TUMOR SUPPRESSORS AND DIFFERENTIATED THYROID CANCER

肿瘤抑制剂和分化型甲状腺癌

基本信息

批准号：
6137717
负责人：
NORMAN L EBERHARDT
金额：
$ 24.94万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-01-05 至 2001-12-31
项目状态：
已结题

项目摘要

Thyroid malignancies, the most common endocrine cancer, account for >17,000 new cases and 1,200 cancer deaths per year in the U.S. The bulk (70-95%) of these neoplasms are primary thyroid carcinomas of follicular cell origin, including differentiated papillary (PTC) and follicular (FTC), and undifferentiated anaplastic thyroid cancers. In the U.S. incidence rates are PTC > FTC >> anaplastic carcinomas, while morbidity/mortality rates associated with these cancers are anaplastic carcinomas >> FTC >PTC. Evidence for progression from benign follicular adenoma (Fa) > FTC has been observed, while PTC appears to arise de novo. While numerous studies have attempted to define the molecular genetics of differentiated thyroid cancer, virtually all of these studies have suffered from lack of significant specimen numbers, insufficient pathological criteria, or both. We have shown extensive evidence for frequent loss of heterozygosity (LOH) on chromosomes 3p, 10q, 13q and 17p in FTC , but not FA or PTC, suggesting that tumor suppressor genes (TSGs) may be involved in the genesis of FTC. Known TSGs mapping near regions of LOH on chromosomes 3p (VHL and FHIT) and 17p (p53) do not appear to be involved, since mutations of these sequences are rare in FTC. Thus as yet undefined TSGs appears to be involved in the genesis of FTC. In the current studies we will perform a detail molecular genetic study of at least 30 specimen/tumor type of a well defined and stratified population of thyroid cancers, in which extensive clinical records are available. Tumor types will include PTC (grades 1,2 and 3), FTC (minimally and widely invasive, oxyphilic and non-oxyphilic carcinomas) and FA. With this population of tumors we will: (i) perform a comprehensive LOH analysis of all chromosomes arms at a resolution of approximately 10 cM, (ii) refine mapping of regions of significant LOH at a resolution of less than or qual to 2 cM, (iii) analyze candidate TSGs that resides within the refine map locations and (iv) clone potential tumor suppressor genes that reside in locations for which no known TSG candidates have been identified. The molecular genetic profiles will be correlated with the clinical records to assess the significance of the genetic changes on morbidity and mortality. These studies will offer one of the first comprehensive analyses of LOH in any well defined tumor population that can be reconciled with the clinical record and will provide detailed insight into the pathogenesis of thyroid cancer.

甲状腺恶性肿瘤是最常见的内分泌癌在美国，每年> 17,000例新病例和1,200例癌症死亡（70-95％）这些肿瘤是卵泡的主要甲状腺癌细胞起源，包括分化的乳头（PTC）和滤泡（FTC）和未分化的甲状腺癌。在美国发病率是PTC> ftc >>肿瘤癌，而与这些癌症相关的发病率/死亡率是变性的癌>> FTC> PTC。良性卵泡进展的证据已经观察到腺瘤（FA）> FTC，而PTC似乎出现DE Novo。虽然许多研究试图定义分子分化甲状腺癌的遗传学，几乎所有这些研究缺乏大量标本数量，病理标准不足，或两者兼而有之。我们已经表现出广泛的染色体3P上杂合性（LOH）经常丧失的证据， FTC中的10q，13q和17p，而不是FA或PTC，表明肿瘤抑制基因（TSG）可能与FTC的起源有关。已知染色体3p（VHL和FHIT）上LOH区域附近的TSG映射，并且 17p（p53）似乎不涉及，因为这些突变序列在FTC中很少见。因此，尚未定义的TSG似乎是参与FTC的起源。在当前的研究中，我们将执行细节的至少30种标本/肿瘤类型的分子遗传研究甲状腺癌的定义明确和分层的人群提供广泛的临床记录。肿瘤类型将包括PTC （1,2和3年级），FTC（微创和广泛侵入性，氧气和非氧气癌）和FA。在这一肿瘤中我们威尔：（i）对所有染色体臂进行全面的LOH分析在大约10厘米的分辨率下，（ii）区域的完善映射在小于或质量至2厘米的分辨率下的明显LOH，（iii）分析位于精炼地图位置内的候选TSG和（iv）驻留在位置的克隆潜在抑制肿瘤基因尚未确定已知的TSG候选者。分子遗传特征将与临床记录相关以评估遗传变化对发病率和死亡率的重要性。这些研究将提供LOH的首次全面分析之一在任何明确的肿瘤种群中，可以与临床记录，并将提供有关发病机理的详细见解甲状腺癌。