High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma

Cutaneous melanoma is one of the most aggressive human cancers due to its high invasiveness. Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes f...
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Autor*in:	Catarina Campos [verfasserIn] Sofia Fragoso [verfasserIn] Rafael Luís [verfasserIn] Filipe Pinto [verfasserIn] Cheila Brito [verfasserIn] Susana Esteves [verfasserIn] Margarida Pataco [verfasserIn] Sidónia Santos [verfasserIn] Patrícia Machado [verfasserIn] João B. Vicente [verfasserIn] Joaninha Costa Rosa [verfasserIn] Branca M. Cavaco [verfasserIn] Cecília Moura [verfasserIn] Marta Pojo [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2020

Schlagwörter:	cutaneous melanoma germline mutations WES hereditary melanoma

Übergeordnetes Werk:	In: Genes - MDPI AG, 2010, 11(2020), 4, p 403
Übergeordnetes Werk:	volume:11 ; year:2020 ; number:4, p 403

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/genes11040403

Katalog-ID:	DOAJ002568926

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520			\|a Cutaneous melanoma is one of the most aggressive human cancers due to its high invasiveness. Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes for hereditary melanoma, we performed whole exome sequencing (WES) on eight patients with multiple primary melanomas, high number of nevi, and negative for high and intermediate-risk germline mutations. Thirteen new potentially pathogenic variants were identified after bioinformatics analysis and validation. <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< were identified as the most promising susceptibility genes in hereditary melanoma. <i<In silico</i< analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations. Then, we also evaluated the clinical value of <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< expression in sporadic melanoma by using the TCGA dataset (<i<n</i< = 461). No differences were observed in <i<BRD9</i< expression between melanoma and normal skin samples, nor with melanoma stage, whereas <i<ARHGEF40</i< was found overexpressed, and <i<CDH23</i< was downregulated and its loss was associated with worse survival. Altogether, these results reveal three novel genes with clinical relevance in hereditary and sporadic melanoma.
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allfields	10.3390/genes11040403 doi (DE-627)DOAJ002568926 (DE-599)DOAJ75c7b15645d143f397b431736acb3a28 DE-627 ger DE-627 rakwb eng QH426-470 Catarina Campos verfasserin aut High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cutaneous melanoma is one of the most aggressive human cancers due to its high invasiveness. Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes for hereditary melanoma, we performed whole exome sequencing (WES) on eight patients with multiple primary melanomas, high number of nevi, and negative for high and intermediate-risk germline mutations. Thirteen new potentially pathogenic variants were identified after bioinformatics analysis and validation. <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< were identified as the most promising susceptibility genes in hereditary melanoma. <i<In silico</i< analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations. Then, we also evaluated the clinical value of <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< expression in sporadic melanoma by using the TCGA dataset (<i<n</i< = 461). No differences were observed in <i<BRD9</i< expression between melanoma and normal skin samples, nor with melanoma stage, whereas <i<ARHGEF40</i< was found overexpressed, and <i<CDH23</i< was downregulated and its loss was associated with worse survival. Altogether, these results reveal three novel genes with clinical relevance in hereditary and sporadic melanoma. cutaneous melanoma germline mutations WES hereditary melanoma Genetics Sofia Fragoso verfasserin aut Rafael Luís verfasserin aut Filipe Pinto verfasserin aut Cheila Brito verfasserin aut Susana Esteves verfasserin aut Margarida Pataco verfasserin aut Sidónia Santos verfasserin aut Patrícia Machado verfasserin aut João B. Vicente verfasserin aut Joaninha Costa Rosa verfasserin aut Branca M. Cavaco verfasserin aut Cecília Moura verfasserin aut Marta Pojo verfasserin aut In Genes MDPI AG, 2010 11(2020), 4, p 403 (DE-627)614096537 (DE-600)2527218-4 20734425 nnns volume:11 year:2020 number:4, p 403 https://doi.org/10.3390/genes11040403 kostenfrei https://doaj.org/article/75c7b15645d143f397b431736acb3a28 kostenfrei https://www.mdpi.com/2073-4425/11/4/403 kostenfrei https://doaj.org/toc/2073-4425 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 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 2020 4, p 403
