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；与一个国际联盟（GenoMEL）合作，继续寻找1p22上新的黑色素瘤易感基因。与GenoMEL合作，我们评估了先前在个体群体中报道的与来自3大洲17个群体的385个家庭的CDKN2A突变可能性相关的四个特征。150个家庭有CDKN2A突变；235人没有。评估的特征是家族中患黑色素瘤的个体数量；家族中存在多发性原发性黑色素瘤患者；早发黑色素瘤；以及家族中是否存在胰腺癌。总体而言，每个个体特征都与家族的CDKN2A状态高度显著相关。然而，当同时评估这些特征时，地理区域之间存在明显差异。在澳大利亚，与胰腺癌没有明显的联系。此外，CDKN2A突变风险增加的条件是，家族中黑色素瘤发病年龄小于40岁，至少有两人患有多发性原发性黑色素瘤，家族中有6人以上受到影响。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CDKN2A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，4个或更多的家庭成员与CDKN2A状态相关。GenoMEL正在收集数据来评估这些差异。在466个家庭中，178个家庭存在影响p16的CDKN2A突变，7个家庭存在影响ARF的突变，5个家庭存在CDK4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CDK4和ARF的突变相似，在2-3%之间。胰腺癌与CDKN2A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CDKN2A突变没有明显的关联。基于少量数据，我们发现ARF与神经肿瘤有轻微的显著相关性。在美国家庭中，MC1R的变异与CDKN2A突变家庭的黑色素瘤风险相关。MC1R的多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，CDKN2A突变非常罕见，但MC1R变异是没有金发/皮肤表型的个体的重要危险因素。全基因组扫描已经完成；联动分析基本完成。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。<BR><BR><BR><BR>家族性脊索瘤是一种罕见的、低级别的、起源于脊索残余的恶性骨肿瘤，目前对家族性脊索瘤的研究已扩展到其他家族。寻找更多家庭的额外努力已经找到了另一个家庭。在确定的连锁区间的候选基因测序继续。<BR><BR><BR><BR>研究淋巴增生性肿瘤的家族一直是人们长期关注的问题。我们对合适的CLL种类进行了连锁分析，确定了几个值得进一步研究的领域。我们在感兴趣区域附近分析了102个额外的微卫星标记，证实了13q21.33仍然是一个高度感兴趣的区域。额外的精细映射已经确定了一个新的候选区域。我们已经与梅奥诊所的调查人员开展了合作，以确定其他家庭。我们对霍奇金淋巴瘤和华登斯特罗姆巨球蛋白血症进行了全基因组连锁扫描。联系分析确定了感兴趣的领域，其中有一些重叠。候选基因测试正在进行中。一项确定其他霍奇金淋巴瘤家族的初步研究正在进行中。<BR><BR><BR><BR>我们继续与泌尿外科肿瘤科合作，对肾癌家庭进行评估。我们已经确定了独特的富马酸水合酶突变家族遗传性平滑肌瘤病和肾细胞癌在北美。我们正在评估这些家庭成员发生子宫平滑肌瘤和平滑肌肉瘤的危险因素。子宫平滑肌瘤的危险因素分析正在进行中。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 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.<BR><BR><BR><BR> 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.<BR><BR><BR><BR> 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. We have analyzed 102 additional microsatellite markers near regions on interest, which confirmed that 13q21.33 remained an area of high interest. Additional fine mapping has identified a novel candidate region. We have developed a collaboration with investigators from the Mayo clinic to identify additional families. We have conducted a whole genome linkage scan of Hodgkin lymphoma and Waldenstrom's Macroglobulinemia. The linkage analyses have identified areas of interest, with some overlap. Candidate gene testing is proceeding. A pilot study to identify additional Hodgkin lymphoma families is being conducted. <BR><BR><BR><BR> We have continued working with the Urologic Oncology Branch in the evaluation of families with renal cancers. We have identified unique fumarate hydratase mutations in families with Hereditary Leiomyomatosis and Renal Cell Cancer in North America. We are evaluating the risk factors for uterine leiomyomas and leiomyosarcomas in these family members. Analyses of the risk factors for uterine leiomyomas is in progress. 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