Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA.
Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Genes (Basel). 2023 Aug 23;14(9):1668. doi: 10.3390/genes14091668.
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 (, , ) or less commonly mutated (, ) genes. Another group of genes frequently mutated in CMs include and , with known roles in telomere maintenance and chromatin remodeling/epigenetic regulation. Uveal melanoma-related genes (, , ) 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 (, , 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).
结膜黑色素瘤（CM）是一种罕见但侵袭性很强的癌症。在过去的十年中，利用快速发展的技术进行的分子研究极大地提高了我们对 CM 遗传学的理解。CM 的主要特征是 MAPK 和 PI3K/AKT/mTOR 通路失调，由常见突变（，，）或较少突变（，）的基因驱动。另一组在 CM 中经常突变的基因包括 和 ，它们在端粒维持和染色质重塑/表观遗传调控中具有已知作用。Uveal melanoma 相关基因（，，）也可以在 CM 中突变，尽管频率较低。使用更全面的遗传分析，越来越多的 CM 相关突变基因已被识别出来，有待在更多的研究中进一步证实。由于 CM 是一种发生在部分暴露于阳光的粘膜组织中的肿瘤，因此其具有独特的基因组特征，包括频繁存在紫外线（UV）特征（高突变负荷）和常见的大结构变异（分布在整个基因组中）以及特定基因突变。迄今为止，CM 遗传研究获得的知识为新的治疗方法提供了依据，包括使用靶向和/或免疫疗法，这些方法在几种情况下都取得了有希望的结果。因此，将肿瘤基因检测纳入 CM 患者的常规临床护理有望进一步改善和个性化他们的治疗方法。同样，对 CM 中与预后不良相关的遗传变化（CM 中的不良预后相关基因改变、Uveal melanoma 特征性突变和 10q 染色体缺失）的了解不断增加，可能最终指导未来的预后检测策略，以进一步提高临床结果（通过调整监测并考虑高危原发性肿瘤患者的预防性治疗）。