spelling	10.3390/genes11040403 doi (DE-627)DOAJ002568926 (DE-599)DOAJ75c7b15645d143f397b431736acb3a28 DE-627 ger DE-627 rakwb eng QH426-470 Catarina Campos verfasserin aut High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cutaneous melanoma is one of the most aggressive human cancers due to its high invasiveness. Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes for hereditary melanoma, we performed whole exome sequencing (WES) on eight patients with multiple primary melanomas, high number of nevi, and negative for high and intermediate-risk germline mutations. Thirteen new potentially pathogenic variants were identified after bioinformatics analysis and validation. <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< were identified as the most promising susceptibility genes in hereditary melanoma. <i<In silico</i< analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations. Then, we also evaluated the clinical value of <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< expression in sporadic melanoma by using the TCGA dataset (<i<n</i< = 461). No differences were observed in <i<BRD9</i< expression between melanoma and normal skin samples, nor with melanoma stage, whereas <i<ARHGEF40</i< was found overexpressed, and <i<CDH23</i< was downregulated and its loss was associated with worse survival. Altogether, these results reveal three novel genes with clinical relevance in hereditary and sporadic melanoma. cutaneous melanoma germline mutations WES hereditary melanoma Genetics Sofia Fragoso verfasserin aut Rafael Luís verfasserin aut Filipe Pinto verfasserin aut Cheila Brito verfasserin aut Susana Esteves verfasserin aut Margarida Pataco verfasserin aut Sidónia Santos verfasserin aut Patrícia Machado verfasserin aut João B. Vicente verfasserin aut Joaninha Costa Rosa verfasserin aut Branca M. Cavaco verfasserin aut Cecília Moura verfasserin aut Marta Pojo verfasserin aut In Genes MDPI AG, 2010 11(2020), 4, p 403 (DE-627)614096537 (DE-600)2527218-4 20734425 nnns volume:11 year:2020 number:4, p 403 https://doi.org/10.3390/genes11040403 kostenfrei https://doaj.org/article/75c7b15645d143f397b431736acb3a28 kostenfrei https://www.mdpi.com/2073-4425/11/4/403 kostenfrei https://doaj.org/toc/2073-4425 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 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 2020 4, p 403
allfields_unstemmed	10.3390/genes11040403 doi (DE-627)DOAJ002568926 (DE-599)DOAJ75c7b15645d143f397b431736acb3a28 DE-627 ger DE-627 rakwb eng QH426-470 Catarina Campos verfasserin aut High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cutaneous melanoma is one of the most aggressive human cancers due to its high invasiveness. Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes for hereditary melanoma, we performed whole exome sequencing (WES) on eight patients with multiple primary melanomas, high number of nevi, and negative for high and intermediate-risk germline mutations. Thirteen new potentially pathogenic variants were identified after bioinformatics analysis and validation. <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< were identified as the most promising susceptibility genes in hereditary melanoma. <i<In silico</i< analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations. Then, we also evaluated the clinical value of <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< expression in sporadic melanoma by using the TCGA dataset (<i<n</i< = 461). No differences were observed in <i<BRD9</i< expression between melanoma and normal skin samples, nor with melanoma stage, whereas <i<ARHGEF40</i< was found overexpressed, and <i<CDH23</i< was downregulated and its loss was associated with worse survival. Altogether, these results reveal three novel genes with clinical relevance in hereditary and sporadic melanoma. cutaneous melanoma germline mutations WES hereditary melanoma Genetics Sofia Fragoso verfasserin aut Rafael Luís verfasserin aut Filipe Pinto verfasserin aut Cheila Brito verfasserin aut Susana Esteves verfasserin aut Margarida Pataco verfasserin aut Sidónia Santos verfasserin aut Patrícia Machado verfasserin aut João B. Vicente verfasserin aut Joaninha Costa Rosa verfasserin aut Branca M. Cavaco verfasserin aut Cecília Moura verfasserin aut Marta Pojo verfasserin aut In Genes MDPI AG, 2010 11(2020), 4, p 403 (DE-627)614096537 (DE-600)2527218-4 20734425 nnns volume:11 year:2020 number:4, p 403 https://doi.org/10.3390/genes11040403 kostenfrei https://doaj.org/article/75c7b15645d143f397b431736acb3a28 kostenfrei https://www.mdpi.com/2073-4425/11/4/403 kostenfrei https://doaj.org/toc/2073-4425 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 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 2020 4, p 403
