Epidemiology of Syndromic GI Stromal Tumors

描述(申请人提供)：胃肠道间质瘤(GIST)是间充质的隐匿性肿瘤，目前占所有软组织肉瘤的5%。在翻译科学的胜利之后，GIST被认为是一个特定的实体，其中针对它们的主要分子缺陷的治疗方法变得可用，并推动了基础科学对肿瘤的特征描述，不仅允许预测活性和耐药性，而且还可以开发第二种成功的药物，所有这些都在不到十年的时间里(7)。医生是Cajal间质细胞的肿瘤，通常由KIT原癌基因特定外显子的功能获得突变驱动，以甲磺酸伊马替尼为靶点(8)。随着肿瘤的认识，积极的项目开始注意到有家族病史暗示有家族综合症的患者的出现。我们的小组报告了两个这样的家族，并认识到可以测试那些可以被证明携带KIT或PDGFRA基因(1，2)胚系突变的GIST患者的家庭成员。然而，我们也意识到，几乎没有信息可以提供未受影响的突变携带者估计他们与其胚系状态相关的GIST肿瘤的风险，可能是综合征一部分的其他肿瘤的谱，或这些基因中胚系突变的良性表现的范围和性质。在按照该领域的标准进行基因测试之前，这些信息是至关重要的。在这份修订后的申请中，我们建议从两家活跃的肉瘤诊所招募GIST患者，以完成风险因素问卷并允许审查病历。第二组志愿者将在活跃的GIST支持网站上回应这项研究的通知。受试者将向遗传咨询师提供家族史信息，并可能为试剂盒和PDGFRA基因的分子分析提供DNA。那些有足够的个人或家族病史表明可能存在综合症的人将对他们的样本进行分析。使用符合HIPAA的程序，我们还将邀请这些受试者的亲属参与研究，组建一个队列，从临床和分子角度描述家族性和遗传性GIST综合征的特征。我们的目标是定义症状性GIST的谱系，并产生将形成GIST家族成员临床咨询基础的信息，无论KIT或PDGFRA有或没有胚系突变。

DESCRIPTION (provided by applicant): Gastrointestinal stromal tumors (GISTs) were obscure tumors of the mesenchyma that now comprise 5% of all soft tissue sarcomas. GIST was recognized as a specific entity after a triumph of translational science in which a therapy targeting their major molecular defects became available, and drove the basic science to characterize the tumors and permit not only prediction of activity and resistance, but also the development of a second successful agent, all within less than a decade(7). GISTs are neoplasms of the interstitial cells of Cajal often driven by a gain-of-function mutation in specific exons of the KIT proto-oncogene, targeted by the agent imatinib mesylate(8). As the tumors became recognized, active programs began to note the appearance of patients with family histories suggestive of a familial syndrome. Our groups reported two of these kindreds, and recognized that it is possible to test family members of patients with GIST who can be shown to carry germline mutations in the KIT or PDGFRA genes (1,2) However, we also realized that there was little information with which to provide unaffected mutation carriers estimates of their risks of GIST tumors associated with their germline status, the spectrum of other neoplasms that might be part of a syndrome, or the extent and nature of benign manifestations of germline mutations in these genes. Such information is critical before genetic testing should be undertaken, consistent with standards in the field. In this revised application, we propose to recruit patients with GISTs from two active sarcoma clinics to complete a risk-factor questionnaire and permit medical records review. A second group will volunteer in response to notice of the study on active GIST support websites. Subjects will provide family history information to genetic counselors, and may provide DNA for molecular analysis of the KIT and PDGFRA genes. Those with sufficient personal or family history suggesting the potential presence of a syndrome will have their specimens analyzed. Using HIPAA compliant procedures, we will also invite relatives of these subjects into the study, assembling a cohort in which to characterize familial and hereditary GIST syndromes both clinically and molecularly. Our goal is to define the spectrum of syndromic GISTs, and to generate the information that will form the basis for clinical counseling for members of GIST kindreds, with and without germline mutations in KIT or PDGFRA.