Immunogenetics of Cervical Cancer A Family-Based Design

描述(由申请人提供)： 宫颈持续致癌性人乳头瘤病毒(HPV)感染和宫颈肿瘤的特点是从细胞介导(HPV抑制)转向体液(HPV允许)免疫反应。白介素12(IL12)是一种细胞因子，通过激活巨噬细胞和自然杀伤细胞来促进细胞介导的反应，并增加主要组织相容性复合体I类细胞表面受体的表达。另一方面，IL10通过下调巨噬细胞上某些细胞因子、MHC II类受体和共刺激分子的表达来抑制细胞介导的反应。先前的流行病学调查表明，宫颈癌家族史与这种疾病的风险增加有关，但尚未确定可能导致这种疾病的特定基因和遗传变异。我们假设，编码细胞因子IL10和IL12(IL10、IL12A和IL12B)的基因变异与持续感染HPV的妇女患浸润性宫颈癌的风险有关。为了验证这一假设，我们建议使用一项基于家族的研究设计来检验IL10、IL12A和IL12B单核苷酸多态和单倍型与浸润性宫颈癌风险之间的关系。我们目前正在招募侵袭性宫颈癌病例加入一项正在进行的基于人群的HPV辅助因子和肛门癌的病例对照研究。在这项拟议的研究中，140名年龄在18-49岁之间的侵袭性宫颈癌患者的父母将被招募到一项方案中，该方案包括采集血液或口腔细胞和电话采访。我们将基于孟德尔遗传学的规则，估计与携带16个多态(预计包括大约23个单倍型)相关的侵袭性宫颈癌的相对风险。这项拟议的研究将有助于我们理解免疫反应和遗传学在浸润性宫颈癌病因中的作用，这两者都可能对疫苗的开发产生直接影响。

DESCRIPTION (provided by applicant): Persistent oncogenic human papillomavirus (HPV) infection in the cervix and cervical neoplasia are marked by a shift away from a cell-mediated (HPV-suppressive) and toward a humoral (HPV-permissive) immune response. Interleukin 12 (IL12) is a cytokine that promotes a cell-mediated response by activating macrophages and natural killer cells and increases the expression of major histocompatibility complex class I cell surface receptors. IL10, on the other hand, suppresses a cell-mediated response by down-regulating the expression of certain cytokines, MHC class II receptors, and co-stimulatory molecules on macrophages. Prior epidemiologic investigations have shown that a family history of cervical cancer is associated with an increased risk of this disease but have not identified specific genes and genetic variants that may be responsible. We hypothesize that variation in the genes encoding the cytokines IL10 and IL12 (IL10, IL12A and IL12B) is associated with invasive cervical cancer risk in women persistently infected with HPV. To test this hypothesis we propose to examine the association between IL10, IL12A, and IL12B single nucleotide polymorphisms and haplotypes and risk of invasive cervical cancer using a family-based study design. We are currently recruiting invasive cervical cancer cases into an on-going population-based case-control study of HPV cofactors and anogenital cancers. In the proposed study, mothers and fathers of 140 invasive cervical cancer cases 18-49 years of age will be recruited into a protocol consisting of blood or buccal cell collection and a telephone interview. We will estimate the relative risk of invasive cervical cancer associated with carriership of 16 polymorphisms (expected to comprise approximately 23 haplotypes) based on the rules of Mendelian genetics. The proposed study will contribute to our understanding of the role of immune response and genetics in invasive cervical cancer etiology, both of which may have a direct impact on vaccine development.