allfieldsGer	10.3390/genes11040403 doi (DE-627)DOAJ002568926 (DE-599)DOAJ75c7b15645d143f397b431736acb3a28 DE-627 ger DE-627 rakwb eng QH426-470 Catarina Campos verfasserin aut High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cutaneous melanoma is one of the most aggressive human cancers due to its high invasiveness. Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes for hereditary melanoma, we performed whole exome sequencing (WES) on eight patients with multiple primary melanomas, high number of nevi, and negative for high and intermediate-risk germline mutations. Thirteen new potentially pathogenic variants were identified after bioinformatics analysis and validation. <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< were identified as the most promising susceptibility genes in hereditary melanoma. <i<In silico</i< analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations. Then, we also evaluated the clinical value of <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< expression in sporadic melanoma by using the TCGA dataset (<i<n</i< = 461). No differences were observed in <i<BRD9</i< expression between melanoma and normal skin samples, nor with melanoma stage, whereas <i<ARHGEF40</i< was found overexpressed, and <i<CDH23</i< was downregulated and its loss was associated with worse survival. Altogether, these results reveal three novel genes with clinical relevance in hereditary and sporadic melanoma. cutaneous melanoma germline mutations WES hereditary melanoma Genetics Sofia Fragoso verfasserin aut Rafael Luís verfasserin aut Filipe Pinto verfasserin aut Cheila Brito verfasserin aut Susana Esteves verfasserin aut Margarida Pataco verfasserin aut Sidónia Santos verfasserin aut Patrícia Machado verfasserin aut João B. Vicente verfasserin aut Joaninha Costa Rosa verfasserin aut Branca M. Cavaco verfasserin aut Cecília Moura verfasserin aut Marta Pojo verfasserin aut In Genes MDPI AG, 2010 11(2020), 4, p 403 (DE-627)614096537 (DE-600)2527218-4 20734425 nnns volume:11 year:2020 number:4, p 403 https://doi.org/10.3390/genes11040403 kostenfrei https://doaj.org/article/75c7b15645d143f397b431736acb3a28 kostenfrei https://www.mdpi.com/2073-4425/11/4/403 kostenfrei https://doaj.org/toc/2073-4425 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 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 2020 4, p 403
allfieldsSound	10.3390/genes11040403 doi (DE-627)DOAJ002568926 (DE-599)DOAJ75c7b15645d143f397b431736acb3a28 DE-627 ger DE-627 rakwb eng QH426-470 Catarina Campos verfasserin aut High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cutaneous melanoma is one of the most aggressive human cancers due to its high invasiveness. Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes for hereditary melanoma, we performed whole exome sequencing (WES) on eight patients with multiple primary melanomas, high number of nevi, and negative for high and intermediate-risk germline mutations. Thirteen new potentially pathogenic variants were identified after bioinformatics analysis and validation. <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< were identified as the most promising susceptibility genes in hereditary melanoma. <i<In silico</i< analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations. Then, we also evaluated the clinical value of <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< expression in sporadic melanoma by using the TCGA dataset (<i<n</i< = 461). No differences were observed in <i<BRD9</i< expression between melanoma and normal skin samples, nor with melanoma stage, whereas <i<ARHGEF40</i< was found overexpressed, and <i<CDH23</i< was downregulated and its loss was associated with worse survival. Altogether, these results reveal three novel