- 學位論文
以次世代定序尋找家族性非髓質型甲狀腺癌致病基因
Using Next-Generation Sequencing to Identify Causative Genes of Familial Non-Medullary Thyroid Cancer
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摘要
甲狀腺癌（thyroid cancer）是內分泌系統中相對常見的惡性腫瘤之一，全球癌症發病率排名第九。在台灣，甲狀腺癌的發病率近年急速上升，特別是女性患者占比較高。甲狀腺癌可以分為髓質型甲狀腺癌（medullary thyroid carcinoma）和非髓質型甲狀腺癌（non-medullary thyroid carcinoma兩大類），其中非髓質型甲狀腺癌占絕大多數，包含乳突型甲狀腺癌（papillary thyroid carcinoma）、濾泡型甲狀腺癌（follicular thyroid carcinoma）、低分化型甲狀腺癌（poorly differentiated thyroid carcinoma）以及未分化型甲狀腺癌（anaplastic thyroid carcinoma）。家族性非髓質型甲狀腺癌（familial non-medullary thyroid cancer）的遺傳基礎複雜多樣，可能涉及單基因或多基因遺傳模式，但對其致病因素尚不完全了解。 Lin等人在2020年的文獻指出，在一般人群中，非髓質型甲狀腺癌的患病率為0.16％，然而在已有患者家族中的一等親屬中，患病率卻高達0.64％，顯示家族性患病風險比一般人群增加了5.47倍。此外，根據2022年的文獻報告，在有兩位受影響成員的家庭中，約有4.6%的家庭至少有一位成員患有甲狀腺癌；而在有三位或更多受影響成員的家庭中，這一比例增加到了22.7%。這突顯了家族性非髓質型甲狀腺癌的重要性及其對遺傳風險研究的重要意義。 本研究旨在探討家族性非髓質型甲狀腺癌中的致病基因。我們對11名家族性非髓質型甲狀腺癌的先證者的血液樣品進行了全基因組定序（whole genome sequencing），檢測了單核苷酸變異（single nucleotide variant）、小片段插入或缺失變異（small InDel）以及結構變異（SVs）。結果顯示，共鑑定出22個變異，其中包括6個良性變異，1個疑似致病變異。經過IGV審核後，該變異可能是實驗過程中的錯誤。其餘的15個變異具有不確定的臨床意義（VUS），其中13個位於目標基因的內含子區域，對基因功能影響有限。 研究中存在一些限制，可能影響了結果的全面性和準確性。因此，擴展血液樣品量和基因範圍，使用DRAGEN分析平台及長片段定序技術（如Nanopore和PacBio）將有助於進一步探索家族性非髓質型甲狀腺癌的遺傳基礎。
並列摘要
Thyroid cancer is one of the relatively common malignancies in the endocrine system, ranking ninth in global cancer incidence. In Taiwan, the incidence of thyroid cancer has been rapidly increasing in recent years, particularly among females. Thyroid cancer can be categorized into medullary thyroid carcinoma (MTC) and non-medullary thyroid carcinoma (NMTC), with NMTC comprising the majority, including papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC). Familial non-medullary thyroid cancer (FNMTC) exhibits complex genetic underpinnings, potentially involving both monogenic and polygenic inheritance patterns, though its pathogenic factors remain incompletely understood. Lin et al. highlighted in 2020 that the incidence of NMTC in the general population is 0.16%, whereas it rises to 0.64% among first-degree relatives of affected individuals, indicating a 5.47-fold increased familial risk. Furthermore, according to a 2022 report, approximately 4.6% of families with two affected members have at least one member diagnosed with thyroid cancer, rising to 22.7% in families with three or more affected members, underscoring the significance of studying familial risk in NMTC. This study aims to explore the pathogenic genes involved in FNMTC. Whole genome sequencing was performed on blood samples from 11 probands with familial NMTC, detecting single nucleotide variants (SNVs), small insertion/deletion variants (InDels), and structural variants (SVs). The results identified a total of 22 variants, including 6 benign variants and 1 likely pathogenic variant. Following IGV scrutiny, this variant was deemed likely an experimental artifact. The remaining 15 variants exhibit uncertain clinical significance (VUS), with 13 located primarily in intronic regions of target genes, exerting limited impact on gene function. The study faces limitations that may affect the comprehensiveness and accuracy of its findings. Therefore, expanding blood sample size and gene coverage, employing the DRAGEN analysis platform, and utilizing long-read sequencing technologies such as Nanopore and PacBio will facilitate further exploration of the genetic basis of familial non-medullary thyroid cancer.
參考文獻
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