Genetic Epidemiology

这个遗传流行病学项目中的许多调查都来自于对癌症高危家庭或其他病因学研究的观察。来自黑色素瘤遗传学联合会的80个有记录的CDKN2A突变和多个皮肤黑色素瘤病例的家庭被分析以检查外显性。总体而言，CDKN2A突变外显率在50岁时估计为0.30(95%可信区间=0.12-0.62)，在80岁时为0.67(95%可信区间=0.31-0.96)。在统计上，居住在黑色素瘤高发地区有显著的相关性。到50岁时，CDKN2A突变外显率在欧洲达到0.13，在美国达到0.50，在澳大利亚达到0.32；到80岁时，在欧洲达到0.58，在美国达到0.76，在澳大利亚达到0.91。对儿童髓母细胞瘤的检查发现，在Sonic Hedgehog(SHH)信号通路的SUFU(编码人类融合抑制因子)中，有一个亚群携带种系和体细胞突变。SuFU是一种新发现的肿瘤抑制基因，它通过一种新发现的机制调节SHH信号通路，使人易患髓母细胞瘤。对以色列一项犹太人群卵巢癌病例对照研究的数据分析显示，卵巢切除术和其他妇科手术似乎对创始人BRCA1/2突变的携带者和非携带者都具有保护作用。作为最近完成的DCEG对成年脑瘤患者的全面病例对照研究的后续行动，正在对480例符合条件的胶质瘤病例的父母、兄弟姐妹和成年子女进行基于家庭的研究。亲属被问及个人和家庭、病史和其他风险因素，并被要求提供口腔细胞作为DNA的来源。在关联性研究和分析中，这些亲属将被用作胶质瘤病例的对照，以评估遗传易感性和环境暴露对胶质瘤和病因相关肿瘤风险的作用。一项在意大利东北部对183例黑色素瘤病例和179名对照进行的病例对照研究确定了非家族性黑色素瘤的最强风险因素，并确定了这些因素的组合如何导致地中海人群中的黑色素瘤风险。在调整了年龄、性别和色素沉着特征后，发育不良痣的存在、晒黑倾向低、眼睛浅和肤色浅都与黑色素瘤风险高度相关。DNA修复能力是黑色素瘤风险的重要修饰者，存在其他强烈的危险因素，如晒黑倾向低和发育不良痣的存在。用美能达CR-300型色度计和最小红斑量(MED)分别测定皮肤本质性颜色和紫外线敏感性。黑色素瘤的风险随着皮肤亮度和MED的增加而增加，特别是在阳光曝晒水平最高的受试者中。从丹麦和瑞典的合作者那里获得了癌症、人口和出院登记的相关数据，其中包括淋巴增殖性(LP)癌症的病例，包括霍奇金氏病、非霍奇金淋巴瘤、慢性淋巴细胞性白血病和多发性骨髓瘤、配对对照以及病例和对照的一级亲属。将测试研究病例亲属中LP癌和自身免疫性疾病风险增加的假设。

Many of the investigations in this genetic epidemiology project arise from observations in families at high risk of cancer or in other etiologic studies. Eighty families with documented CDKN2A mutations and multiple cases of cutaneous melanoma from The Melanoma Genetics Consortium were analyzed to examine penetrance. Overall, CDKN2A mutation penetrance was estimated to be 0.30 (95% confidence interval = 0.12-0.62) by age 50 years and 0.67 (95% confidence interval =0.31-0.96) by age 80 years. There was a statistically significant association with residing in a region with a high incidence of melanoma. By age 50 years CDKN2A mutation penetrance reached 0.13 in Europe, 0.50 in the United States, and 0.32 in Australia; by age 80 years, it was 0.58 in Europe, 0.76 in the United States, and 0.91 in Australia. Examination of children with medulloblastoma revealed that a subset carry germline and somatic mutations in SUFU (encoding the human suppressor of fused) of the sonic hedgehog (SHH) signaling pathway. SUFU is a newly identified tumor suppressor gene that predisposes individuals to medulloblastoma by modulating the SHH signaling pathway through a newly identified mechanism. Analyses of the data from a case-control study of ovarian cancer in Israel of the Jewish population revealed that oophorectomy and other gynecology surgery appeared protective among both carriers and noncarriers of founder BRCA1/2 mutations. As a follow-up to a recently completed DCEG comprehensive case-control study of adults with brain tumors, a family-based study of the parents, siblings and adult children of the 480 eligible glioma cases is being conducted. Relatives are interviewed about personal and family medical history and other risk factors and are asked to provide buccal cells as a source of DNA. The relatives will be used as controls for the glioma cases in association studies and in analyses to evaluate the roles of genetic susceptibility and environmental exposures on the risk of gliomas and etiologically related tumors. A case-control study of 183 incident melanoma cases and 179 controls conducted in northeastern Italy identified the strongest risk factors for non-familial melanoma and determined how the combinations of these factors contributed to melanoma risk in Mediterranean populations. Presence of dysplastic nevi, low propensity to tan, light eye and light skin color were all highly associated with melanoma risk after adjustment for age, gender, and pigmentation characteristics. DNA repair capacity was an important modifier of melanoma risk in the presence of other strong risk factors, such as low propensity to tan and presence of dysplastic nevi. Constitutive skin color and UV sensitivity were assessed by Minolta CR-300 colorimeter and minimal erythema dose (MED), respectively. Melanoma risk increased with skin brightness and MED, particularly in subjects with the highest levels of sun exposure. Linked data from cancer, population, and hospital discharge registries have been obtained from collaborators in Denmark and Sweden which includes cases of lymphoproliferative (LP) cancers including Hodgkin's disease, Non-Hodgkin's Lymphoma, Chronic Lymphocytic Leukemia, and Multiple Myeloma, matched controls, and first degree relatives of cases and controls. Hypotheses to examine increased risks of LP cancers and autoimmune disorders among relatives of cases will be tested.