Genetic Epidemiology

这个遗传流行病学项目中的许多调查来自于对癌症高危家庭的观察或其他病因学研究。 对来自黑色素瘤遗传学联盟的80个有记录的CDKN 2A突变的家庭和多例皮肤黑色素瘤病例进行了分析，以检查外显率。总体而言，CDKN 2A突变率估计为0.30（95%置信区间= 0.12-0.62），年龄50岁和0.67（95%置信区间=0.31-0.96），年龄80岁。居住在黑色素瘤高发地区与黑色素瘤发病率有统计学显著相关性。到50岁时，CDKN 2A突变率在欧洲为0.13，在美国为0.50，在澳大利亚为0.32;到80岁时，欧洲为0.58，在美国为0.76，在澳大利亚为0.91。 对儿童髓母细胞瘤的检查显示，一个亚群携带音刺猬（SHH）信号通路的SUFU（编码融合的人类抑制因子）的种系和体细胞突变。SUFU是一种新发现的肿瘤抑制基因，通过一种新发现的机制调节SHH信号通路，使个体易患髓母细胞瘤。 对以色列犹太人卵巢癌病例对照研究数据的分析显示，卵巢切除术和其他妇科手术在创始人BRCA 1/2突变的携带者和非携带者中均具有保护作用。 作为最近完成的DCEG成人脑肿瘤综合病例对照研究的后续研究，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以家庭为基础的研究。对亲属进行面谈，询问其个人和家族病史以及其他风险因素，并要求其提供口腔细胞作为DNA来源。在关联研究和分析中，亲属将被用作神经胶质瘤病例的对照，以评估遗传易感性和环境暴露对神经胶质瘤和病因相关肿瘤风险的作用。 在意大利东北部进行的一项对183例黑色素瘤病例和179例对照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的黑色素瘤风险。在校正年龄、性别和色素沉着特征后，发育不良痣、较低的晒黑倾向、浅色眼睛和浅色皮肤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一个重要调节因素，在其他强风险因素的存在下，如晒黑倾向低和发育不良痣的存在。分别用Minolta CR-300比色计和最小红斑量（MED）评估皮肤组成颜色和紫外线敏感性。黑色素瘤风险随着皮肤亮度和MED的增加而增加，特别是在阳光照射水平最高的受试者中。 从丹麦和瑞典的合作者处获得了来自癌症、人群和出院登记处的关联数据，其中包括淋巴增生性（LP）癌症病例，包括霍奇金病、非霍奇金淋巴瘤、慢性淋巴细胞白血病和多发性骨髓瘤、匹配对照以及病例和对照的一级亲属。将检验在病例亲属中检查LP癌症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.