Brocca Ginevra, Ferraresso Serena, Zamboni Clarissa, Martinez-Merlo Elena M, Ferro Silvia, Goldschmidt Michael H, Castagnaro Massimo
Department of Comparative Biomedicine and Food Science, University of Padua, Legnaro, Italy.
Department of Animal Medicine and Surgery, Complutense University, Madrid, Spain.
Front Oncol. 2019 Dec 12;9:1397. doi: 10.3389/fonc.2019.01397. eCollection 2019.
Human Mucosal Melanoma (hMM) is an aggressive neoplasm of neuroectodermal origin with distinctive features from the more common cutaneous form of malignant melanoma (cMM). At the molecular level, hMMs are characterized by large chromosomal aberrations rather than single-nucleotide mutations, typically observed in cMM. Given the scarcity of available cases, there have been many attempts to establish a reliable animal model. In pet dogs, Canine Oral Melanoma (COM) is the most common malignant tumor of the oral cavity, sharing clinical and histological aspects with hMM. To improve the knowledge about COM's genomic DNA alterations, in the present work, formalin-fixed, paraffin-embedded (FFPE) samples of COM from different European archives were collected to set up an array Comparative Genomic Hybridization (aCGH) analysis to estimate recurrent Copy Number Aberrations (CNAs). DNA was extracted in parallel from tumor and healthy fractions and 19 specimens were successfully submitted to labeling and competitive hybridization. Data were statistically analyzed through GISTIC2.0 and a pathway-enrichment analysis was performed with ClueGO. Recurrent gained regions were detected, affecting chromosomes CFA 10, 13 and 30, while lost regions involved chromosomes CFA 10, 11, 22, and 30. In particular, CFA 13 showed a whole-chromosome gain in 37% of the samples, while CFA 22 showed a whole-chromosome loss in 25%. A distinctive sigmoidal trend was observed in CFA 10 and 30 in 25 and 30% of the samples, respectively. Comparative analysis revealed that COM and hMM share common chromosomal changes in 32 regions. MAPK- and PI3K-related genes were the most frequently involved, while pathway analysis revealed statistically significant perturbation of cancer-related biological processes such as immune response, drug metabolism, melanocytes homeostasis, and neo-angiogenesis. The latter is a new evidence of a significant involvement of neovascularization-related pathways in COMs and can provide the rationale for future application in anti-cancer targeted therapies.
人类黏膜黑色素瘤（hMM）是一种起源于神经外胚层的侵袭性肿瘤，具有与更常见的皮肤型恶性黑色素瘤（cMM）不同的特征。在分子水平上，hMM的特征是存在大片段染色体畸变，而非cMM中常见的单核苷酸突变。鉴于可用病例稀少，人们进行了许多尝试来建立可靠的动物模型。在宠物狗中，犬口腔黑色素瘤（COM）是口腔最常见的恶性肿瘤，在临床和组织学方面与hMM有相似之处。为了增进对COM基因组DNA改变的了解，在本研究中，收集了来自不同欧洲档案库的COM福尔马林固定、石蜡包埋（FFPE）样本，以建立阵列比较基因组杂交（aCGH）分析，来估计复发性拷贝数变异（CNA）。同时从肿瘤和健康组织中提取DNA，19个样本成功进行了标记和竞争性杂交。通过GISTIC2.0对数据进行统计分析，并使用ClueGO进行通路富集分析。检测到复发性获得区域，影响犬染色体（CFA）10、13和30，而缺失区域涉及CFA 10、11、22和30。特别是，37%的样本中CFA 13显示整条染色体获得，而25%的样本中CFA 22显示整条染色体缺失。分别在25%和30%的样本中，CFA 10和30观察到独特的S形趋势。比较分析显示，COM和hMM在32个区域存在共同的染色体变化。MAPK和PI3K相关基因是最常涉及的，而通路分析显示癌症相关生物过程如免疫反应、药物代谢、黑素细胞稳态和新血管生成存在统计学上的显著扰动。后者是新血管生成相关通路在COM中显著参与的新证据，可为未来在抗癌靶向治疗中的应用提供理论依据。
