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。这些研究往往是长期的，有不同的活动。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继续；与国际联盟（GenoMEL）合作，继续在家族和全基因组关联研究中寻找新的黑色素瘤易感基因。在美国黑色素瘤易发家族中，我们评估了来自28个家族（19个CDKN2A+和9个CDKN2A -）的537个个体中152个涉及DNA修复、细胞凋亡和免疫反应途径的基因中的1536个snp，试图识别潜在的修饰基因。我们发现CDKN2A +和-家族存在一些差异；几个候选基因在基因检测中表现显著；在对多个比较进行校正后，IL9是显著的，可能是一个候选修饰因子。我们还研究了另外两个感兴趣的候选基因，1p336中的CHD5和9p23-24.1中的PTPRD作为主要易感基因；这两个家庭都没有遗传突变。我们继续在美国和意大利积累和评估新的家庭。我们继续评估遗传性视网膜母细胞瘤和黑色素瘤个体的家庭。<BR><BR><BR><BR>家族性脊索瘤是一种罕见的、低级别的、起源于脊索残余的恶性骨肿瘤，目前对家族性脊索瘤的研究已扩展到其他家族。去年，随着连锁分析显示在不同染色体区域存在连锁的证据，我们对该区域的基因进行了广泛的研究。分析正在进行中。<BR><BR><BR><BR>研究淋巴增生性肿瘤的家族一直是人们长期关注的问题。我们使用与黑色素瘤研究相同的Illumina定制平台，其中包含152个基因的1536个snp，以评估165例无血缘关系的CLL、Waldenstrom巨球蛋白血症（WM）或霍奇金淋巴瘤（HL）家族病例和107例配偶对照的基因和途径。我们发现IL10启动子多态性与CLL和WM相关，IL6变异与HL相关。我们还与校外研究人员合作，评估了一个具有破坏KLHDC8B的互惠易位的大家庭。然后，我们在其他家族中测试了KLHDC8B作为候选基因，发现5' UTR多态性与其他家族的HL相关，与疾病共分离，并且在一例Reed Sternberg细胞中存在LOH。此外，通过RNA干扰使KLHDC8B缺失导致双核细胞。<BR><BR><BR><BR>我们继续与泌尿外科肿瘤科合作，对肾癌家庭进行评估。在北美遗传平滑肌瘤病和肾细胞癌（HLRCC）的富马酸水合酶突变家族中，我们评估了子宫平滑肌瘤的危险因素。这些家庭的女性在30岁前因多发性子宫平滑肌瘤进行子宫切除术的比例很高。患有HLRCC或FH突变的个体发生平滑肌瘤的风险要高得多。我们还与CCR研究人员合作，继续对着色性干皮病进行家族研究，以评估XP杂合子的癌症风险。数据收集正在进行中。我们也有文献记载，与未受影响的孩子相比，携带患病儿童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 the American melanoma-prone families, we evaluated 1536 SNPs in 152 genes involved in DNA repair, apoptosis, and immune response pathways among 537 individuals from 28 families (19 CDKN2A+ and 9 CDKN2A -) to try to identify potential modifier genes. We found some differences in CDKN2A + and - families; several candidate genes appeared significant in gene-based tests; IL9 was significant after correction for multiple comparisone and may be of interest as a candidate modifier. We also investigated two other candidate genes of interest, CHD5 in 1p336 and PTPRD in 9p23-24.1 as major susceptibility genes; neither had inherited mutations in these families. We continue to accrue and evaluate new families in both the U.S and Italy. We have continued to evaluate families of individuals with heritable retinoblastoma and melanoma.<BR><BR><BR><BR> 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 linkage analyses showing evidence of linkage in a different chromosomal area last year, we have extensively investigated genes in the region. Analyses are ongoing.<BR><BR><BR><BR> Studying families with lymphoproliferative cancers has been a long-standing interest. We used the same Illumina custom platform of 1536 SNPs in 152 genes as in the melanoma study to evaluate the genes and pathways among 165 unrelated familial cases with CLL, Waldenstrom macroglobulinemia (WM), or Hodgkin lymphoma (HL) and 107 spouse controls. We found that a polymorphism in IL10 promoter was associated with both CLL and WM and vairations in IL6 were associated with HL. We also collaborated with extramural investigators in evaluating one of our large families with a reciprocal translocation that disrupts KLHDC8B. We then tested KLHDC8B as a condidate gene in other families and found that a 5' UTR polymorphism is associated with HL in other families, cosegregates with disease, and had LOH in Reed Sternberg cells from one case. In addition, depletion of KLHDC8B by RNA interference led to binucleated cells. <BR><BR><BR><BR> 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.