Genetic Susceptibility to Cervical Cancer

宫颈癌的遗传易感性

• 批准号: 8138867
• 负责人: Janet S. Rader
• 金额: $ 14.9万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8138867
• 关键词: Genetic; Susceptibility; Cervical; Cancer

DESCRIPTION (provided by applicant): Human papillomavirus (HPV) infection of the cervix is usually self-limiting, but it can progress to cervical cancer, which kills ~273,500 women each year worldwide. Even in the United States, cervical cancer is the third most common cause of cancer death in women aged 15-34 ranks fourth for average years of life lost, and it disproportionately affects minority groups and women of low socioeconomic status. Epidemiologic studies suggest that heritability accounts for ~27% of the variation in the risk for cervical tumors. Through a candidate gene approach that used family-based controls, we have identified variations in the host genome that associate with disease progression. Many associations are stronger in a subgroup of women with invasive cervical cancer (ICC) who are infected by the high-risk HPV types 16, 18, and related subtypes. To accelerate the discovery of genetic factors involved in the development of cervical cancer, we propose three specific aims. Aim 1 will validate candidate genes involved in cervical carcinogenesis and identify novel single nucleotide polymorphisms (SNPs) of disease, using a genome-wide association study. In stage 1 of this Aim, we will use a case-control sample of 500 unrelated Caucasian women with ICC (collected previously) and 2000 Caucasian female population controls identified from publicly available genotyping control databases. In stage 2, we will investigate a second independent case-control set (similar to the first) to validate 1000 SNPs identified from the list of well-motivated candidate genes and the top ~5000 hits from the genome-wide association study. In the statistical analysis, we will combine the stage 1 and stage 2 data. In Aim 2 we will explore interactions among susceptible SNPS and perform subgroup analysis among the 1000 cases and 4000 controls. Heterogeneity will be explored in various subsets of cases such as HPV type, age at diagnosis, and histology. The SNPs that show the most significant associations with ICC will be validated in other minority groups in Aim 3, using DNA samples from African American family-based trios of ICC and in situ disease and a cohort of Hispanic women with ICC/CIN 3. This study will enable us to validate markers of susceptibility to ICC while using available resources economically. Determining how variations in host DNA influence women's vulnerability to cervical cancer is important for several reasons. First, such studies could uncover genetic markers for identifying women who are at high risk for developing the disease. Second, they could reveal how the body defends itself after HPV infection, which might suggest new strategies for vaccine design or drug development. Finally, a database and corresponding blood samples and tumors from cases of ICC and DNA from family members would be an invaluable resource for future studies.

描述（由申请人提供）：子宫颈的人乳头瘤病毒（HPV）通常是自限制的，但可以发展为宫颈癌，宫颈癌每年杀死约273,500名女性。即使在美国，宫颈癌也是15-34岁女性癌症死亡的第三大最常见原因，在平均寿命中排名第四，这对少数群体和社会经济地位低下的妇女产生了不成比例的影响。流行病学研究表明，遗传力占宫颈肿瘤风险变化的约27％。通过使用基于家庭对照的候选基因方法，我们已经确定了与疾病进展相关的宿主基因组中的变化。在患有侵入性宫颈癌（ICC）的女性亚组中，许多联想更强​​，这些女性受到高危HPV类型16、18和相关亚型的感染。为了加快宫颈癌发展中涉及的遗传因素的发现，我们提出了三个具体目标。 AIM 1将使用全基因组关联研究来验证参与宫颈癌的候选基因，并确定疾病的新型单核苷酸多态性（SNP）。在此目标的第1阶段中，我们将使用500名与ICC无关的高加索妇女（以前收集）和2000年白种女性人群对照组的病例对照样本，并从公开可用的基因分型控制数据库中确定。在第2阶段，我们将研究第二个独立的病例对照组（类似于第一个），以验证从动机良好的候选基因列表中鉴定出的1000个SNP，以及全基因组关联研究中的最高5000次命中。在统计分析中，我们将结合第1阶段和第2阶段数据。在AIM 2中，我们将探索易感SNP之间的相互作用，并在1000例和4000个对照中执行亚组分析。在HPV类型，诊断年龄和组织学的各种情况下，将探索异质性。显示与ICC最重要关联的SNP将在AIM 3中的其他少数群体中得到验证，使用来自非裔美国人家庭的ICC和原位疾病的TRIO的DNA样本以及ICC/CIN 3的一群西班牙裔女性。这项研究将使我们能够使我们能够在经济上使用可用资源来验证ICC的易感标记。确定宿主DNA的变化如何影响妇女的宫颈癌脆弱性，这是有几个原因的重要性。首先，这样的研究可能会发现遗传标记，以识别患这种疾病高风险的女性。其次，他们可以揭示人体在HPV感染后如何防御自己，这可能暗示了疫苗设计或药物开发的新策略。最后，来自家庭成员的ICC和DNA病例的数据库和相应的血液样本和肿瘤将是未来研究的宝贵资源。

项目成果

Polymorphisms in immune mediators associate with risk of cervical cancer.

• DOI: 10.1016/j.ygyno.2014.07.106
• 发表时间: 2014-10
• 期刊: Gynecologic oncology
• 影响因子: 4.7
• 作者: Zhang Z;Fye S;Borecki IB;Rader JS
• 通讯作者: Rader JS

A microRNA expression signature for cervical cancer prognosis.

宫颈癌预后的 microRNA 表达特征。

• DOI: 10.1158/0008-5472.can-09-3289
• 发表时间: 2010-02-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Hu X;Schwarz JK;Lewis JS Jr;Huettner PC;Rader JS;Deasy JO;Grigsby PW;Wang X
• 通讯作者: Wang X

TP53, MDM2, NQO1, and susceptibility to cervical cancer.

• DOI: 10.1158/1055-9965.epi-09-0886
• 发表时间: 2010-03
• 期刊: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
• 作者: Hu X;Zhang Z;Ma D;Huettner PC;Massad LS;Nguyen L;Borecki I;Rader JS
• 通讯作者: Rader JS

Polymorphisms in MMP9 and SIPA1 are associated with increased risk of nodal metastases in early-stage cervical cancer.

• DOI: 10.1016/j.ygyno.2009.09.037
• 发表时间: 2010-03
• 期刊: Gynecologic oncology
• 影响因子: 4.7
• 作者: Brooks R;Kizer N;Nguyen L;Jaishuen A;Wanat K;Nugent E;Grigsby P;Allsworth JE;Rader JS
• 通讯作者: Rader JS

Pathway-specific analysis of gene expression data identifies the PI3K/Akt pathway as a novel therapeutic target in cervical cancer.

• DOI: 10.1158/1078-0432.ccr-11-2485
• 发表时间: 2012-03-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Schwarz JK;Payton JE;Rashmi R;Xiang T;Jia Y;Huettner P;Rogers BE;Yang Q;Watson M;Rader JS;Grigsby PW
• 通讯作者: Grigsby PW