Family Studies

大多数遗传流行病学分支调查评估宿主易感性和环境暴露在癌症发生中的作用。在家族性研究中，宿主的易感性指标通常是特定基因的改变(S)。虽然已经发现了两个与黑色素瘤易感性相关的基因(CDKN2A和CDK4)，但在黑色素瘤易感家族中只有一小部分发现了这些基因的变化。与一个国际财团合作，继续寻找其他基因。为了进一步探索黑色素瘤与我们家族子集中1p36上的标记之间的联系，我们对候选基因CDC2L1的突变和多态进行了评估。在一种黑色素瘤细胞系中发现了一种突变。在家族成员之间和黑色素瘤细胞系中发现了启动子区域的四个多态。我们还评估了具有CDKN2A突变、CDK4突变和未发现突变(CDKN2A或CDK4)的个体的黑素细胞损伤。在这些个体中，黑色素瘤或发育不良痣的临床或组织学特征没有实质性差异。总体而言，在这些家系中发生的预期黑色素瘤的分期没有明显的差异。对意大利黑色素瘤家族的基因分析仍在继续。一项试验性研究正在进行中，以评估新的意大利黑色素瘤倾向家庭的收益。家族性脊索瘤是一种罕见的、低级别的恶性骨肿瘤，来源于脊索残留物，研究范围扩大到包括两个新的家系。基于这些家系，多点分析仅显示标记D7S500的最大LOD得分为4.78，标记D7S512至标记D7S684的2-LOD支持区间。鉴定该基因的尝试仍在继续。对淋巴增殖性癌症家族的研究一直是人们的兴趣所在。我们描述了CLL的家系，评估的候选基因(如ATM)，潜在的易感标记(如端粒酶)，预期(家族性病例的早期发病)以及在家族背景下的关键预后因素(CD38和VH基因突变状态)。最近，我们对合适的CLL家系进行了连锁分析。我们正在主办一个国际会议，以建立一个研究家族性CLL的联盟。我们计划与其他主要群体合作，扩大联系研究。一项关于Waldenstrom巨球蛋白血症的新研究也已启动，目前正处于现场阶段。非霍奇金淋巴瘤家族已经重新启动，并正在考虑发展另一个新的联盟。

Most Genetic Epidemiology Branch investigations evaluate the contributions of host susceptibility and environmental exposure in the development of cancer. In family studies, the host susceptibility measure is frequently an alteration in specific gene(s). Although two genes associated with melanoma susceptibility have been identified (CDKN2A and CDK4), alterations in these genes are found in only a small percentage of melanoma-prone families. The search for other genes continues in collaboration with an international consortium. To further pursue a preliminary finding of linkage between melanoma and markers on 1p36 within a subset of our families, mutations and polymorphisms in a candidate gene, CDC2L1 were evaluated. One mutation was found in a melanoma cell line. Four polymorphisms in the promoter region were found among family members and within melanoma cell lines. We also evaluated melanocytic lesions among individuals with CDKN2A mutations, CDK4 mutations, and no identified mutations (in CDKN2A or CDK4). There were no substantive differences in the clinical or histologic features of melanomas or dysplastic nevi among these individuals. Overall, there was no apparent difference in the stage of prospective melanomas occuring in these families. Genetic analyses of Italian melanoma families continue. A pilot study is underway to assess the accrual of new Italian melanoma-prone families. The study of familial chordoma, a rare, low-grade, malignant bone tumor derived from remnants of the notochord, was expanded to include two new families. Based on these families, multipoint analyses of affecteds only revealed a maximum LOD score of 4.78 at marker D7S500, with a 2-LOD support interval from marker D7S512 to marker D7S684. Attempts to identify the gene continue. Studying families with lymphoproliferative cancers has been a long-standing interest. We have described CLL kindreds, evaluated candidate genes (i.e. ATM), potential susceptibility markers (i.e. telomerase), anticipation (early onset of disease in familial cases) and a key prognostic factor in the familial setting (CD38 and Vh gene mutation status). Most recently we have conducted a linkage analysis on suitable CLL kindreds. We are hosting an international meeting to develop a consortium to study familial CLL. We plan to expand the linkage study in cooperation with other major groups. A new study of Waldenstrom's macroglobulinemia was also initiated and is currently in the field phase. The non-Hodgkin's lymphoma families have been reactivated, and the development of another new consortium is being contemplated.