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)。这些研究往往是非常长期的，活动各不相同。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。对其他基因的搜索仍在继续；与一个国际联盟(GenMEL)合作，继续在家族内和全基因组关联研究中寻找新的黑色素瘤易感基因。在一项方法学研究中，我们比较了变性高效液相色谱检测CDKN2A突变的方法和通常在GenMEL中进行的九个不同中心的筛查。我们发现，跨组的突变检测是一致的，而且质量很高。我们继续积累和评估新的家庭。对来自埃米利奥罗马尼亚地区的51个没有CDKN2A或CDK4突变的意大利黑色素瘤家族进行全基因组连锁分析，没有发现显著的连锁证据。我们继续评估遗传性视网膜母细胞瘤和黑色素瘤患者的家庭。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更多的家族。对于这些额外的家系，连锁分析显示有证据表明在不同的染色体区域存在连锁。继续对两个已识别的连锁区间中的候选基因进行测序。对淋巴增殖性癌症家族的研究一直是人们的兴趣所在。在两个联盟的合作下，我们对206个CLL家系进行了连锁分析，确定了几个值得进一步研究的领域。我们在染色体2q21.2上获得了3.02(p=0.001)的最大非参数连锁。同一地区在感病的一般隐性模式下也表现出最高的多点异质性LOD值(HLOD值=3.11；p<0.0001)。另外两个区域6p22.1(人类白细胞抗原区域)和18q21.1的HLOD评分高于2。我们继续与泌尿外科肿瘤科合作评估肾癌家族。在北美患有遗传性子宫肌瘤病和肾癌(HLRCC)的富马酸水合酶突变家族中，我们评估了子宫肌瘤的危险因素。这些家庭中的女性在30岁之前因多发性子宫肌瘤而接受子宫切除术的比率很高。无论是临床上感染HLRCC的个体，还是FH基因突变的个体，发生肌瘤的风险都要高得多。我们还与CCR研究人员合作，继续了一项关于着色性干皮病的家族研究，以评估XP杂合子的癌症风险。数据收集工作正在进行中。我们还记录了，怀孕患有三甲营养不良的孩子的母亲比怀上未受影响的孩子的母亲有更多的妊娠并发症。

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). These studies tend to be very long term with varying activity. 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 (GenoMEL), a search for a new melanoma susceptibility genes continues both within families and a genome-wide association study. In a methodologic study, we compared CDKN2A mutation detection using denaturing high performance liquid chromatography to usual screening acorss nine different centers in GenoMEL. We found that mutation detection across the groups was consistent and of high quality. We continue to accrue and evaluate new families. Genome-wide linkage analyses of 51 Italian melanoma families from the Emilio Romagna area without CDKN2a or CDK4 mutations have found no significant evidence of linkage. We have continued to evaluate families of individuals with heritable retinoblastoma and melanoma. The study of familial chordoma, a rare, low-grade, malignant bone tumor derived from remnants of the notochord, was expanded to include additional families. With these additional families, linkage analyses showed evidence of linkage in a different chromosomal area. Sequencing of candidate genes in the both identified linkage intervals continues. Studying families with lymphoproliferative cancers has been a long-standing interest. In a collaboration between two consrotia, we have conducted a linkage analysis on 206 CLL kindreds which identified several areas of interest for further study. We obtained a maximal nonparametric linkage (NPL) score of 3.02 (p=0.001) on chromosome 2q21.2. The same area also showed the highest multipoint hetergeneity LOD score uncer a common recessive modal of susceptibilit (HLOD = 3.11; p less than 0.0001). Two other areas 6p22.1 (HLA region) and 18q21.1 had HLOD scores above 2. We have continued working with the Urologic Oncology Branch in the evaluation of families with renal cancers. In families with fumarate hydratase mutations with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) in North America, we evaluated the risk factors for uterine leiomyomas. Women in these families had high rates of hysterectomy before age 30 for multiple uterine leiomyomas. Risk of developing leiomyomas was much higher in individuals either clinically affected with HLRCC or with mutations in FH. We also continued a family study of Xeroderma pigmentosum in collaboration with CCR investigators to assess risk of cancer in XP heterozygotes. Data collection is underway. We have also documented that mothers carrying affected children with tricothiodystrophy have more pregnancy complications than when carrying unaffected children.