Demirci Hakan, Vo Josh N, Wu Yi-Mi, Elner Victor, Chinnaiyan Arul M, Robinson Dan, Demirci F Yesim
Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan.
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
Ophthalmol Sci. 2025 Apr 23;5(5):100801. doi: 10.1016/j.xops.2025.100801. eCollection 2025 Sep-Oct.
Targeted next-generation sequencing-based genomic and transcriptomic analyses of conjunctival squamous cell carcinoma (cSCC) samples using a panel of >1700 cancer-related genes.
Prospective case series.
Twenty patients with invasive cSCC consecutively managed at an academic ocular oncology setting.
Integrative exome and transcriptome analysis of fresh-frozen tumor and matching normal samples.
Molecular characterization of invasive cSCCs (for somatic mutations, tumor mutation burden (TMB) and signatures, structural variations, viral transcripts, outlier gene expression) and its potential clinical applications.
Of the 20 invasive cSCCs, only 2 were positive for human papillomavirus (HPV). All 18 HPV-negative tumors had genetic alterations in and 16 also had alterations in . The 2 HPV-positive tumors showed no alterations in these cell cycle regulators but harbored mutations in . Other frequently altered genes included (70%), 3 (65%), and 3 (60%), which were implicated in both the HPV-negative and positive tumors. The average TMB was 58.41 mutations per megabase (Mut/Mb). The TMB was >20 Mut/Mb in 13 cases (65%, range: 49.3-160.8 Mut/Mb), of which 11 had ultraviolet (UV) mutational signature, 3 had APOBEC signature, and 2 had microsatellite instability. Most UV-driven tumors (8 of 11) also harbored promoter mutations. The most recurrent large-scale copy number alterations were the deletions affecting chromosomes 3p, 9p, and 14q. Uncommon but potentially drug-targetable copy number gains were also detected affecting several oncogenes. The most frequent gene expression outlier was the aberrantly expressed found in 19 tumors.
In our invasive cSCC cohort, HPV infection was not a major contributor to tumor etiopathogenesis. Our results confirmed the central role of genetic alterations and the common presence of UV signature in the HPV-negative cSCCs. Irrespective of HPV status, other commonly observed genetic alterations included those affecting chromatin modifiers followed by Hippo or Notch pathway-related genes. Ultraviolet-driven promoter mutations co-occurred with other driver gene alterations. The commonly observed high TMB makes immunotherapy a good treatment choice for invasive cSCC. Moreover, several cSCC-associated molecular alterations represent potentially actionable targets, while further studies are necessary to understand their roles in cSCC development and invasion.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
使用一组超过1700个癌症相关基因，对结膜鳞状细胞癌（cSCC）样本进行基于靶向新一代测序的基因组和转录组分析。
前瞻性病例系列研究。
20例在学术性眼科肿瘤中心接受连续治疗的浸润性cSCC患者。
对新鲜冷冻的肿瘤样本和匹配的正常样本进行外显子组和转录组综合分析。
浸润性cSCC的分子特征（体细胞突变、肿瘤突变负荷（TMB）及特征、结构变异、病毒转录本、异常基因表达）及其潜在的临床应用。
在20例浸润性cSCC中，仅2例人乳头瘤病毒（HPV）呈阳性。所有18例HPV阴性肿瘤均存在[具体基因]的基因改变，16例还存在[另一具体基因]的改变。2例HPV阳性肿瘤在这些细胞周期调节因子中未显示改变，但存在[某基因]的突变。其他常见的改变基因包括[具体基因]（70%）、[具体基因]3（65%）和[具体基因]3（60%），这些基因在HPV阴性和阳性肿瘤中均有涉及。平均TMB为每兆碱基58.41个突变（Mut/Mb）。13例（65%，范围：49.3 - 160.8 Mut/Mb）的TMB > 20 Mut/Mb，其中11例具有紫外线（UV）突变特征，3例具有载脂蛋白B mRNA编辑酶催化多肽样3（APOBEC）特征，2例具有微卫星不稳定性。大多数由紫外线驱动的肿瘤（11例中的8例）也存在[具体基因]启动子突变。最常见的大规模拷贝数改变是影响染色体3p、9p和14q的缺失。还检测到影响多个癌基因的罕见但可能可药物靶向的拷贝数增加。最常见的基因表达异常是在19个肿瘤中发现的异常表达的[具体基因]。
在我们的浸润性cSCC队列中，HPV感染并非肿瘤发病机制的主要因素。我们的结果证实了[具体基因]改变的核心作用以及HPV阴性cSCC中紫外线特征的普遍存在。无论HPV状态如何，其他常见的基因改变包括影响染色质修饰因子的改变，其次是与Hippo或Notch通路相关的基因。紫外线驱动的[具体基因]启动子突变与其他驱动基因改变同时出现。普遍观察到的高TMB使免疫疗法成为浸润性cSCC的良好治疗选择。此外，几种与cSCC相关的分子改变代表了潜在的可操作靶点，而需要进一步研究以了解它们在cSCC发生和侵袭中的作用。
本文末尾的脚注和披露中可能会发现专有或商业披露信息。
