Genetic Alterations in Families with Multiple Lymphomas

描述（由申请人提供）：非霍奇金淋巴瘤（nhl）是美国第五大最常见的恶性肿瘤，其发病率在过去十年中显著增加。来自DFCI成人淋巴瘤诊所以及哈佛联合放射治疗中心（JCRT）治疗的霍奇金淋巴瘤患者的初步数据显示，这些患者中有6-9%的一级亲属也患有淋巴增生性疾病。本研究计划的目标是系统地识别和表征与明显家族易感性相关的淋巴瘤亚群，并确定其遗传基础是否可以识别。本项目的具体目的是：(1)确定至少有两个一级亲属患有淋巴增生性恶性肿瘤的家庭，建立包括血清、外周血淋巴细胞、种系DMA和肿瘤组织在内的数据和组织库；(2)研究家族性淋巴瘤是否具有典型的杂合性缺失位点，并试图在这些区域内鉴定候选基因；(3)研究家族性淋巴瘤是否具有全局基因表达的特征性模式；(4)进行连锁分析，以确定生殖系中可能易导致淋巴瘤发展的候选基因。这些新颖的实验应该阐明家族性淋巴瘤的生物学基础，这应该反过来导致靶向治疗和可能的筛选或预防方法。该项目将使候选人能够利用其在分子生物学方面的科学训练，在淋巴瘤的临床/转化研究方面发展学术生涯，将新的科学发现应用于临床。该研究将主要在丹娜-法伯癌症研究所和哈佛医学院进行，那里有广泛的临床、科学和教师资源，可以确保项目的完成。

DESCRIPTION (provided by applicant): Non-Hodgkin's lymphomas (NHLs) are the 5th most common malignancy in the United States, with an incidence that has increased significantly over the last decade. Preliminary data obtained from Adult Lymphoma clinic at DFCI, as well as from Hodgkin's lymphoma patients treated at the Harvard Joint Center for Radiation Therapy (JCRT), show that 6-9% of these patients have a first-degree relative who also has a lymphoproliferative disorder. The goals of this research proposal are to systematically identify and characterize the subset of lymphomas associated with apparent familial predisposition and to determine whether their genetic basis can be identified. The Specific Aims of this project are: (1) to identify families with at least two first-degree relatives with lymphoproliferative malignancy and establish a data and tissue bank including serum, peripheral blood lymphocytes, germline DMA, and tumor tissue; (2) to investigate whether familial lymphomas have characteristic sites of loss of heterozygosity and to attempt to identify candidate genes within those regions; (3) to investigate whether familial lymphomas have characteristic patterns of global gene expression; (4) to perform a linkage analysis to identify candidate genes in the germline that may predispose to lymphoma development. These novel experiments should illuminate the biological underpinnings of familial lymphoma, which should in turn lead to targeted therapies and possibly methods of screening or prevention. This project will enable the candidate to use her scientific training in molecular biology to develop an academic career in clinical / translational investigation in lymphoma, applying novel scientific discoveries to the clinic. The research will be conducted primarily at Dana-Farber Cancer Institute and Harvard Medical School, where extensive clinical, scientific and faculty resources are available to ensure the completion of the project.