Defining the Germline Genomic Landscape of a Novel GIST Multi-tumor Syndrome

定义新型胃肠道间质瘤多肿瘤综合征的种系基因组景观

• 批准号: 9025331
• 负责人: Jason Keith Sicklick
• 金额: $ 18.45万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-04 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9025331
• 关键词: Accounting; Age-Years; BRAF gene; Benign; Biological Markers; Carcinoid Tumor; Cells; Childhood; Clinic; Clinical; Colorectal; Colorectal Cancer; DNA; DNA Repair; DNA Repair Gene; DNA Sequence Alteration; Data; Demographic Analyses; Development; Dideoxy Chain Termination DNA Sequencing; Disease; Epidemiology; Esophageal; Family; Family history of; Fanconi' s Anemia; Gastrointestinal Stromal Tumors; Gene Family; Gene Mutation; Genes; Genetic Counseling; Genetic Screening; Genomics; Germ-Line Mutation; Goals; Hepatobiliary; Hereditary Breast and Ovarian Cancer Syndrome; Hereditary Neoplastic Syndromes; Hereditary Nonpolyposis Colorectal Neoplasms; Incidence; Individual; Inherited; Lead; Link; Lung; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Molecular; Mutate; Mutation; Neurofibromatosis Type 1 Protein; Neurosecretory Systems; Non-Hodgkin' s Lymphoma; Non-Small-Cell Lung Carcinoma; Organ; Outcome; PDGFRB gene; Pancreas; Pathway interactions; Patients; Peer Review; Phenotype; Platelet-Derived Growth Factor alpha Receptor; Predisposition; Prevalence; Prevention strategy; Prostate; Proteolysis; Recommendation; Renal Cell Carcinoma; Research; Risk; Screening for cancer; Somatic Mutation; Succinate Dehydrogenase; Syndrome; Testing; Time; Tissues; Tumor Suppression; Tumor Suppressor Genes; Ubiquitin; Ubiquitination; United States; Variant; Von Hippel-Lindau Syndrome; base; cancer therapy; cohort; demographics; epidemiologic data; exome; exome sequencing; genetic variant; genomic data; hepatobiliary cancer; melanoma; multicatalytic endopeptidase complex; next generation sequencing; novel; patient population; protein degradation; public health relevance; sarcoma; screening; tumor; tumorigenic

 DESCRIPTION (provided by applicant): Gastrointestinal Stromal Tumor (GIST) is the most common sarcoma in the U.S. Sporadic GIST is often caused by somatic mutations in KIT, PDGFR, or BRAF genes, while hereditary GIST syndromes are caused by germline KIT, NF-1, or succinate dehydrogenase (SDH) mutations. Our epidemiologic data under peer review suggests that 17.1% of "sporadic" GIST patients develop ≥1 additional malignancies not associated with familial GIST syndromes, including Non-Hodgkin's lymphoma, carcinoid tumors, and melanoma, as well as colorectal, esophageal, pancreatic, hepatobiliary, non-small cell lung, prostate, and renal cell cancers. This raises the question as to whether a subset of "sporadic" GIST patients have an unacknowledged multi-tumor syndrome(s) caused by yet to be determined heritable genomic alteration(s). We hypothesize the existence of GIST multiple tumor syndrome(s) (GMTS) with distinct tumor phenotype(s) from those previously identified in known familial GIST syndromes that result from the inheritance of one or more deleterious germline mutation(s). Our overall objective is to determine the heritable genomic cause(s) that may lead to the concomitant development of GIST and additional malignancies that we have identified as having higher incidences/prevalence within the GIST patient population. In Aim 1, we will sequence the germline whole exome of 50 unrelated individuals with "sporadic" GIST and one or more additional malignancies. We will select: 1) ≥10 patients with at least two additional malignancies; 2) 10 patients that are 40-50 years of age with one or more additional malignancies; and 3) patients with a strong family history of cancer with one or more additional malignancies. Next generation sequencing and variant selection will be performed in order to characterize the genomic germline landscape of these patients. We will then perform Sanger sequencing in order to validate any critical/pathogenic mutations identified by whole exome sequencing. Once we have identified a set of critical mutations/genes/pathways, we will perform focused, independent Sanger sequencing in the germline DNA of a cohort of sporadic GIST patients without GMTS (N=50) in order to validate our findings as unique to GMTS patients. In Aim 2, we will sequence these patients' respective GIST for somatic KIT, PDGFRα, and BRAF mutations in order to determine if one or more somatic mutations are unique in this patient population or correlate with germline genomic findings, and therefore may serve as a potential somatic biomarker of GMTS in "sporadic" GIST patients. Concomitant with these analyses, we will analyze the demographics and tumor-specific details for each patient studied. If germline mutations are identified as putative disease drivers, our proposal has the potential for rapid translational application to the clinic as the characterization of novel hereditary cancer syndrome(s) would have implications for: 1) altered cancer screening recommendations; 2) prevention strategies; 3) familial genetic counseling and screening; and 4) developing anti-cancer therapies against unappreciated targets in these diseases.

