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。该联盟内的其他研究包括确定CDKN2A突变家族中黑色素瘤的外显率。将对高风险国家和低风险国家的外显率进行比较。一项国际合作研究确定了最常见的CDKN2A突变Gly101Trp的起源。来自法国、意大利和美国的20个家庭进行了单倍型分析，以确定Gly101trp突变可能是大约97代前的单一祖先造成的。在一项联合研究中，对48个黑色素瘤高危家庭进行了候选易感基因p19INK4D的胚系突变筛查。虽然没有发现突变，但考虑到其染色体上的易位位置，p19INK4D可能是一种罕见的易感基因。对20个以深色皮肤为主的意大利黑色素瘤倾向家系的临床评估表明，临床特征与在白皮肤人群中观察到的相似。在这些家系中，发育不良的痣与黑色素瘤有很强的相关性。对这20个黑色素瘤易感家系的分子检测显示，没有编码区CDKN2A或CDK4突变，这表明其他基因可能与这一低风险人群有关。回顾NF2家族成员脊柱肿瘤的放射学和临床资料表明，与神经鞘肿瘤或脑膜瘤相比，髓内肿瘤的发病率较低。NF2基因影响脊柱肿瘤表型：与其他类型突变的患者相比，无义或移码突变患者的髓内肿瘤比例更高，这些肿瘤和神经鞘肿瘤的平均数量也更高。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通过SEER系统确诊的脊索瘤患者。已经确定了三个新的家庭，并正在进行评估。对该基因进行定位的尝试仍在继续。慢性淋巴细胞性白血病的研究也通过使用时事通讯和网站得到扩大。对易感基因的全基因组搜索正在进行中。其他实验室研究包括候选基因座的蛋白质表达特征、细胞表面标记分析、肿瘤细胞中端粒酶活性的特征以及表达的免疫球蛋白重链的分析。还启动了一项关于Waldenstrom巨球蛋白血症的新研究。

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. Other studies within the consortium include a determination of the penetrance of melanoma in families with CDKN2A mutations. Comparison of penetrance in high-risk and low-risk countries will be made. An international collaborative study determined the origin of the most common CDKN2A mutation Gly101Trp. Twenty families from France, Italy, and the United States were haplotyped to determine that the Gly101trp mutation probably resulted from a single ancestor approximately 97 generations ago. In a consortium study, 48 families at high risk of melanoma were screened for germline mutations in a candidate susceptibility gene p19 INK4D. Although no mutations were found, given its chromosomal location at a translocation site, p19 INK4D may be a rare susceptibility gene. Clinical evaluation of 20 Italian melanoma-prone families with predominantly dark complexions showed that clinical features were similar to those observed in fair skinned populations. There was a strong correlation between dysplastic nevi and melanoma in these families. Molecular examination of these 20 melanoma-prone families revealed no coding region CDKN2A or CDK4 mutations, suggesting that other genes are likely involved in this lower risk population. Review of radiologic and clinical data on spinal tumors in members of NF2 families suggested that intramedullary tumors were associated with less morbidity than nerve sheath tumors or meningiomas. NF2 genotype influenced spinal tumor phenotype: a higher percentage of patients with nonsense or frameshift mutations had intramedullary tumors as well as higher mean numbers of these and nerve sheath tumors than patients with other types of mutations. The study of familial chordoma, a rare, low-grade, malignant bone tumor derived from remnants of the notochord, was expanded to include individuals with chordoma identified through the SEER system. Three new families have been identified and are being evaluated. Attempts to localize the gene continue. The study of chronic lymphocytic leukemia was also expanded by use of a newsletter and a website. A genome-wide search for susceptibility genes is in progress. Other laboratory investigations include characterization of protein expression of candidate loci, cell surface marker analysis, characterization of telomerase activity in tumor cells, and analysis of expressed immunoglobulin heavy chains. A new study of Waldenstrom's macroglobulinemia was also initiated.