Epidemiology of Syndromic GI Stromal Tumors

描述（由申请人提供）：胃肠道间质瘤（gist）是一种不明显的间质肿瘤，目前占所有软组织肉瘤的5%。在转化科学取得胜利之后，GIST被认为是一种特殊的实体，在转化科学中，针对其主要分子缺陷的治疗方法成为可能，并推动了基础科学对肿瘤的表征，不仅允许预测活性和耐药性，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)。gist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，甲磺酸伊马替尼靶向(8)。随着肿瘤被发现，积极的程序开始注意到有家族综合症家族史的患者的出现。我们的研究小组报告了其中的两种类型，并认识到有可能检测GIST患者的家庭成员，这些患者可以携带KIT或PDGFRA基因的种系突变（1,2）。然而，我们也意识到，很少有信息可以提供未受影响的突变携带者估计他们患GIST肿瘤的风险与他们的种系状态有关，其他肿瘤的谱可能是综合征的一部分。或者这些基因中生殖系突变的良性表现的程度和性质。在进行符合该领域标准的基因检测之前，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，并允许医疗记录审查。第二组志愿者将响应活跃的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病史表明可能存在综合症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加入研究，组建一个队列，在临床和分子上表征家族性和遗传性GIST综合征。我们的目标是定义综合征型GIST的频谱，并生成信息，这些信息将形成GIST种类成员的临床咨询基础，无论是否存在KIT或PDGFRA的种系突变。

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.