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，继续寻找1 p22上的新黑色素瘤易感基因。在与GenoMEL的合作中，我们评估了来自3大洲17个群体的385个家庭中先前在单个群体中报告的与家族具有CDKN 2A突变的可能性相关的4个特征。其中150个家族有CDKN 2A突变，235个没有。评价的特征是家族中患有黑色素瘤的个体数量;家族中患有多原发性黑色素瘤的个体的存在;黑色素瘤发病的早期年龄;以及家族中胰腺癌的存在。总的来说，每个个体特征与家族的CDKN 2A状态高度显著相关。然而，当同时评估这些特征时，地理区域存在明显差异。在澳大利亚，与胰腺癌没有显着关联。此外，要增加CDKN 2A突变的风险，家族中黑色素瘤的发病年龄小于40岁，至少有两个人患有多发性原发性黑色素瘤，并且家族中有超过6个人受到影响。在北美，发病年龄小于40岁和一个或多个患有多发性原发性黑色素瘤的个体与CDKN 2A状态显著相关。在欧洲，胰腺癌、一个或多个患有多发性原发性黑色素瘤的个体、年龄在50岁以下以及4个或更多家庭成员与CDKN 2A状态相关。GenoMEL正在收集数据以评估这些差异。在466个家族中，其中178个家族有影响p16的CDKN 2A突变，7个家族有影响ARF的突变，5个家族有CDK 4突变，评估了其他癌症与突变的关系。在不同的地理区域，不同的创始人突变是频繁的。影响CDK 4和ARF的突变相似，在2- 3%之间。胰腺癌与CDKN 2A突变之间的关系很强，但因特定突变而异。与神经肿瘤或葡萄膜黑色素瘤和CDKN 2A突变没有明显的关联。在少数病例中，ARF和神经肿瘤之间存在轻微的显著相关性。在美国家族中，MC 1 R的变异与CDKN 2A突变家族中的黑色素瘤风险相关。MC 1 R的多个变异等位基因与多发性原发性黑色素瘤相关。我们继续积累和评估新的家庭。来自Emilio Romagna地区的意大利黑色素瘤家族的遗传分析表明，CDKN 2A的突变非常罕见，但MC 1 R的变体是没有金发/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。为查明更多家庭所作的进一步努力又发现了一个家庭。继续对所鉴定的连锁区间中的候选基因进行测序。研究淋巴增生性癌症的家庭一直是一个长期的兴趣。我们对合适的CLL激酶进行了连锁分析，确定了几个感兴趣的领域进行进一步研究。

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.