Family Studies

大多数遗传流行病学分支研究评估宿主易感性和环境暴露在癌症发展中的作用。在家系研究中，宿主易感性的测量通常是特定基因的改变。这些研究往往是非常长期的，具有不同的活动。虽然已经确定了与黑色素瘤易感性相关的两个基因（CDKN 2A和CDK 4），但这些基因的改变仅在一小部分黑色素瘤易感家族中发现。对其他基因的研究仍在继续;与国际财团（GenoMEL）合作，在家族内和全基因组关联研究中继续寻找新的黑色素瘤易感基因。在一项方法学研究中，我们比较了使用变性高效液相色谱法检测CDKN 2A突变与GenoMEL九个不同中心的常规筛查。我们发现，各组的突变检测是一致的，质量很高。我们继续积累和评估新的家庭。来自Emilio Romagna地区的51个无CDKN 2a或CDK 4突变的意大利黑色素瘤家族的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族。 家族性脊索瘤是一种罕见的、低度恶性的骨肿瘤，起源于脊索的残余，其研究被扩大到包括其他家族。这些额外的家庭，连锁分析显示在不同的染色体区域的连锁证据。继续对两个鉴定的连锁区间中的候选基因进行测序。 研究淋巴增生性癌症的家庭一直是一个长期的兴趣。在两个consrotia之间的合作，我们已经进行了连锁分析206 CLL激酶，确定了几个感兴趣的领域进行进一步研究。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（NPL）评分。同一地区也显示出最高的多点异质性LOD得分，低于常见的隐性模式的可育性（HLOD = 3.11; p小于0.0001）。另外两个区域6p22.1（HLA区域）和18q21.1的HLOD评分高于2。 我们继续与泌尿肿瘤学分支合作，对肾癌家族进行评估。在北美的富马酸水合酶突变遗传性平滑肌瘤病和肾细胞癌（HLRCC）家族中，我们评估了子宫平滑肌瘤的危险因素。这些家庭中的妇女在30岁以前因多发性子宫肌瘤而行子宫切除术的比率较高。在临床上患有HLRCC或FH突变的个体中，发生平滑肌瘤的风险要高得多。我们还继续与CCR研究人员合作进行着色性干皮病的家族研究，以评估XP杂合子的癌症风险。数据收集正在进行中。我们还记录了携带患有毛发营养不良的儿童的母亲比携带未受影响的儿童时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.