Clinical and genetic studies in familial nonmedullary thyroid cancer (FNMTC)

背景：甲状腺癌是美国增长最快的癌症诊断之一。非甲状腺髓样癌占所有甲状腺癌病例的95%。所有非髓样甲状腺癌中高达8%是遗传性的。家族性非髓样甲状腺癌（FNMTC）比散发性疾病更具侵袭性。尚未发现FNMTC的易感基因。筛查FNMTC风险家庭成员的最佳方法尚不清楚。本方案旨在确定FNMTC的自然史和最佳筛选策略，并鉴定FNMTC的易感基因。 总结：这是一项针对患有或有风险患非甲状腺髓样癌的个体的前瞻性研究。将在其家庭背景下对个人进行长期研究，以量化家庭成员中癌症的预期风险，建立FNMTC的自然史，定义家庭内的疾病谱，识别前体状态，尝试评估风险的遗传和环境成分的贡献，并制定有效的筛查策略。我们对家族性和散发性非甲状腺髓样癌病例的肿瘤和生殖系DNA进行了几项基因组研究。与年龄和癌症阶段相匹配的散发性和家族性肿瘤的microRNA谱显示与正常甲状腺组织相比明显不同的失调microRNA模式。此外，我们发现，与未受影响的家庭成员，散发性甲状腺癌病例和健康志愿者相比，家族性非甲状腺髓样癌病例在生殖系DNA中的端粒长度较短。我们目前正在确定是否有任何端粒相关蛋白可以解释这种差异，并正在使用非甲状腺髓样癌家族性病例的验证队列来确认家族性非甲状腺髓样癌中存在较短的端粒作为风险因素。

Background: Thyroid cancer is one of the fastest growing cancer diagnoses in the United States. Non-medullary thyroid cancer accounts for 95% of all thyroid cancer cases. Up to 8% of all non-medullary thyroid cancers are hereditary. Familial non-medullary thyroid cancer (FNMTC) is more aggressive than sporadic disease. No susceptibility gene for FNMTC has been identified. The best approach for screening at risk family members for FNMTC is unknown. This protocol is designed to determine the natural history and best screening strategy for FNMTC, and to identify susceptibility gene(s) for FNMTC. Summary: This is a prospective study of individuals with or at risk for non-medullary thyroid cancer. Individuals will be studied over time within the context of their families in order to quantify prospective risks of cancers in family members, to establish the natural history of FNMTC, define the spectrum of diseases within the families, to identify precursor states, to try to assess the contribution of genetic and environmental components of risk, and to develop effective screening strategies. We have performed several genomic studies in tumor and germline DNA from familial and sporadic cases of non-medullary thyroid cancer. MicroRNA profiling of the sporadic and familial tumors matched for age and stage of cancer show distinctly different patterns of deregulated microRNA as compared to normal thyroid tissue. Also, we have found that cases of familial non-medullary thyroid cancer as compared to unaffected family members, sporadic thyroid cancer cases and healthy volunteer have short telomere length in germline DNA. We are currently determining if any of the telomere related protein may account for this difference, and are using a validation cohort of familial case of non-medullary thyroid cancer to confirm the presence of shorter telomere in familial non-medullary thyroid cancer as a risk factor.