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 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. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Paulina Maria Nawrocka [verfasserIn] Paulina Galka-Marciniak [verfasserIn] Martyna Olga Urbanek-Trzeciak [verfasserIn] Ilamathi M-Thirusenthilarasan [verfasserIn] Natalia Szostak [verfasserIn] Anna Philips [verfasserIn] Laura Susok [verfasserIn] Michael Sand [verfasserIn] Piotr Kozlowski [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

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

Übergeordnetes Werk:	In: Frontiers in Oncology - Frontiers Media S.A., 2012, 11(2021)
Übergeordnetes Werk:	volume:11 ; year:2021

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3389/fonc.2021.752579

Katalog-ID:	DOAJ008111111

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allfields	10.3389/fonc.2021.752579 doi (DE-627)DOAJ008111111 (DE-599)DOAJb95ea444c96542f2b8fe78b2d27006fa DE-627 ger DE-627 rakwb eng RC254-282 Paulina Maria Nawrocka verfasserin aut Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. basal cell carcinoma (BCC) cancer somatic mutations noncoding mutations immune checkpoint copy number alterations cancer drivers Neoplasms. Tumors. Oncology. Including cancer and carcinogens Paulina Galka-Marciniak verfasserin aut Martyna Olga Urbanek-Trzeciak verfasserin aut Ilamathi M-Thirusenthilarasan verfasserin aut Natalia Szostak verfasserin aut Anna Philips verfasserin aut Laura Susok verfasserin aut Michael Sand verfasserin aut Michael Sand verfasserin aut Piotr Kozlowski verfasserin aut In Frontiers in Oncology Frontiers Media S.A., 2012 11(2021) (DE-627)684965518 (DE-600)2649216-7 2234943X nnns volume:11 year:2021 https://doi.org/10.3389/fonc.2021.752579 kostenfrei https://doaj.org/article/b95ea444c96542f2b8fe78b2d27006fa kostenfrei https://www.frontiersin.org/articles/10.3389/fonc.2021.752579/full kostenfrei https://doaj.org/toc/2234-943X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021
spelling	10.3389/fonc.2021.752579 doi (DE-627)DOAJ008111111 (DE-599)DOAJb95ea444c96542f2b8fe78b2d27006fa DE-627 ger DE-627 rakwb eng RC254-282 Paulina Maria Nawrocka verfasserin aut Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. basal cell carcinoma (BCC) cancer somatic mutations noncoding mutations immune checkpoint copy number alterations cancer drivers Neoplasms. Tumors. Oncology. Including cancer and carcinogens Paulina Galka-Marciniak verfasserin aut Martyna Olga Urbanek-Trzeciak verfasserin aut Ilamathi M-Thirusenthilarasan verfasserin aut Natalia Szostak verfasserin aut Anna Philips verfasserin aut Laura Susok verfasserin aut Michael Sand verfasserin aut Michael Sand verfasserin aut Piotr Kozlowski verfasserin aut In Frontiers in Oncology Frontiers Media S.A., 2012 11(2021) (DE-627)684965518 (DE-600)2649216-7 2234943X nnns volume:11 year:2021 https://doi.org/10.3389/fonc.2021.752579 kostenfrei https://doaj.org/article/b95ea444c96542f2b8fe78b2d27006fa kostenfrei https://www.frontiersin.org/articles/10.3389/fonc.2021.752579/full kostenfrei https://doaj.org/toc/2234-943X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021
allfields_unstemmed	10.3389/fonc.2021.752579 doi (DE-627)DOAJ008111111 (DE-599)DOAJb95ea444c96542f2b8fe78b2d27006fa DE-627 ger DE-627 rakwb eng RC254-282 Paulina Maria Nawrocka verfasserin aut Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. basal cell carcinoma (BCC) cancer somatic mutations noncoding mutations immune checkpoint copy number alterations cancer drivers Neoplasms. Tumors. Oncology. Including cancer and carcinogens Paulina Galka-Marciniak verfasserin aut Martyna Olga Urbanek-Trzeciak verfasserin aut Ilamathi M-Thirusenthilarasan verfasserin aut Natalia Szostak verfasserin aut Anna Philips verfasserin aut Laura Susok verfasserin aut Michael Sand verfasserin aut Michael Sand verfasserin aut Piotr Kozlowski verfasserin aut In Frontiers in Oncology Frontiers Media S.A., 2012 11(2021) (DE-627)684965518 (DE-600)2649216-7 2234943X nnns volume:11 year:2021 https://doi.org/10.3389/fonc.2021.752579 kostenfrei https://doaj.org/article/b95ea444c96542f2b8fe78b2d27006fa kostenfrei https://www.frontiersin.org/articles/10.3389/fonc.2021.752579/full kostenfrei https://doaj.org/toc/2234-943X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021