genes with clinical relevance in hereditary and sporadic melanoma. cutaneous melanoma germline mutations WES hereditary melanoma Genetics Sofia Fragoso verfasserin aut Rafael Luís verfasserin aut Filipe Pinto verfasserin aut Cheila Brito verfasserin aut Susana Esteves verfasserin aut Margarida Pataco verfasserin aut Sidónia Santos verfasserin aut Patrícia Machado verfasserin aut João B. Vicente verfasserin aut Joaninha Costa Rosa verfasserin aut Branca M. Cavaco verfasserin aut Cecília Moura verfasserin aut Marta Pojo verfasserin aut In Genes MDPI AG, 2010 11(2020), 4, p 403 (DE-627)614096537 (DE-600)2527218-4 20734425 nnns volume:11 year:2020 number:4, p 403 https://doi.org/10.3390/genes11040403 kostenfrei https://doaj.org/article/75c7b15645d143f397b431736acb3a28 kostenfrei https://www.mdpi.com/2073-4425/11/4/403 kostenfrei https://doaj.org/toc/2073-4425 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 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 2020 4, p 403
language	English
source	In Genes 11(2020), 4, p 403 volume:11 year:2020 number:4, p 403
sourceStr	In Genes 11(2020), 4, p 403 volume:11 year:2020 number:4, p 403
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authorswithroles_txt_mv	Catarina Campos @@aut@@ Sofia Fragoso @@aut@@ Rafael Luís @@aut@@ Filipe Pinto @@aut@@ Cheila Brito @@aut@@ Susana Esteves @@aut@@ Margarida Pataco @@aut@@ Sidónia Santos @@aut@@ Patrícia Machado @@aut@@ João B. Vicente @@aut@@ Joaninha Costa Rosa @@aut@@ Branca M. Cavaco @@aut@@ Cecília Moura @@aut@@ Marta Pojo @@aut@@
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callnumber-first	Q - Science
author	Catarina Campos
spellingShingle	Catarina Campos misc QH426-470 misc cutaneous melanoma misc germline mutations misc WES misc hereditary melanoma misc Genetics High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma
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topic_title	QH426-470 High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma cutaneous melanoma germline mutations WES hereditary melanoma
topic	misc QH426-470 misc cutaneous melanoma misc germline mutations misc WES misc hereditary melanoma misc Genetics
topic_unstemmed	misc QH426-470 misc cutaneous melanoma misc germline mutations misc WES misc hereditary melanoma misc Genetics
topic_browse	misc QH426-470 misc cutaneous melanoma misc germline mutations misc WES misc hereditary melanoma misc Genetics
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title	High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma
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title_full	High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma
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author_browse	Catarina Campos Sofia Fragoso Rafael Luís Filipe Pinto Cheila Brito Susana Esteves Margarida Pataco Sidónia Santos Patrícia Machado João B. Vicente Joaninha Costa Rosa Branca M. Cavaco Cecília Moura Marta Pojo
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title_sort	high-throughput sequencing identifies 3 novel susceptibility genes for hereditary melanoma
callnumber	QH426-470
title_auth	High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma
abstract	Cutaneous melanoma is one of the most aggressive human cancers due to its high invasiveness. Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes for hereditary melanoma, we performed whole exome sequencing (WES) on eight patients with multiple primary melanomas, high number of nevi, and negative for high and intermediate-risk germline mutations. Thirteen new potentially pathogenic variants were identified after bioinformatics analysis and validation. <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< were identified as the most promising susceptibility genes in hereditary melanoma. <i<In silico</i< analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations. Then, we also evaluated the clinical value of <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< expression in sporadic melanoma by using the TCGA dataset (<i<n</i< = 461). No differences were observed in <i<BRD9</i< expression between melanoma and normal skin samples, nor with melanoma stage, whereas <i<ARHGEF40</i< was found overexpressed, and <i<CDH23</i< was downregulated and its loss was associated with worse survival. Altogether, these results reveal three novel genes with clinical relevance in hereditary and sporadic melanoma.
