Department of Biomedicine and Genetics, Medical University of Lodz, Pomorska 251 St, 92-213, Lodz, Poland.
Department of Endocrine, General and Vascular Surgery, Chair of Endocrinology, Medical University of Lodz, Pabianicka 62 St, 93-513, Lodz, Poland.
Mol Diagn Ther. 2019 Jun;23(3):369-382. doi: 10.1007/s40291-019-00387-0.
Loss of heterozygosity (LOH) and microsatellite instability (MSI) are frequent molecular events in thyroid tumor etiopathogenesis occurring in several chromosomal critical areas, including 3p12-25.3, 7q21-31, 10q22-24, and 15q11-13, with loci of tumor suppressor genes.
We evaluated the usefulness of LOH/MSI as a diagnostic/prognostic biomarker in lesions derived from thyroid follicular cells: follicular thyroid carcinoma (FTC); follicular adenoma (FA), papillary thyroid carcinoma (PTC), and nodular goiter (NG).
We performed allelotyping (GeneMapper Software v. 4.0.) of ten microsatellite markers linked to the 1p31.2, 3p21.3, 3p24.2, 9p21.3, 11p15.5, and 16q22.1 region on DNA from 93 primary thyroid lesions then evaluated the LOH/MSI frequency and overall frequency of allelic loss (OFAL).
We found regions with significantly increased frequency of LOH/MSI for specific histotypes: the 3p24.2 region for FA and 1p31.2 for FTC. LOH/MSI in 3p21.3 was significantly elevated in PTC and FTC. LOH/MSI in 3p21.3 was increased for small size tumors (T1a + T1b), tumors with no regional lymph node involvement (N0 + Nx), American Joint Committee on Cancer (AJCC) stage I tumors, and tumor diameter (Td) < 10 mm; in 1p31.2 for T2-3, N1, stage II-IV, and Td 10-30 mm; in 11p15.5 for T2-3, N1, stage II-IV, and Td > 30 mm. OFAL values were significantly higher in younger patients (< 40 years), in men, in those with T2-3 stage tumors, in those with increased Td, and in FA and FTC compared with NG and PTC.
We confirmed the occurrence of LOH/MSI in 3p21.3 at an early stage of tumorigenesis and mapped 1p31.2 and 11p15.5 as characteristic for advanced-stage tumors. The results of our study may enable consideration of OFAL, defined as LOH/MSI coincidence in various chromosomal regions, as a tumor progression marker. OFAL values were significantly higher in follicular neoplasms (FA and FTC) than in PTC or NG; hence, increased OFAL values can be regarded as a characteristic feature of the follicular phenotype.
杂合性缺失（LOH）和微卫星不稳定性（MSI）是甲状腺肿瘤发病机制中的常见分子事件，发生在包括 3p12-25.3、7q21-31、10q22-24 和 15q11-13 在内的几个染色体关键区域，涉及肿瘤抑制基因的位点。
我们评估 LOH/MSI 作为甲状腺滤泡细胞来源病变的诊断/预后生物标志物的有用性：滤泡状甲状腺癌（FTC）；滤泡性腺瘤（FA）、甲状腺乳头状癌（PTC）和结节性甲状腺肿（NG）。
我们对 93 例原发性甲状腺病变的 DNA 进行了十个微卫星标记的等位基因分型（GeneMapper 软件 v. 4.0.），这些标记与 1p31.2、3p21.3、3p24.2、9p21.3、11p15.5 和 16q22.1 区域相关，然后评估了 LOH/MSI 的频率和总的等位基因缺失频率（OFAL）。
我们发现特定组织型的 LOH/MSI 频率存在显著增加的区域：FA 的 3p24.2 区域和 FTC 的 1p31.2 区域。3p21.3 中的 LOH/MSI 在 PTC 和 FTC 中显著升高。3p21.3 中的 LOH/MSI 在小肿瘤（T1a+T1b）、无区域淋巴结受累（N0+Nx）、美国癌症联合委员会（AJCC）I 期肿瘤和肿瘤直径（Td）<10mm 时增加；在 1p31.2 中，T2-3、N1、II-IV 期和 Td 为 10-30mm；在 11p15.5 中，T2-3、N1、II-IV 期和 Td>30mm。在年龄较小（<40 岁）的患者、男性、T2-3 期肿瘤患者、Td 增加的患者以及 FA 和 FTC 中，OFAL 值明显高于 NG 和 PTC。
我们在肿瘤发生的早期阶段证实了 3p21.3 中的 LOH/MSI 的发生，并将 1p31.2 和 11p15.5 映射为晚期肿瘤的特征。我们研究的结果可能使 OFAL（定义为各种染色体区域的 LOH/MSI 一致性）被视为肿瘤进展的标志物。在滤泡性肿瘤（FA 和 FTC）中 OFAL 值明显高于 PTC 或 NG；因此，增加的 OFAL 值可以被视为滤泡表型的特征。
