27006fa2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.752579/fullhttps://doaj.org/toc/2234-943XBasal 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.Paulina Maria NawrockaPaulina Galka-MarciniakMartyna Olga Urbanek-TrzeciakIlamathi M-ThirusenthilarasanNatalia SzostakAnna PhilipsLaura SusokMichael SandMichael SandPiotr KozlowskiFrontiers Media S.A.articlebasal cell carcinoma (BCC)cancer somatic mutationsnoncoding mutationsimmune checkpointcopy number alterationscancer driversNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	basal cell carcinoma (BCC) cancer somatic mutations noncoding mutations immune checkpoint copy number alterations cancer drivers Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	basal cell carcinoma (BCC) cancer somatic mutations noncoding mutations immune checkpoint copy number alterations cancer drivers Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Paulina Maria Nawrocka Paulina Galka-Marciniak Martyna Olga Urbanek-Trzeciak Ilamathi M-Thirusenthilarasan Natalia Szostak Anna Philips Laura Susok Michael Sand Michael Sand Piotr Kozlowski Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants
description	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.
format	article
author	Paulina Maria Nawrocka Paulina Galka-Marciniak Martyna Olga Urbanek-Trzeciak Ilamathi M-Thirusenthilarasan Natalia Szostak Anna Philips Laura Susok Michael Sand Michael Sand Piotr Kozlowski
author_facet	Paulina Maria Nawrocka Paulina Galka-Marciniak Martyna Olga Urbanek-Trzeciak Ilamathi M-Thirusenthilarasan Natalia Szostak Anna Philips Laura Susok Michael Sand Michael Sand Piotr Kozlowski
author_sort	Paulina Maria Nawrocka
title	Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants
title_short	Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants
title_full	Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants
title_fullStr	Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants
title_full_unstemmed	Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants
title_sort	profile of basal cell carcinoma mutations and copy number alterations - focus on gene-associated noncoding variants
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/b95ea444c96542f2b8fe78b2d27006fa
work_keys_str_mv	AT paulinamarianawrocka profileofbasalcellcarcinomamutationsandcopynumberalterationsfocusongeneassociatednoncodingvariants AT paulinagalkamarciniak profileofbasalcellcarcinomamutationsandcopynumberalterationsfocusongeneassociatednoncodingvariants AT martynaolgaurbanektrzeciak profileofbasalcellcarcinomamutationsandcopynumberalterationsfocusongeneassociatednoncodingvariants AT ilamathimthirusenthilarasan profileofbasalcellcarcinomamutationsandcopynumberalterationsfocusongeneassociatednoncodingvariants AT nataliaszostak profileofbasalcellcarcinomamutationsandcopynumberalterationsfocusongeneassociatednoncodingvariants AT annaphilips profileofbasalcellcarcinomamutationsandcopynumberalterationsfocusongeneassociatednoncodingvariants AT laurasusok profileofbasalcellcarcinomamutationsandcopynumberalterationsfocusongeneassociatednoncodingvariants AT michaelsand profileofbasalcellcarcinomamutationsandcopynumberalterationsfocusongeneassociatednoncodingvariants AT michaelsand profileofbasalcellcarcinomamutationsandcopynumberalterationsfocusongeneassociatednoncodingvariants AT piotrkozlowski profileofbasalcellcarcinomamutationsandcopynumberalterationsfocusongeneassociatednoncodingvariants
_version_	1718405984263602176

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

Ejemplares similares