Family Studies

大多数遗传流行病学分支调查评估宿主易感性和环境暴露在癌症发生中的作用。在家族性研究中，宿主的易感性指标通常是特定基因的改变(S)。这些研究往往是非常长期的，活动各不相同。虽然已经发现了两个与黑色素瘤易感性相关的基因(CDKN2A和CDK4)，但在黑色素瘤易感家族中只有一小部分发现了这些基因的变化。对其他基因的搜索仍在继续；与一个国际联盟(GenMEL)合作，在1p22上继续搜索新的黑色素瘤易感基因。与GenMEL合作，我们评估了先前在单个组中报告的四个特征，这些特征与来自三大洲17个组的385个家庭发生CDKN2A突变的可能性有关。其中150个家系有CDKN2A突变；235个没有突变。评估的特征包括家族中患有黑色素瘤的个体数量；家族中存在多原发黑色素瘤的个体；黑色素瘤的早期发病年龄；以及家族中存在胰腺癌。总体而言，每个单独的特征与家系的CDKN2A状态高度显著相关。然而，当这些特征被同时评估时，在地理区域有明显的差异。在澳大利亚，与胰腺癌没有明显的联系。此外，为了增加CDKN2A突变的风险，该家族中黑色素瘤的发病年龄小于40岁，至少有两个人必须患有多原发黑色素瘤，且该家族中有超过6个人受到影响。在北美，发病年龄小于40岁以及一个或多个人患有多发性黑色素瘤与CDKN2A状态显著相关。在欧洲，胰腺癌、一个或多个有多个原发黑色素瘤的个体、年龄在50岁以下以及4个或更多的家庭成员与CDKN2A相关。基诺梅尔正在收集数据来评估这些差异。在466个家系中，有178个CDKN2A突变影响p16，7个突变影响ARF，5个CDK4突变，对其他癌症与突变的关系进行了评估。在不同的地理位置，不同的创始人突变是频繁的。影响CDK4和ARF的突变相似，在2-3%之间。CDKN2A基因突变与胰腺癌关系密切，但因突变的特异性不同而不同。与神经肿瘤或葡萄膜黑色素瘤及CDKN2A突变均无明显关联。基于少数病例，ARF和神经肿瘤之间存在轻微显著的相关性。在美国家庭中，MC1R基因的变异与CDKN2A突变家庭的黑色素瘤风险相关。MC1R的多个变异等位基因与多原发黑色素瘤相关。我们继续积累和评估新的家庭。对来自埃米利奥·罗马尼亚地区的意大利黑色素瘤家族的遗传分析表明，CDKN2A的突变非常罕见，但MC1R的变异是没有白发/皮肤表型的个体的重要风险因素。全基因组扫描已经完成；连锁分析也即将完成。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庭。家族性脊索瘤是一种罕见的、低级别的恶性骨肿瘤，来源于脊索残留物，研究范围扩大到包括更多的家族。识别更多家庭的额外努力已经产生了另一个家庭。继续对识别的连锁区间中的候选基因进行测序。对淋巴增殖性癌症家族的研究一直是人们的兴趣所在。我们对合适的CLL家系进行了连锁分析，确定了几个值得进一步研究的领域。

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 gene on 1p22 continues. In collaboration with GenoMEL, we evaluated four features previously reported in individual groups to be associated with likelihood of the family having a CDKN2A mutation in 385 families from 17 groups in 3 continents. One hundred fifty of the families had CDKN2A mutations; 235 did not. The features evaluated were number of individuals with melanoma in the family; presence of individuals with multiple primary melanomas within the family; early age of onset of melanoma; and presence of pancreatic cancer in the family. Overall, each individual feature was highly significantly associated with CDKN2A status of the families.There were, however, clear differences in geographic areas when the features were simultaneously evaluated. In Australia, there was no significant association with pancreatic cancer. In addition, to have an increased risk of CDKN2A mutation, the age of onset of melanoma in the family was less than 40, at least two individuals had to have multiple primary melanomas, and more that 6 individuals in the family were affected. In North America, Age of onset less than 40 and one or more individuals with multiple primary melanoma were significantly associated with CDKN2A status. In Europe, pancreatic cancer, one or more individuals with multiple primary melanomas, age under 50 and 4 or more family members were associated with CDKN2A status. GenoMEL is collecting data to evaluate these differences. Among 466 families, of whom 178 had mutations in CDKN2A affecting p16, 7 had mutations affecting ARF, and 5 had mutations in CDK4, the relationship between other cancers and mutations were evaluated. Across the geographic locales, different founder mutations were frequent. The mutations affecting CDK4 and ARF were similar, between 2-3%. The relationship between pancreatic cancer and CDKN2A mutation was strong, but varied by specific mutation. There was no apparent association with either neural tumors or uveal melanoma and CDKN2A mutations. A marginally significant association of ARF and neural tumors, based on small numbers, was seen. In the American families, vairants in MC1R were related to melanoma risk in families with CDKN2A mutations. Multiple variant alleles of MC1R were associated with multiple primary melanomas. We continue to accrue and evaluate new families. Genetic analyses of Italian melanoma families from the Emilio Romagna area have shown that mutations in CDKN2A are quite rare, but variants of MC1R are important risk factors in individuals without the fair hair/skin phenotype. A whole genome scan has been completed; linkage analyses are almost completed. 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. Additional efforts to identify more families have yielded another family. Sequencing of candidate genes in the identified linkage interval continues. Studying families with lymphoproliferative cancers has been a long-standing interest. We have conducted a linkage analysis on suitable CLL kindreds which identified several areas of interest for further study.