High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma
High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma
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DOI：
10.3390/genes11040403
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发表时间：
2020-04-01
期刊：
影响因子：
3.5
通讯作者：
Pojo, Marta
中科院分区：
文献类型：
--
作者：
Campos, Catarina;Fragoso, Sofia;Pojo, Marta
由于其高侵袭性，皮肤黑色素瘤是最具侵袭性的人类癌症之一。高风险黑色素瘤易感基因的种系突变与遗传性黑色素瘤的发生有关；然而，大多数基因罪魁祸首仍然难以捉摸。为了揭示遗传性黑色素瘤的新易感基因，我们对八名患有多发性原发性黑色素瘤、大量痣且高风险和中风险种系突变呈阴性的患者进行了全外显子组测序 (WES)。经过生物信息学分析和验证，发现了 13 个新的潜在致病变异。 CDH23、ARHGEF40 和 BRD9 被确定为遗传性黑色素瘤中最有希望的易感基因。 CDH23 和 ARHGEF40 变体的计算机分析为与已识别突变相关的蛋白质结构和功能改变提供了线索。然后，我们还使用 TCGA 数据集 (n = 461) 评估了 CDH23、ARHGEF40 和 BRD9 表达在散发性黑色素瘤中的临床价值。黑色素瘤和正常皮肤样本之间的 BRD9 表达没有观察到差异，黑色素瘤分期也没有观察到差异，而 ARHGEF40 过度表达，CDH23 下调，其缺失与较差的生存率相关。总而言之，这些结果揭示了在遗传性和散发性黑色素瘤中具有临床相关性的三个新基因。
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.