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;与一个国际财团（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。在美国和意大利的黑色素瘤易感家族中，我们正在使用新的技术，包括阵列比较基因组杂交（aCGH）和下一代测序，以寻找新的高风险黑色素瘤易感基因。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。最近，我们使用阵列计算全息图，以确定重复的T基因（短尾畸形），这是重要的脊索发育，并表示在大多数散发性脊索瘤，共分离的成员，四个多重脊索瘤家族。这是第一个基因重复导致家族性癌症易感性的例子。目前，我们正在使用外显子组测序，以寻找致病突变的choroidal家庭没有T基因重复。研究淋巴增生性癌症的家庭一直是一个长期的兴趣。我们与CLL联盟的遗传流行病学合作，对家族性CLL进行更大规模的研究。我们在101例来自高危CLL家族的MBL病例中进行了免疫表型和表达研究。总共检测到91个独特的MBL克隆：73个CLL样MBL（CD 5（+）CD 20（dim）sIg（dim）），11个非典型MBL（CD 5（+）CD 20（+）sIg（+））和7个CD 5（neg）MBL（CD 5（neg）CD 20（+）sIg（neg））。对这些MBL亚型进行了扩展的免疫表型表征，并且在各组之间观察到CD 23、CD 49 d、CD 79 b和FMC-7的细胞表面表达的显著差异。CLL中的风险标记物如CD 38、ZAP 70和CD 49 d在CLL样MBL中很少表达，但在大多数非典型MBL中表达。在35例MBL病例中进行了间期细胞遗传学检查，del 13 q14最常见（22/30例CLL样MBL病例）。使用寡核苷酸阵列对7个CLL样MBL进行基因表达分析，并显示B细胞受体相关途径的激活。我们的研究结果强调了MBL亚型的多样性，并进一步阐明了MBL和其他淋巴组织增生性疾病之间的关系。我们在407例CLL病例（其中102例有CLL家族史）和296例对照中进行了GWAS研究，并专门研究了家族性病例。我们在252例家族性CLL病例和965例对照的额外样本中评估了这些分析的最高命中率。使用所有可用的数据，我们确定并证实了4个单核苷酸多态性（SNP）的独立关联，这些SNP在IRF 8（干扰素调节因子8）基因（组合P值3.37 10（-8））中达到全基因组统计学显著性，位于先前确定的16q24.1位点。亚组为家族性CLL病例，我们发现并证实了染色体6p21.3上的一个新位点（合并P值= 6.92 × 10（-9））。这个新的区域含有HLA-DQA 1和HLA-DRB 5基因。我们的研究结果支持这一假设，即家族性CLL病例有额外的遗传变异没有看到在散发性CLL.We还继续与CCR研究人员合作着色性干皮病的家族研究，以评估XP杂合子癌症的风险。数据收集正在进行中。神经退行性变是XP患者发病和死亡的主要原因，并因亚组而异。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 new melanoma susceptibility genes continues both within families and a genome-wide association study. In the American and Italian melanoma-prone families, we are using novel technologies including array comparative genomic hybridization (aCGH) and next generation sequencing to search for new high-risk melanoma susceptibility genes. 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. Recently we used array CGH to determine that duplications of the T gene (brachyury), which is important in notocord development, and is expressed in most sporadic chordomas, co-segregated with chordoma in members of four multiplex chordoma families. This was the first example of gene duplication conferring major familial susceptibility to cancer. We are currently using exome sequencing to search for disease-causing mutations in chordoma families without T gene duplications. Studying families with lymphoproliferative cancers has been a long-standing interest. We have collaborated with the Genetic Epidemiology of CLL Consortium to conduct larger studies of familial CLL. We conducted immunophenotypic and expression studies in 101 MBL cases from high risk CLL families. In all, 91 unique MBL clones were detected: 73 CLL-like MBL (CD5(+)CD20(dim)sIg(dim)), 11 atypical MBL (CD5(+)CD20(+)sIg(+)) and 7 CD5(neg) MBL (CD5(neg)CD20(+)sIg(neg)). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70 and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on seven CLL-like MBL, and showed activation of B-cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders. We performed a GWAS study in 407 CLL cases (of which 102 had a family history of CLL) and 296 controls and also looked specifically at the familial cases. Our top hits from these analyses were evaluated in an additional sample of 252 familial CLL cases and 965 controls. Using all available data, we identified and confirmed an independent association of 4 single-nucleotide polymorphisms (SNPs) that met genome-wide statistical significance within the IRF8 (interferon regulatory factor 8) gene (combined P values 3.37 10(-8)), located in the previously identified 16q24.1 locus. Subsetting to familial CLL cases, we identified and confirmed a new locus on chromosome 6p21.3 (combined P value = 6.92 10(-9)). This novel region harbors the HLA-DQA1 and HLA-DRB5 genes. Our findings support the hypothesis that familial CLL cases have additional genetic variants not seen in sporadic CLL.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. Neurologic degeneration is a major cause of morbidity and mortality among XP patients, and varies by subgroup. We have also documented that mothers carrying affected children with tricothiodystrophy have more pregnancy complications than when carrying unaffected children.