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53个家族（23个CDKN 2A+和30个CDKN 2A-）的562名个体（183名黑色素瘤患者）中9 p21处21个基因中的233个标记SNP，以尝试识别其他基因。基于单核苷酸多态性和基因的回归分析用于评估与单核苷酸多态性和基因相关的黑色素瘤、痣计数、皮肤肤色和晒黑能力的风险。MTAP中的SNP rs7023329与痣的数量相关（P（趋势）= 0.003），证实了在遗传富集的黑色素瘤病例和对照中的全基因组关联研究的最新发现。此外，ACO 1中的3个SNP显示与黑色素瘤风险的最强关联（rs7855483 [P（趋势）= 0.002]; rs 17288067 [P（趋势）=0.0009]; rs 10813813 [p（趋势）= 0.005]）。基于基因的分析还表明，ACO 1与黑色素瘤显著相关（p=0.0004）。这些结果与9 p21中改变黑色素瘤风险的其他基因一致。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。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。与连锁分析显示在不同的染色体区域的连锁的证据，我们广泛调查该地区的基因。使用高分辨率阵列CGH，我们确定了独特的重复区域6 q27在四个多重家庭。该区域仅包含T（短尾畸形）基因，该基因在脊索发育中很重要，并且在大多数散发性脊索瘤中表达。这是第一个基因重复导致家族性癌症易感性的例子。研究淋巴增生性癌症的家庭一直是一个长期的兴趣。几年前，我们描述了CLL的潜在前驱病变，单克隆B细胞淋巴细胞增多症（MBL）。在一般人群中，MBL随着年龄的增长而增加，在60岁以上的个体中患病率为5-9%。我们对来自140个CLL多重家系的505名无淋巴组织增生性疾病个人史的一级亲属进行了多参数流式细胞术检测。17%的亲属患有MBL。年龄是最重要的决定因素，90岁时发生MBL的概率为61%。MBL在特定的家庭中聚集，但这种聚集与已知的CLL病例数无关。男性MBL的风险较高（p = 0.04），与CLL的男性优势相似。MBL患者的淋巴细胞计数和B细胞计数均高于正常亲属。 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 233 tagging SNPs in 21 genes at 9p21 among 562 individuals (183 melanoma pts) from 53 families (23 CDKN2A+ and 30 CDKN2A -) to try to identify additional genes. Single SNP- and gene-based regressions analyses were used to assess the risk of melanoma, nevus count, skin complexion, and tanning ability associated with the SNPs and genes. SNP rs7023329 in MTAP was associated with number of nevi (P(trend) = 0.003), confirming a recent finding by a genome-wide association study in genetically enriched melanoma cases and controls. In addition, 3 SNPs in ACO1 showed the strongest association with melanoma risk (rs7855483 [P(trend) = 0.002]; rs17288067 [P (trend) =0.0009]; rs10813813 [p (trend) = 0.005]). Gene-based analyses also demonstrated that ACO1 was significantly associated with melanoma (p=0.0004). These results are consistent with other genes in 9p21 modifying melanoma risk. 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. 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, we extensively investigated genes in the region. Using high resolution array-CGH, we identified unique duplications of a region on 6q27 in four multiplex families. This region only contains the the T (brachyury) gene, which is important in notocord development, and is expressed in most sporadic chordomas. This is the first example of gene duplication conferring major familial susceptibility to cancer. Studying families with lymphoproliferative cancers has been a long-standing interest. We described a potential precursor lesion for CLL, monoclonal B-cell lymphocytosis (MBL)several years ago. In the general population, MBL increases with age with a prevalence of 5-9% in individuals over age 60. We conducted multi-parameter flow cytometry among 505 first-degree relatives with no personal history of lymphoproliferative disorders from 140 multiplex families with CLL. Seventeen percent of relatives had MBL. Age was the most important determinant; the probablity of developing MBL by age 90 was 61%. MBL clustered in specific families, but this clustering was independent of the number of known cases of CLL. Males had a higher risk of MBL (p = 0.04), similar to the male predominance of CLL. MBL patients had higher lymphocyte counts, and higher B-cell counts than the normal relatives. 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.