Genetic and Pharmacogenetic Modifiers of Cancer Risk and Intervention Outcomes

这些研究中的第一项--三苯氧胺相关乳腺癌风险的遗传修饰物：NSABP P1G3[CAS 7220]--是对249名浸润性乳腺癌患者(84名服用他莫昔芬；165名服用安慰剂)中19个不同基因的39个SNP进行的病例/病例分析。通过单SNP关联和单倍型分析，这是一项无效研究。然而，在他莫昔芬(耐药基因类型)存在的病例中出现的等位基因群特征与未暴露(安慰剂)病例不同。这种途径分析方法产生了一个等位基因标记，可能作为他莫昔芬耐药性的预测生物标记物。这些结果刚刚发表。这个项目现在已经完成了。利用前列腺癌、肺癌、结肠癌和卵巢癌(PLCO)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风险之间的关系[CAS 7300]，数据表明IGFS可能代表潜在的可改变的癌症危险因素。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，以及800名匹配的非腺瘤受试者。对7个IGF相关基因(IGF1、IGF-BP3、ALS、IGF-1R、IGF-BP5、IGF2和GH)中的37个SNP进行了基因分型，并检测了循环中IGF-1、IGF-2和IGFBP-3的水平。后者证明，在控制IGF-2、IGF-BP3和许多其他协变量的情况下，IGF-1最高四分位数与最低四分位数相比，腺瘤风险增加1.7倍(95%C.I.1.2-2.5)。这些数据现在正在印刷中。尽管我们证实了先前观察到的IGF-BP3-01(Rs2854744)与IGF-BP3-07(Rs6413441)和对照组中循环IGF-BP3水平之间的新关联，但将遗传变异作为进展期腺瘤的主要危险因素的评估是无效的。这两个SNP使IGF-BP-3水平降低222个单位和148个单位(平均IGF-BP3水平4,000个单位)。这项研究通过增加DCEG罕见癌症iSelect研究的额外基因分型数据进行了扩展，该研究偶然地分析了同一组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例晚期结直肠腺瘤和1,503例匹配对照，并产生了28个IGF途径基因中570个单核苷酸多态(SNPs)的数据。在对多重检测进行基于基因的校正后，两个SNP关联在统计学上仍然显著。Rs12305513的G等位基因位于癌基因KRAS的一个内含子上，与腺瘤的危险性增加相关(OR值为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，与腺瘤风险降低相关(OR值为0.83，95%CI=0.73~0.95，P=0.006)。一份手稿正在准备中。我们已经开发了一系列评估骨肉瘤遗传风险因素的项目[中国科学院10375]。骨肉瘤(OS)是最常见的恶性原发骨肿瘤，最常发生在青春期。作为1995年与美国国立卫生研究院和哈佛大学牙学院共同开展的一项关于OS的前瞻性病例对照研究的一部分，我们研究了与细胞生长调控有关的许多基因/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区块。该基因组区域(靠近外显子16)由CpG岛组成，对该区块中SNP的功能分析表明，与OS风险相关的特定SNP导致了该SNP位点的差异甲基化。由于OS是具有生殖系TP53突变(即Li-Fraumeni综合征)的患者的症候定义恶性肿瘤之一，我们调查了TP53胚系遗传变异作为OS危险因素的作用。这些数据并未表明TP53基因变异与OS风险之间存在明显联系，尽管它们确实提供了与TP53变异IVS2+38和Pro72Arg相关的OS风险增加的初步证据。我们最近在两个独立的出版物中更新了OS的描述性流行病学：一个基于NCI的SEER计划的美国数据，另一个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风险因素的荟萃分析。数据证实，身高是OS的一个重要风险因素。与出生体重有关的证据并不是决定性的。最后，我们启动了一个国际合作项目，该项目将支持一项旨在确定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调查人员。GWAS将由大约2000个操作系统案例组成；对照将来自现有的NCI研究。第一轮基因分型工作已经完成，数据分析正在进行中。

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.