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，我们在53个家族（23个CDKN2A+和30个CDKN2A -）的562名个体（183名黑色素瘤患者）中评估了21个基因9p21的233个标记snp，以试图识别其他基因。使用单SNP和基于基因的回归分析来评估与SNP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与痣数量相关（P（趋势）= 0.003），证实了最近在遗传富集的黑色素瘤病例和对照组中进行的全基因组关联研究的发现。此外，ACO1中的3个snp与黑色素瘤风险相关性最强(rs7855483 [P(trend) = 0.002]；rs17288067 [P (trend) =0.0009]；Rs10813813 [p（趋势）= 0.005])。基于基因的分析也表明，ACO1与黑色素瘤显著相关（p=0.0004）。这些结果与9p21修饰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个体的家庭。家族性脊索瘤是一种罕见的、低级别的恶性骨肿瘤，起源于脊索的残余，其研究已扩展到其他家族。随着连锁分析显示在不同染色体区域的连锁证据，我们广泛地研究了该区域的基因。使用高分辨率阵列- cgh，我们在四个多重家族中发现了6q27上一个区域的独特重复。该区域仅包含T （brachyury）基因，该基因在脊索发育中很重要，并在大多数散发脊索瘤中表达。这是第一个基因复制导致主要家族性癌症易感性的例子。研究淋巴增生性癌症的家族一直是一个长期的兴趣。几年前，我们描述了CLL的潜在前体病变，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岁以上的人群中患病率为5-9%。我们对来自140个CLL多重家族的505名无淋巴细胞增生性疾病个人病史的一级亲属进行了多参数流式细胞术。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聚集在特定的家族中，但这种聚集与已知CLL病例的数量无关。男性患MBL的风险较高（p = 0.04），与男性患CLL的优势相似。MBL患者淋巴细胞计数和b细胞计数均高于正常亲属。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 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.