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。在美国黑色素瘤易感家族中，我们评估了来自28个家族（19个CDKN 2A+和9个CDKN 2A-）的537个个体中涉及DNA修复、细胞凋亡和免疫应答途径的152个基因中的1536个SNP，以尝试识别潜在的修饰基因。我们发现CDKN 2A+和-家族中存在一些差异;几个候选基因在基于基因的测试中表现出显著性; IL 9在多次比较校正后具有显著性，可能是一种感兴趣的候选修饰剂。我们还研究了另外两个感兴趣的候选基因，1 p336中的CHD 5和9 p23 -24.1中的PTPRD作为主要易感基因;在这些家族中都没有遗传突变。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患者的家族。<BR><BR><BR><BR>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。去年的连锁分析显示，在不同的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>研究淋巴增生性癌症的家庭一直是一个长期的兴趣。我们使用了与黑色素瘤研究中相同的152个基因中1536个SNP的Illumina定制平台，以评估165例CLL，Waldenstrom巨球蛋白血症（WM）或霍奇金淋巴瘤（HL）和107例配偶对照的基因和途径。IL 10基因多态性与慢性淋巴细胞白血病和白血病相关，IL 6基因多态性与白血病相关。我们还与校外调查人员合作，评估了我们的一个大家庭，该家庭具有破坏KLHDC 8B的相互易位。然后我们在其他家系中检测了KLHDC 8B作为条件基因，发现5' UTR多态性与其他家系中的HL相关，与疾病共分离，并且在一个病例的Reed斯滕贝格细胞中存在洛。此外，通过RNA干扰耗尽KLHDC 8B导致双核细胞。<BR><BR><BR><BR>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 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.