Genetic and Pharmacogenetic Modifiers of Cancer Risk and Intervention Outcomes

癌症风险和干预结果的遗传和药物遗传学修饰因素

• 批准号: 8565430
• 负责人: MARK H GREENE
• 金额: $ 55.43万
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8565430
• 关键词: Acute; Adolescent; Alleles; Anabolism; Australia; Biological Availability; Biological Markers; Birth Weight; Bone neoplasms; Cancer Etiology; Cancer Intervention; Cancer Prevention Intervention; Case-Control Studies; Children' s Oncology Group; Clinical Trials Cooperative Group; Collaborations; Colon; Colorectal Adenoma; CpG Islands; DNA; DNA Repair; Data; Data Analyses; Databases; Dental Schools; Descriptive Epidemiology; Division of Cancer Epidemiology and Genetics; Drug Metabolic Detoxication; Europe; Evaluation; Event; Exons; Exposure to; Extramural Activities; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Germ Lines; Goals; Growth; Haplotypes; Height; IGF1 gene; IGF2 gene; IGF2R gene; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; International; Introns; Investigation; Ionizing radiation; KRAS2 gene; Li-Fraumeni Syndrome; Link; Lung; Malignant - descriptor; Malignant Neoplasms; Manuscripts; Measures; Meta-Analysis; Methylation; Minor; Morbidity - disease rate; Mutation; Myelosuppression; National Surgical Adjuvant Breast and Bowel Project; Oncogenes; Outcome; Participant; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenetics; Placebos; Population; Preparation; Prostate; Protein-Serine-Threonine Kinases; Publications; Publishing; Research Personnel; Resistance; Resources; Risk; Risk Factors; Role; SEER Program; Sampling; Screening for Ovarian Cancer; Second Primary Cancers; Series; Signal Pathway; Signaling Pathway Gene; Single Nucleotide Polymorphism; Site; Somatomedins; Syndrome; TP53 gene; Tamoxifen; Testing; Time; Treatment Efficacy; Update; Variant; Woman; adenoma; base; cancer epidemiology; cancer risk; cancer therapy; cell growth regulation; chemical carcinogen; clinical decision-making; experience; exposed human population; genetic risk factor; genetic variant; genome wide association study; hormone metabolism; improved; interest; malignant breast neoplasm; osteosarcoma; prospective; treatment response

The first of these studies - Genetic Modifiers of Tamoxifen-Related Breast Cancer Risk: NSABP P1G3 [CAS 7220]- was a case/case analysis of 39 SNPs in 19 different genes among 249 women with invasive breast cancer (84 exposed to tamoxifen; 165 placebo). This was a null study by single SNP association and haplotype analysis. However, the constellation of alleles characterizing cases emerging in the presence of tamoxifen (resistant genotypes) was distinct from that in the unexposed (placebo) cases. This pathway analysis approach generated an allelic signature that may have potential as a predictive biomarker of tamoxifen resistance. These results have just been published. This project is now complete. Utilizing the resources of the Prostate, Lung, Colon and Ovarian (PLCO) Cancer screening trial, we have been investigating the relationship between the Insulin-Like Growth Factor (IGF) Signaling Pathway and Risk of Advanced Colorectal Adenoma [CAS 7300], prompted by data suggesting that IGFs may represent potentially modifiable cancer risk factors. We have analyzed 800 participants found to have an advanced colorectal adenoma at the time of baseline screen, and 800 matched non-adenoma subjects. Genotyping has been completed on 37 SNPs in 7 IGF-related genes (IGF1, IGF-BP3, ALS, IGF-1R, IGF-BP5, IGF2 and GH), and circulating levels of IGF-1, IGF-2 and IGFBP-3 have been measured. The