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

 描述（由申请人提供）：胃肠道间质瘤（GIST）是美国最常见的肉瘤。散发性GIST通常由KIT、PDGFR β或BRAF基因的体细胞突变引起，而遗传性GIST综合征由生殖系KIT、NF-1或琥珀酸脱氢酶（SDH）突变引起。我们的同行评议流行病学数据表明，17.1%的“散发性”GIST患者发生≥1种与家族性GIST综合征无关的其他恶性肿瘤，包括非霍奇金淋巴瘤、类癌和黑色素瘤，以及结直肠癌、食管癌、胰腺癌、肝胆癌、非小细胞肺癌、前列腺癌和肾细胞癌。这就提出了一个问题，即一个“散发性”GIST患者子集是否具有由尚未确定的遗传性基因组改变引起的未确认的多肿瘤综合征。我们假设存在GIST多发性肿瘤综合征（GMTS），其肿瘤表型与先前在已知家族性GIST综合征中鉴定的肿瘤表型不同，这些家族性GIST综合征由一种或多种有害生殖系突变遗传引起。我们的总体目标是确定可能导致GIST和我们已确定在GIST患者人群中具有较高发生率/患病率的其他恶性肿瘤伴随发展的遗传基因组原因。在目标1中，我们将对50个患有“散发性”GIST和一种或多种其他恶性肿瘤的无关个体的生殖系全外显子组进行测序。我们将选择：1）≥10例患者至少有两种其他恶性肿瘤; 2）10例患者年龄在40-50岁之间，有一种或多种其他恶性肿瘤; 3）患者有很强的癌症家族史，有一种或多种其他恶性肿瘤。将进行下一代测序和变体选择，以表征这些患者的基因组种系景观。然后我们将进行桑格测序，以验证通过全外显子组测序鉴定的任何关键/致病突变。一旦我们确定了一组关键突变/基因/途径，我们将在一组无GMTS的散发性GIST患者（N=50）的生殖系DNA中进行集中的独立桑格测序，以验证我们的发现是GMTS患者独有的。在目标2中，我们将对这些患者各自的GIST进行体细胞KIT、PDGFRα和BRAF突变测序，以确定一种或多种体细胞突变在该患者人群中是否独特或与生殖系基因组结果相关，因此可能作为“散发性”GIST患者中GMTS的潜在体细胞生物标志物。伴随这些分析，我们将分析每例研究患者的人口统计学和肿瘤特异性详情。如果生殖系突变被鉴定为推定的疾病驱动因素，我们的建议具有快速转化应用于临床的潜力，因为新型遗传性癌症综合征的表征将对以下方面产生影响：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重视的靶点开发抗癌疗法。

 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.