abstractGer	Cutaneous melanoma is one of the most aggressive human cancers due to its high invasiveness. Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes for hereditary melanoma, we performed whole exome sequencing (WES) on eight patients with multiple primary melanomas, high number of nevi, and negative for high and intermediate-risk germline mutations. Thirteen new potentially pathogenic variants were identified after bioinformatics analysis and validation. <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< were identified as the most promising susceptibility genes in hereditary melanoma. <i<In silico</i< analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations. Then, we also evaluated the clinical value of <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< expression in sporadic melanoma by using the TCGA dataset (<i<n</i< = 461). No differences were observed in <i<BRD9</i< expression between melanoma and normal skin samples, nor with melanoma stage, whereas <i<ARHGEF40</i< was found overexpressed, and <i<CDH23</i< was downregulated and its loss was associated with worse survival. Altogether, these results reveal three novel genes with clinical relevance in hereditary and sporadic melanoma.
abstract_unstemmed	Cutaneous melanoma is one of the most aggressive human cancers due to its high invasiveness. Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes for hereditary melanoma, we performed whole exome sequencing (WES) on eight patients with multiple primary melanomas, high number of nevi, and negative for high and intermediate-risk germline mutations. Thirteen new potentially pathogenic variants were identified after bioinformatics analysis and validation. <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< were identified as the most promising susceptibility genes in hereditary melanoma. <i<In silico</i< analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations. Then, we also evaluated the clinical value of <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< expression in sporadic melanoma by using the TCGA dataset (<i<n</i< = 461). No differences were observed in <i<BRD9</i< expression between melanoma and normal skin samples, nor with melanoma stage, whereas <i<ARHGEF40</i< was found overexpressed, and <i<CDH23</i< was downregulated and its loss was associated with worse survival. Altogether, these results reveal three novel genes with clinical relevance in hereditary and sporadic melanoma.
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title_short	High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma
url	https://doi.org/10.3390/genes11040403 https://doaj.org/article/75c7b15645d143f397b431736acb3a28 https://www.mdpi.com/2073-4425/11/4/403 https://doaj.org/toc/2073-4425
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author2	Sofia Fragoso Rafael Luís Filipe Pinto Cheila Brito Susana Esteves Margarida Pataco Sidónia Santos Patrícia Machado João B. Vicente Joaninha Costa Rosa Branca M. Cavaco Cecília Moura Marta Pojo
author2Str	Sofia Fragoso Rafael Luís Filipe Pinto Cheila Brito Susana Esteves Margarida Pataco Sidónia Santos Patrícia Machado João B. Vicente Joaninha Costa Rosa Branca M. Cavaco Cecília Moura Marta Pojo
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up_date	2024-07-04T01:42:05.999Z
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Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes for hereditary melanoma, we performed whole exome sequencing (WES) on eight patients with multiple primary melanomas, high number of nevi, and negative for high and intermediate-risk germline mutations. Thirteen new potentially pathogenic variants were identified after bioinformatics analysis and validation. <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< were identified as the most promising susceptibility genes in hereditary melanoma. <i<In silico</i< analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations. Then, we also evaluated the clinical value of <i<CDH23</i<, <i<ARHGEF40,</i< and <i<BRD9</i< expression in sporadic melanoma by using the TCGA dataset (<i<n</i< = 461). No differences were observed in <i<BRD9</i< expression between melanoma and normal skin samples, nor with melanoma stage, whereas <i<ARHGEF40</i< was found overexpressed, and <i<CDH23</i< was downregulated and its loss was associated with worse survival. 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High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma

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