latter documented a 1.7-fold increase in adenoma risk (95% C.I. 1.2-2.5) in highest vs. lowest quartiles of IGF-1, controlled for IGF-2, IGF-BP3 and numerous other covariates. These data are now in press. The evaluation of genetic variants as primary risk factors for advance adenoma was null, although we confirmed the previously-observed strong relationship between IGF-BP3-01 (rs2854744), and a new association between IGF-BP3-07 (rs6413441) and circulating levels of IGF-BP3 among controls. These two SNPs decrease IGF-BP-3 levels by 222 and 148 units per minor allele (mean IGF-BP3 level 4,000 units). This study has been expanded by adding additional genotyping data from the DCEG Rare Cancers iSELECT study which, serendipitously, analyzed the same set of DNA samples. These data provide a more comprehensive interrogation of IGF signaling pathway genes: 1,338 advanced colorectal adenoma cases and 1,503 matched controls were studied, and data generated for 570 single nucleotide polymorphisms (SNPs) in 28 IGF pathway genes. Two SNP associations remained statistically significant after a gene-based correction for multiple testing. The G allele of rs12305513, which is located in an intron of the oncogene, KRAS, was associated an increased risk of adenoma (ORper allele=1.36, 95% CI =1.13-1.63, P=0.001). The G allele of rs180531, located in the serine/threonine kinase gene, RPS6KB1, was associated with a reduced risk of adenoma (ORper allele=0.83, 95% CI=0.73-0.95, P=0.006). A manuscript is in preparation. We have developed a portfolio of projects evaluating Genetic Risk Factors for Osteogenic Sarcoma [CAS 10375]. Osteogenic sarcoma (OS), the most common malignant primary bone tumor, occurs most commonly during the adolescent growth spurt. As part of a prospective case-control study of OS initiated in 1995 with the NCI and Harvard Dental School, we studied genetic variation in many genes/pathways implicated in the cellular regulation of growth. We identified a small haplotype block that was associated with risk of OS in the IGF2R gene. This genomic region (near exon 16) consists of CpG islands, and functional analysis of the SNPs in this block suggested that a specific SNP associated with OS risk resulted in differential methylation at that SNP site. Because OS is one of the syndrome-defining malignancies in patients with germ-line TP53 mutations (i.e., the Li-Fraumeni Syndrome), we investigated the role of germ-line genetic variants in TP53 as OS risk factors. These data did not indicate a strong link between variation in TP53 and OS risk, although they did provide preliminary evidence of an increased risk of OS associated with TP53 variants IVS2+38 and Pro72Arg. We recently updated the descriptive epidemiology of OS in two separate publications: one based on US data from NCI's SEER program, and the other based on multiple international cancer epidemiology databases. We published a meta-analysis of height and birth weight as OS risk factors. The data confirmed that height is a significant risk factor for OS. The evidence related to birth weight was not definitive. Finally, we have launched an international collaborative project which will support a genome-wide association study (GWAS) aimed at identifying genetic risk factors for OS. Collaborators include the Children's Oncology Group, and multiple investigators in Europe and Australia. The GWAS will consist of approximately 2000 OS cases; controls will be derived from existing NCI studies. The initial round of genotyping has been completed, and data analysis is underway.

