DNA methylation markers for early detection of thyroid cancer

描述（由申请人提供）：直到最近，甲状腺癌（TC）在美国一直被忽视，因为大多数甲状腺癌病例的预后非常好，5年生存率约为96%，但那些在晚期诊断的患者的5年生存率低于60%。因此，尽管在科学和临床方面取得了进展，但晚期甲状腺癌仍然无法治愈。令人担忧的是，TC在女性中的发病率上升最快，在男性中上升第二快，每年的百分比变化约为5%，使甲状腺癌成为女性中第六常见的癌症。对于患有早期疾病的个体，没有准确的标志物来预测他们是否会发展为转移性或复发性疾病。此外，这几乎是不可能的 明确区分滤泡性甲状腺癌（FTC）与良性滤泡性增生（滤泡性腺瘤{FA}）术前（通过细针穿刺（{FNA}），由于形态重叠。一个单一的假阴性FNA可以显着延迟手术治疗，导致更高的血管和包膜浸润率和晚期疾病，使其无法治愈。目前的挑战是获得可靠的，术前标记物，区分良性和恶性甲状腺结节，检测早期TC，以提高区分腺瘤，乳头状甲状腺癌（PTC），和FTC，从而划定甲状腺亚型，以改善患者的管理。在过去的15年里，分子技术的应用集中在遗传事件上。甲状腺特异性基因的甲基化，如钠/碘转运体（NIS）和促甲状腺激素受体的甲基化在甲状腺癌的临床放射性碘治疗中具有意义。候选基因的方法，以确定甲基化标志物特异性甲状腺癌类型和亚型将是一个重要的第一步，TC特异性生物标志物。这项研究的基本假设是，候选基因的方法将确定与TC相关的甲基化基因。我们将在320例回顾性队列中评估21个报告为TC高甲基化的候选基因，其中包括80例PTC，80例FTC，80例滤泡性腺瘤（良性）和80例正常（对照）甲状腺组织。这些将作为结果的预测因子（早期与晚期、复发和生存），以潜在地改善腺瘤、PTC和FTC的区分，描述甲状腺亚型（常规PTC与PTC-滤泡变体和FTC与其变体FTC-Hurthle），以及术前区分滤泡性甲状腺癌与良性滤泡增生。 公共卫生相关性：晚期甲状腺癌（TC）具有毁灭性的5年生存率，并且仍然无法治愈。此外，几乎不可能明确区分 良性甲状腺疾病引起的滤泡性甲状腺癌（FTC）。这项研究将确定甲状腺特异性DNA甲基化标志物作为结果的预测因子（早期与晚期，复发和生存），以潜在地提高腺瘤，乳头状甲状腺癌（PTC）和FTC的区分，描绘甲状腺亚型（传统PTC与PTC-滤泡变体和FTC与其变体FTC-Hurthle），以及术前区分FTC与良性滤泡增殖。

DESCRIPTION (provided by applicant): Until recently, thyroid cancer (TC) has been largely ignored in the US because the majority of thyroid cancer cases have very good prognosis, with 5-year survival rates of approximately 96%, but those diagnosed at late stages have a devastating 5-year survival rate of fewer than 60%. Thus, despite advances on scientific and clinical fronts, advanced thyroid cancers remain incurable. Alarmingly, TC has the fastest rising incidence rates in women, and the second fastest in men with an annual percentage change of approximately 5%, making thyroid cancer the sixth most common cancer in women. For individuals who present with early-stage disease, there is no accurate marker(s) to predict whether they will develop metastatic or recurrent disease. Additionally, it is virtually impossible to definitively differentiate follicular thyroid cancer (FTC) from a benign follicular proliferatio (follicular adenomas {FA}) preoperatively (by fine needle aspiration ({FNA}) due to morphologic overlap. A single false-negative FNA can significantly delay surgical treatment, leading to higher rates of vascular and capsular invasion and advanced stage disease, making it incurable. The present challenge is to obtain reliable, preoperative markers that differentiate benign and malignant thyroid nodules, to detect early TC, to improve discrimination of adenoma, papillary thyroid cancer (PTC), and FTC so as to delineate thyroid subtypes in order to improve patient management. Over the past 15 years, the application of molecular technologies has focused on genetic events. Methylation of thyroid-specific genes, such as those for sodium/iodide symporter (NIS) and thyroid-stimulating hormone receptor have implications in clinical radioiodine treatment of thyroid cancer. A candidate gene approach to identify methylation markers specific to thyroid cancer types and subtypes would be an essential first step for TC-specific biomarkers. The underlying hypothesis of this research is that a candidate gene approach will identify methylated genes relevant to TC. We will evaluate 21 candidate genes reported to be hypermethylated in TC for promoter hypermethylation in a retrospective cohort of 320 cases comprising of 80 PTC, 80 FTC, 80 follicular adenomas (benign) and 80 normal (control) thyroid tissues. These will be useful as predictors of outcome (early versus late stage, recurrence and survival), to potentially improve discrimination of adenoma, PTC, and FTC, to delineate thyroid subtypes (conventional PTC vs PTC-follicular variant and FTC vs its variant FTC-Hurthle), as well as differentiate follicular thyroid carcinoma from a benign follicular proliferation preoperatively. PUBLIC HEALTH RELEVANCE: Advanced thyroid cancer (TC) has a devastating 5-year survival rate and remains incurable. Also, it is virtually impossible to definitively differentiate follicular thyroid cancer (FTC) from benign thyroid disease. This research will identify thyroid-specific DNA methylation markers as predictors of outcome (early versus late stage, recurrence and survival), to potentially improve discrimination of adenoma, papillary thyroid cancer (PTC), and FTC, to delineate thyroid subtypes (conventional PTC vs PTC-follicular variant and FTC vs its variant FTC-Hurthle), as well as differentiate FTC from a benign follicular proliferation preoperatively.