Family Studies

大多数遗传流行病学分部的调查评估宿主易感性和环境暴露在癌症发展中的作用。在家庭研究中，宿主的易感性测量通常是特定基因的改变。虽然已经确定了两个与黑色素瘤易感性相关的基因（CDKN2A和CDK4），但这些基因的改变仅在一小部分易患黑色素瘤的家族中被发现。对其他基因的研究仍在与一个国际财团合作进行。该联盟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。对来自法国、意大利和美国的20个家庭进行了单倍型分析，确定Gly101trp突变可能来自大约97代以前的一个祖先。在一项联合研究中，对48个黑色素瘤高危家族进行了候选易感基因p19 INK4D的种系突变筛查。虽然未发现突变，但鉴于其染色体易位位置，p19 INK4D可能是一个罕见的易感基因。对20个意大利黑色素瘤易发家族的临床评估显示，这些家族主要是深色肤色，其临床特征与白皮肤人群相似。在这些家族中，发育不良的痣和黑色素瘤之间存在很强的相关性。对这20个黑色素瘤易发家族的分子检查显示，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。对NF2家族成员脊柱肿瘤的影像学和临床资料的回顾表明，髓内肿瘤的发病率低于神经鞘肿瘤或脑膜瘤。NF2基因型影响脊柱肿瘤表型：无义突变或移码突变患者髓内肿瘤的比例较高，这些肿瘤和神经鞘肿瘤的平均数量高于其他类型突变的患者。家族性脊索瘤是一种罕见的、低级别的、源自脊索残余的恶性骨肿瘤，其研究范围扩大到包括通过SEER系统识别的脊索瘤患者。已经确定了三个新的家庭，正在进行评估。定位该基因的努力仍在继续。慢性淋巴细胞白血病的研究也通过通讯和网站得到了扩展。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表达表征、细胞表面标记分析、肿瘤细胞端粒酶活性表征以及表达的免疫球蛋白重链分析。一项关于华登斯特罗姆巨球蛋白血症的新研究也开始了。

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.