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

Catarina Campos,Branca M Cavaco,Susana Esteves,João B Vicente,Cheila Brito,Margarida Pataco,Filipe Pinto,Joaninha Costa Rosa,Sofia Fragoso,Sidónia Santos,Cecília Moura,Marta Pojo,Rafael Luís,Patrícia Machado

doi:10.3390/genes11040403

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. CDH23, ARHGEF40, and BRD9 were identified as the most promising susceptibility genes in hereditary melanoma. In silico 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 CDH23, ARHGEF40, and BRD9 expression in sporadic melanoma by using the TCGA dataset (n = 461). No differences were observed in BRD9 expression between melanoma and normal skin samples, nor with melanoma stage, whereas ARHGEF40 was found overexpressed, and CDH23 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.

Highlights

Skin cancer incidence has been rising alarmingly fast, becoming a concerning public health issue [1].Of all skin cancers, melanoma stands out due to its high invasive capacity, being considered one of the most aggressive skin cancers, accounting for ~69% of deaths caused by cutaneous malignancies [2]
Data of eight patients with multiple primary melanomas (MPM), which were negative for all the susceptibility genes for melanoma (CDKN2A, CDK4, MITF, BAP1) and telomere maintenance complex genes such as Telomerase Reverse Transcriptase (TERT), Protection of Telomeres 1 (POT1), Shelterin
We aimed to identify novel rare genetic variants responsible for hereditary melanoma susceptibility

Summary

Introduction

Skin cancer incidence has been rising alarmingly fast, becoming a concerning public health issue [1].Of all skin cancers, melanoma stands out due to its high invasive capacity, being considered one of the most aggressive skin cancers, accounting for ~69% of deaths caused by cutaneous malignancies [2]. History comprises approximately 5–15% of melanoma cases; this does not imply that a single genetic mutation is being transmitted [4]; shared sun exposure and other risk factors are more plausible causes of melanoma among families with susceptible skin types [3]. Patients diagnosed with a single primary melanoma are at an increased risk of developing subsequent primary melanomas, which most likely occur within two years after the first diagnosis [5]. This has been demonstrated for 70% of melanoma patients who developed a second primary melanoma, showing the importance of close skin surveillance [6]

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