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.
