PDF(Pubmed)
Abstract：
Conjunctival melanoma (CM) is a rare but aggressive cancer. Over the past decade, molecular studies using rapidly advancing technologies have increasingly improved our understanding of CM genetics. CMs are mainly characterized by dysregulated MAPK and PI3K/AKT/mTOR pathways, driven by commonly mutated (BRAF, NRAS, NF1) or less commonly mutated (KIT, PTEN) genes. Another group of genes frequently mutated in CMs include TERT and ATRX, with known roles in telomere maintenance and chromatin remodeling/epigenetic regulation. Uveal melanoma-related genes (BAP1, SF3B1, GNAQ/11) can also be mutated in CMs, albeit infrequently. Additional CM-related mutated genes have increasingly been identified using more comprehensive genetic analyses, awaiting further confirmation in additional/larger studies. As a tumor arising in a partly sun-exposed mucosal tissue, CM exhibits a distinct genomic profile, including the frequent presence of an ultraviolet (UV) signature (and high mutational load) and also the common occurrence of large structural variations (distributed across the genome) in addition to specific gene mutations. The knowledge gained from CM genetic studies to date has led to new therapeutic avenues, including the use of targeted and/or immuno-therapies with promising outcomes in several cases. Accordingly, the implementation of tumor genetic testing into the routine clinical care of CM patients holds promise to further improve and personalize their treatments. Likewise, a growing knowledge of poor prognosis-associated genetic changes in CMs (NRAS, TERT, and uveal melanoma signature mutations and chromosome 10q deletions) may ultimately guide future strategies for prognostic testing to further improve clinical outcomes (by tailoring surveillance and considering prophylactic treatments in patients with high-risk primary tumors).
摘要：
结膜黑色素瘤（CM）是一种罕见但侵袭性的癌症。在过去的十年里，使用快速发展技术的分子研究日益提高了我们对CM遗传学的理解。CMs的主要特征是MAPK和PI3K/AKT/mTOR通路失调，由通常突变的(BRAF，NRAS,NF1)或较不常见的突变(KIT，PTEN)基因。在CM中经常突变的另一组基因包括TERT和ATRX，在端粒维持和染色质重塑/表观遗传调控中具有已知作用。葡萄膜黑色素瘤相关基因（BAP1，SF3B1，GNAQ/11）也可以在CMs中突变，虽然很少。使用更全面的遗传分析，已经越来越多地确定了其他与CM相关的突变基因。等待在更多/更大的研究中进一步确认。作为在部分暴露于阳光的粘膜组织中出现的肿瘤，CM表现出独特的基因组图谱，包括紫外线（UV）特征的频繁存在（和高突变负荷），以及除特定基因突变外，还常见的大结构变异（分布在整个基因组中）。迄今为止，从CM遗传研究中获得的知识导致了新的治疗途径，包括在一些病例中使用靶向和/或免疫疗法有希望的结果。因此，在CM患者的常规临床护理中实施肿瘤基因检测有望进一步改善和个性化治疗。同样，对CMs不良预后相关遗传变化的认识不断提高(NRAS，TERT,和葡萄膜黑色素瘤特征突变和染色体10q缺失）可能最终指导未来的预后测试策略，以进一步改善临床结局（通过调整监测并考虑对高风险原发性肿瘤患者的预防性治疗）。