 描述(申请人提供)：胃肠道间质瘤是美国最常见的肉瘤。散发性胃肠道间质瘤通常由KIT、PDGFFR或BRAF基因的体细胞突变引起，而遗传性GIST综合征则由生殖系KIT、核因子-1或琥珀酸脱氢酶突变引起。我们同行评审的流行病学数据显示，17.1%的“散发性”胃肠道间质瘤患者会患上与家族性胃肠道间质瘤综合征无关的≥-1其他恶性肿瘤，包括非霍奇金淋巴瘤、类癌和黑色素瘤，以及结直肠癌、食道癌、胰腺癌、肝胆癌、非小细胞肺癌、前列腺癌和肾癌。这就提出了这样一个问题：是否有一部分“散发性”胃肠道间质瘤患者患有不明原因的多肿瘤综合征(S)，这是由尚未确定的可遗传基因组改变(S)引起的。我们假设存在具有不同肿瘤表型的胃肠道间质瘤多发性肿瘤综合征(S)(GMT)，这些肿瘤表型不同于已知的家族性胃肠道间质瘤综合征，这些综合征是由一个或多个有害的生殖系突变(S)遗传引起的。我们的总体目标是确定可能导致胃肠道间质瘤和其他我们已确定的在胃肠道间质瘤患者中有较高发病率/患病率的其他恶性肿瘤伴发的可遗传基因组原因(S)。在目标1中，我们将对50名患有散发性GIST和另外一种或多种恶性肿瘤的无关个体的生殖系完整外显子进行测序。我们将选择：1)10名至少有两种额外恶性肿瘤的≥患者；2)10名年龄在40-50岁之间、有一种或多种额外恶性肿瘤的患者；以及3)有很强癌症家族史的患者，有一种或多种额外恶性肿瘤。将进行下一代测序和变异体选择，以表征这些患者的基因组胚系图景。然后，我们将进行Sanger测序，以验证通过整个外显子组测序确定的任何关键/致病突变。一旦我们确定了一组关键的突变/基因/途径，我们将在一组没有GMTS的零星GIST患者(N=50)的种系DNA中进行有针对性的独立Sanger测序，以验证我们的发现是GMTS患者所独有的。在目标2中，我们将对这些患者各自的GIST进行体细胞试剂盒、PDGFRα和BRAF突变的测序，以确定一个或多个体细胞突变是否在该患者群体中是独一无二的，或与生殖系基因组发现相关，因此可能成为“散发性”GIST患者GMT的潜在体细胞生物标记物。伴随着这些分析，我们将分析每个被研究患者的人口统计学和肿瘤特异性细节。如果胚系突变被确定为可能的致病因素，我们的建议将有可能迅速翻译应用于临床，因为新型遗传性癌症综合征(S)的特征将影响：1)改变癌症筛查建议；2)预防策略；3)家族遗传咨询和筛查；以及4)针对这些疾病中未被认识到的靶点开发抗癌治疗。