Epidemiology of Syndromic GI Stromal Tumors

描述（由申请人提供）：胃肠道间质瘤（GIST）是间质的隐匿性肿瘤，目前占所有软组织肉瘤的5%。在转化科学取得胜利之后，GIST被认为是一个特定的实体，其中靶向其主要分子缺陷的治疗变得可用，并推动基础科学表征肿瘤，不仅允许预测活性和抗性，而且还开发了第二种成功的药物，所有这些都在不到十年的时间内（7）。胃肠道间质瘤是卡哈尔间质细胞的肿瘤，通常由KIT原癌基因特定外显子的功能获得性突变驱动，由甲磺酸伊马替尼药物靶向（8）。随着肿瘤被识别出来，积极的项目开始注意到有家族史的患者的出现，这些家族史暗示了家族综合征。我们的研究小组报告了其中两种激酶，并认识到可以测试在KIT或PDGFRA基因中携带生殖系突变的GIST患者的家庭成员（1，2）。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其与生殖系状态相关的GIST肿瘤风险，可能是综合征一部分的其他肿瘤谱，或这些基因中生殖系突变的良性表现的程度和性质。在按照实地标准进行基因检测之前，这些信息至关重要。在这个修订后的申请中，我们建议从两个活跃的肉瘤诊所招募GIST患者，完成风险因素问卷调查，并允许病历审查。第二组志愿者将响应在活跃的GIST支持网站上的研究通知。受试者将向遗传咨询师提供家族史信息，并可能提供用于KIT和PDGFRA基因分子分析的DNA。那些有足够的个人或家族史表明可能存在综合征的人将对他们的标本进行分析。使用符合HIPAA的程序，我们还将邀请这些受试者的亲属参加研究，组成一个队列，在其中从临床和分子水平表征家族性和遗传性GIST综合征。我们的目标是确定综合征性GIST的谱，并产生将形成GIST激酶成员临床咨询的基础的信息，有和没有KIT或PDGFRA的生殖系突变。

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.