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。来自费城和旧金山黑色素瘤诊所的718名患有侵袭性皮肤黑色素瘤的非西班牙裔白人患者和来自与病例来源相似的门诊诊所的945名匹配对照组的病例对照研究数据正在被用来开发一种风险评估模型，以估计黑色素瘤的绝对风险。此前，在意大利东北部进行的一项病例对照研究中，来自183例黑色素瘤病例和179名对照的受试者的淋巴细胞DNA修复能力(DRC)显示，总体而言，DRC在病例和对照组之间没有差异，但DRC低、皮肤晒黑能力差或发育不良的痣的受试者患黑色素瘤的风险增加。为了探索这些发现的遗传学基础，我们分析了DNA修复基因中的一系列SNP。在DNA聚合酶或基本修复基因中发现的SNP与降低黑色素瘤风险相关，而在NER基因中发现的SNP与老年人更高的风险或DRC降低相关。使用标准化仪器测量受试者的体质肤色和紫外线敏感性，并分析SNPs在潜在色素沉着基因中的作用。结果表明，基于色度计的皮肤亮度和MC1R色素沉着基因的变体都与黑色素瘤的风险相关，并且风险随着MC1R变体的数量增加而增加，即使在调整了传统评估的色素沉着特征后也是如此。在这些病例中，MC1R变异也与黑色素瘤厚度有关。作为DCEG对成年脑瘤患者进行的全面病例对照研究的后续行动，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了一项以家庭为基础的研究。365名胶质瘤患者的亲属接受了关于个人和家庭病史和其他风险因素的采访，并被要求提供口腔细胞作为DNA的来源。与人口控制相比，对一级亲属患癌症风险的分析正在进行中。未来，这些亲属将在关联性研究和分析中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学相关肿瘤风险的作用。回顾临床资料，比较来自单一机构的33名髓母细胞瘤患者和46名未受影响的亲属，发现大多数髓母细胞瘤患者的临床表现很少。结果表明，髓母细胞瘤患者中临床可识别的症状并不常见，然而，ptch1和SUFU突变出现的频率很低，但频率很高。瑞典和丹麦的注册数据仍在继续分析中。一篇新闻文章描述了非霍奇金淋巴瘤(NHL)患者亲属患淋巴增生性(LP)肿瘤的风险。亲属患非霍奇金淋巴瘤和霍奇金淋巴瘤的风险显著增加(风险比=1.7，95%CI，1.4-2.2)和霍奇金淋巴瘤(HL，风险比=1.4，95%CI，1.0-2.0)。患慢性淋巴细胞白血病(CLL)的风险增加，但并不显着。多发性骨髓瘤(MM)的风险没有增加。先证者确诊时的年龄不影响亲属的风险。具有侵袭性亚型的NHL患者的亲属发生NHL的风险进一步增加(危险比=3.6，95%CI，1.8-7.0)。已经提交了一份手稿，描述了MM病例、对照和亲属的结果。多发性骨髓瘤患者的亲属患多发性骨髓瘤的风险显著增加(风险比=1.7，95%可信区间1.0-2.7)，而其他LP肿瘤的风险没有显著增加。自身免疫性疾病和LP肿瘤在病例、对照和亲属中的相关性也已被研究。

Many of the investigations in this genetic epidemiology project arise from observations in families at high risk of cancer or in other etiologic studies. Case-control study data from 718 non-Hispanic white patients with invasive cutaneous melanoma from melanoma clinics in Philadelphia and San Francisco and 945 matched controls from outpatient clinics with similar catchment areas to the cases are being used to develop a risk assessment model for estimating absolute risk of melanoma. Previously, DNA repair capacity (DRC) in lymphocytes from subjects from a case-control study of 183 incident melanoma cases and 179 controls conducted in North-Eastern Italy showed that DRC did not differ between cases and controls overall, but subjects with low DRC and poor tanning ability or dysplastic nevi were at increased risk of melanoma. To explore the genetic basis of these findings, a series of SNPs in DNA repair genes were analyzed. SNPs found in DNA polymerase or abasic repair genes were associated with reduced melanoma risk, while SNPs in NER genes were associated with higher risk in older subjects, or with decreased DRC. Standardized instruments were used to measure subjects constitutive skin color and UV sensitivity, and the role of SNPs was analyzed in potential pigmentation genes. The results showed that both colorimeter-based skin brightness and variants of the MC1R pigmentation gene were associated with melanoma risk, and the risk increased with the number of MC1R variants, even after adjustment for the traditionally assessed pigmentation characteristics. MC1R variants were also associated with melanoma thickness in the cases. As a follow-up to a 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 has been conducted. Relatives of 365 of the glioma cases were interviewed about personal and family medical history and other risk factors and were asked to provide buccal cells as a source of DNA. Analyses to examine the risk of cancer among the first degree relatives compared to population controls are in process. In the future, 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. Retrospective review of clinical data comparing 33 medulloblastoma patients from a single institution to their 46 unaffected relatives revealed a paucity of clinical findings among the majority of medulloblastoma patients. The results suggest that clinically recognizable syndromes are uncommon among patients with medulloblastoma, however, PTCH1 and SUFU mutations were present at a low but significant frequency.Registry data from Sweden and Denmark are continuing to be analyzed. A paper in press describes the risk of lymphoproliferative (LP) tumors in relatives of patients with non-Hodgkin lymphoma (NHL). Relatives were at significantly increased risk for NHL (hazard ratio=1.7, 95% CI, 1.4-2.2) and Hodgkin lymphoma (HL, hazard ratio=1.4, 95% CI,1.0-2.0). The risk for chronic lymphocytic leukemia (CLL) was increased but was not significant. There was no increased risk of multiple myeloma (MM). Age at diagnosis of case proband did not affect risk in relatives. Relatives of cases with an aggressive subtype of NHL were at further increased risk for developing NHL (hazard ratio=3.6, 95% CI, 1.8-7.0). A manuscript describing the results for MM cases, controls and relatives has been submitted. Relatives of MM cases are at significantly increased risk for developing MM (hazard ratio=1.7, 95% CI, 1.0-2.7) but not for other LP tumors. The association of autoimmune diseases and LP tumors in cases, controls, and relatives has also been examined.