Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia.
Department of Biomedical Science, Kulliyyah of Allied Health Sciences, International Islamic University Malaysia, Kuantan, Pahang, Malaysia.
Front Endocrinol (Lausanne). 2023 Jan 4;13:1039494. doi: 10.3389/fendo.2022.1039494. eCollection 2022.
Papillary thyroid cancer (PTC) is the most common thyroid malignancy. Concurrent presence of cytomorphological benign thyroid goitre (BTG) and PTC lesion is often detected. Aberrant protein profiles were previously reported in patients with and without BTG cytomorphological background. This study aimed to evaluate gene mutation profiles to further understand the molecular mechanism underlying BTG, PTC without BTG background and PTC with BTG background.
Patients were grouped according to the histopathological examination results: (i) BTG patients (n = 9), (ii) PTC patients without BTG background (PTCa, n = 8), and (iii) PTC patients with BTG background (PTCb, n = 5). Whole-exome sequencing (WES) was performed on genomic DNA extracted from thyroid tissue specimens. Nonsynonymous and splice-site variants with MAF of ≤ 1% in the 1000 Genomes Project were subjected to principal component analysis (PCA). PTC-specific SNVs were filtered against OncoKB and COSMIC while novel SNVs were screened through dbSNP and COSMIC databases. Functional impacts of the SNVs were predicted using PolyPhen-2 and SIFT. Protein-protein interaction (PPI) enrichment of the tumour-related genes was analysed using Metascape and MCODE algorithm.
PCA plots showed distinctive SNV profiles among the three groups. OncoKB and COSMIC database screening identified 36 tumour-related genes including and in all groups. and 19 additional genes were found only in PTCa and PTCb. "Pathways in cancer", "DNA repair" and "Fanconi anaemia pathway" were among the top networks shared by all groups. However, signalling pathways related to tyrosine kinases were the most significantly enriched in PTCa while "Jak-STAT signalling pathway" and "Notch signalling pathway" were the only significantly enriched in PTCb. Ten SNVs were PTC-specific of which two were novel; c.2786C>G (p.Ala929Gly) and c.8735G>C (p.Ser2912Thr). Four out of the ten SNVs were unique to PTCa.
Distinctive gene mutation patterns detected in this study corroborated the previous protein profile findings. We hypothesised that the PTCa and PTCb subtypes differed in the underlying molecular mechanisms involving tyrosine kinase, Jak-STAT and Notch signalling pathways. The potential applications of the SNVs in differentiating the benign from the PTC subtypes requires further validation in a larger sample size.
甲状腺乳头状癌（PTC）是最常见的甲状腺恶性肿瘤。常发现细胞学良性甲状腺肿（BTG）和 PTC 病变同时存在。先前有报道称，伴有和不伴有 BTG 细胞学背景的患者存在异常的蛋白谱。本研究旨在评估基因突变谱，以进一步了解 BTG、无 BTG 背景的 PTC 和有 BTG 背景的 PTC 背后的分子机制。
根据组织病理学检查结果将患者分为以下几组：（i）BTG 患者（n=9），（ii）无 BTG 背景的 PTC 患者（PTCa，n=8）和（iii）有 BTG 背景的 PTC 患者（PTCb，n=5）。从甲状腺组织标本中提取基因组 DNA 进行全外显子组测序（WES）。将在 1000 基因组计划中的 MAF≤1%的非同义突变和剪接位点变异进行主成分分析（PCA）。通过 OncoKB 和 COSMIC 数据库筛选 PTC 特异性 SNVs，通过 dbSNP 和 COSMIC 数据库筛选新的 SNVs。使用 PolyPhen-2 和 SIFT 预测 SNVs 的功能影响。使用 Metascape 和 MCODE 算法分析肿瘤相关基因的蛋白-蛋白相互作用（PPI）富集情况。
PCA 图谱显示三组之间存在独特的 SNV 图谱。OncoKB 和 COSMIC 数据库筛选出所有组均含有的 36 个肿瘤相关基因，包括 和 。在 PTCa 和 PTCb 中还发现了 和另外 19 个基因。“癌症途径”、“DNA 修复”和“范可尼贫血途径”是所有组共有的顶级网络之一。然而，与酪氨酸激酶相关的信号通路在 PTCa 中最为显著富集，而“Jak-STAT 信号通路”和“Notch 信号通路”是 PTCb 中唯一显著富集的通路。10 个 SNVs 是 PTC 特异性的，其中 2 个是新的； c.2786C>G (p.Ala929Gly) 和 c.8735G>C (p.Ser2912Thr)。这 10 个 SNVs 中有 4 个是 PTCa 特有的。
本研究中检测到的独特基因突变模式与先前的蛋白谱发现相符。我们假设 PTCa 和 PTCb 亚型在涉及酪氨酸激酶、Jak-STAT 和 Notch 信号通路的潜在分子机制上存在差异。这些 SNVs 在区分良性和 PTC 亚型中的潜在应用需要在更大的样本量中进一步验证。