allfieldsGer	10.3389/fonc.2021.752579 doi (DE-627)DOAJ008111111 (DE-599)DOAJb95ea444c96542f2b8fe78b2d27006fa DE-627 ger DE-627 rakwb eng RC254-282 Paulina Maria Nawrocka verfasserin aut Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. basal cell carcinoma (BCC) cancer somatic mutations noncoding mutations immune checkpoint copy number alterations cancer drivers Neoplasms. Tumors. Oncology. Including cancer and carcinogens Paulina Galka-Marciniak verfasserin aut Martyna Olga Urbanek-Trzeciak verfasserin aut Ilamathi M-Thirusenthilarasan verfasserin aut Natalia Szostak verfasserin aut Anna Philips verfasserin aut Laura Susok verfasserin aut Michael Sand verfasserin aut Michael Sand verfasserin aut Piotr Kozlowski verfasserin aut In Frontiers in Oncology Frontiers Media S.A., 2012 11(2021) (DE-627)684965518 (DE-600)2649216-7 2234943X nnns volume:11 year:2021 https://doi.org/10.3389/fonc.2021.752579 kostenfrei https://doaj.org/article/b95ea444c96542f2b8fe78b2d27006fa kostenfrei https://www.frontiersin.org/articles/10.3389/fonc.2021.752579/full kostenfrei https://doaj.org/toc/2234-943X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021
allfieldsSound	10.3389/fonc.2021.752579 doi (DE-627)DOAJ008111111 (DE-599)DOAJb95ea444c96542f2b8fe78b2d27006fa DE-627 ger DE-627 rakwb eng RC254-282 Paulina Maria Nawrocka verfasserin aut Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. basal cell carcinoma (BCC) cancer somatic mutations noncoding mutations immune checkpoint copy number alterations cancer drivers Neoplasms. Tumors. Oncology. Including cancer and carcinogens Paulina Galka-Marciniak verfasserin aut Martyna Olga Urbanek-Trzeciak verfasserin aut Ilamathi M-Thirusenthilarasan verfasserin aut Natalia Szostak verfasserin aut Anna Philips verfasserin aut Laura Susok verfasserin aut Michael Sand verfasserin aut Michael Sand verfasserin aut Piotr Kozlowski verfasserin aut In Frontiers in Oncology Frontiers Media S.A., 2012 11(2021) (DE-627)684965518 (DE-600)2649216-7 2234943X nnns volume:11 year:2021 https://doi.org/10.3389/fonc.2021.752579 kostenfrei https://doaj.org/article/b95ea444c96542f2b8fe78b2d27006fa kostenfrei https://www.frontiersin.org/articles/10.3389/fonc.2021.752579/full kostenfrei https://doaj.org/toc/2234-943X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021
language	English
source	In Frontiers in Oncology 11(2021) volume:11 year:2021
sourceStr	In Frontiers in Oncology 11(2021) volume:11 year:2021
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	basal cell carcinoma (BCC) cancer somatic mutations noncoding mutations immune checkpoint copy number alterations cancer drivers Neoplasms. Tumors. Oncology. Including cancer and carcinogens
isfreeaccess_bool	true
container_title	Frontiers in Oncology
authorswithroles_txt_mv	Paulina Maria Nawrocka @@aut@@ Paulina Galka-Marciniak @@aut@@ Martyna Olga Urbanek-Trzeciak @@aut@@ Ilamathi M-Thirusenthilarasan @@aut@@ Natalia Szostak @@aut@@ Anna Philips @@aut@@ Laura Susok @@aut@@ Michael Sand @@aut@@ Piotr Kozlowski @@aut@@
publishDateDaySort_date	2021-01-01T00:00:00Z
hierarchy_top_id	684965518
id	DOAJ008111111
language_de	englisch
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callnumber-first	R - Medicine
author	Paulina Maria Nawrocka
spellingShingle	Paulina Maria Nawrocka misc RC254-282 misc basal cell carcinoma (BCC) misc cancer somatic mutations misc noncoding mutations misc immune checkpoint misc copy number alterations misc cancer drivers misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants
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topic_title	RC254-282 Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants basal cell carcinoma (BCC) cancer somatic mutations noncoding mutations immune checkpoint copy number alterations cancer drivers
topic	misc RC254-282 misc basal cell carcinoma (BCC) misc cancer somatic mutations misc noncoding mutations misc immune checkpoint misc copy number alterations misc cancer drivers misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_unstemmed	misc RC254-282 misc basal cell carcinoma (BCC) misc cancer somatic mutations misc noncoding mutations misc immune checkpoint misc copy number alterations misc cancer drivers misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
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title	Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants
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title_full	Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants
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title_sort	profile of basal cell carcinoma mutations and copy number alterations - focus on gene-associated noncoding variants
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title_auth	Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants
abstract	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.
abstractGer	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.
abstract_unstemmed	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.
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title_short	Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants
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Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants

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