其中第一项研究 - 他莫昔芬相关乳腺癌风险的基因修饰因素：NSABP P1G3 [CAS 7220] - 对 249 名患有浸润性乳腺癌的女性（84 名暴露于他莫昔芬；165 名安慰剂）中的 19 个不同基因的 39 个 SNP 进行了个案分析。这是一项通过单一 SNP 关联和单倍型分析进行的无效研究。然而，在他莫昔芬（耐药基因型）存在下出现的病例特征性等位基因群与未暴露（安慰剂）病例中的等位基因群不同。这种途径分析方法产生了等位基因特征，可能有潜力作为他莫昔芬耐药性的预测生物标志物。这些结果刚刚发表。该项目现已完成。利用前列腺癌、肺癌、结肠癌和卵巢癌 (PLCO) 癌症筛查试验的资源，我们一直在研究胰岛素样生长因子 (IGF) 信号通路与晚期结直肠腺瘤 [CAS 7300] 风险之间的关系，数据表明 IGF 可能代表潜在的可改变的癌症风险因素。我们分析了 800 名在基线筛查时发现患有晚期结直肠腺瘤的参与者和 800 名匹配的非腺瘤受试者。已完成 7 个 IGF 相关基因（IGF1、IGF-BP3、ALS、IGF-1R、IGF-BP5、IGF2 和 GH）的 37 个 SNP 的基因分型，并测量了 IGF-1、IGF-2 和 IGFBP-3 的循环水平。后者记录了 IGF-1 的最高四分位数与最低四分位数相比，腺瘤风险增加了 1.7 倍（95% C.I. 1.2-2.5），并对照 IGF-2、IGF-BP3 和许多其他协变量。这些数据现已出版。尽管我们证实了先前观察到的 IGF-BP3-01 (rs2854744) 之间的密切关系，以及 IGF-BP3-07 (rs6413441) 与对照中 IGF-BP3 循环水平之间的新关联，但对遗传变异作为晚期腺瘤主要危险因素的评估是无效的。这两个 SNP 将每个小等位基因的 IGF-BP-3 水平降低 222 和 148 个单位（平均 IGF-BP3 水平降低 4,000 个单位）。通过添加来自 DCEG 罕见癌症 iSELECT 研究的额外基因分型数据，这项研究得到了扩展，该研究偶然分析了同一组 DNA 样本。这些数据提供了对 IGF 信号通路基因的更全面的询问：研究了 1,338 个晚期结直肠腺瘤病例和 1,503 个匹配对照，并生成了 28 个 IGF 通路基因中 570 个单核苷酸多态性 (SNP) 的数据。在对多重测试进行基于基因的校正后，两个 SNP 关联仍然具有统计学显着性。 rs12305513 的 G 等位基因位于癌基因 KRAS 的内含子中，与腺瘤风险增加相关（ORper 等位基因=1.36，95% CI =1.13-1.63，P=0.001）。 rs180531 的 G 等位基因位于丝氨酸/苏氨酸激酶基因 RPS6KB1 中，与腺瘤风险降低相关（ORper 等位基因=0.83，95% CI=0.73-0.95，P=0.006）。手稿正在准备中。我们开发了一系列评估骨肉瘤遗传风险因素的项目 [CAS 10375]。成骨肉瘤（OS）是最常见的恶性原发性骨肿瘤，最常见于青春期生长高峰期。作为 1995 年与 NCI 和哈佛牙科学院共同发起的 OS 前瞻性病例对照研究的一部分，我们研究了与细胞生长调节有关的许多基因/途径的遗传变异。我们在 IGF2R 基因中发现了一个与 OS 风险相关的小单倍型块。该基因组区域（靠近外显子 16）由 CpG 岛组成，对该块中的 SNP 的功能分析表明，与 OS 风险相关的特定 SNP 导致该 SNP 位点出现差异甲基化。由于 OS 是具有种系 TP53 突变（即 Li-Fraumeni 综合征）的患者的综合征定义恶性肿瘤之一，因此我们研究了 TP53 种系遗传变异作为 OS 危险因素的作用。这些数据并未表明 TP53 变异与 OS 风险之间存在密切联系，尽管它们确实提供了与 TP53 变体 IVS2+38 和 Pro72Arg 相关的 OS 风险增加的初步证据。我们最近在两份单独的出版物中更新了 OS 的描述性流行病学：一份基于 NCI 的 SEER 计划的美国数据，另一份基于多个国际癌症流行病学数据库。我们发表了一项关于身高和出生体重作为 OS 危险因素的荟萃分析。数据证实，身高是 OS 的一个重要风险因素。与出生体重相关的证据并不明确。最后，我们启动了一个国际合作项目，该项目将支持旨在识别 OS 遗传风险因素的全基因组关联研究 (GWAS)。合作者包括儿童肿瘤学小组以及欧洲和澳大利亚的多名研究人员。 GWAS 将包含大约 2000 个 OS 病例；控制措施将来自现有的 NCI 研究。第一轮基因分型已经完成，数据分析正在进行中。