Genetic and Pharmacogenetic Modifiers of Cancer Risk and Intervention Outcomes

这些研究中的第一项——他莫昔芬相关乳腺癌风险的遗传修饰因子：NSABP P1G3 [CAS 7220]——对249名浸润性乳腺癌女性（84名暴露于他莫昔芬，165名安慰剂）中19种不同基因的39个snp进行了病例/病例分析。单SNP关联和单倍型分析为无效研究。然而，他莫昔芬（耐药基因型）下出现的病例的等位基因群与未暴露（安慰剂）病例的等位基因群不同。这种途径分析方法产生了一个等位基因特征，可能有潜力作为他莫昔芬耐药性的预测性生物标志物。利用前列腺、肺、结肠和卵巢（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风险之间的关系[CAS 7300]，数据表明IGF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。完成了7个igf相关基因（IGF1、IGF-BP3、ALS、IGF-1R、IGF-BP5、IGF2和GH）的37个单核苷酸多态性的基因分型，并测定了IGF-1、IGF-2和IGFBP-3的循环水平。后者记录了在控制IGF-2、IGF-BP3和许多其他协变量的情况下，IGF-1最高四分位数比最低四分位数的腺瘤风险增加1.7倍（95% C.I. 1.2-2.5）。尽管我们证实了之前观察到的IGF-BP3-01 （rs2854744）和IGF-BP3-07 （rs6413441）与对照中IGF-BP3循环水平之间的密切关系，但遗传变异作为晚期腺瘤的主要危险因素的评估是无效的。这两个小等位基因分别使IGF-BP-3水平降低222和148个单位（平均IGF-BP3水平降低4000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，该研究得到了扩展，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研究：研究了1338例晚期结直肠腺瘤病例和1503例匹配对照，并生成了28个IGF通路基因的570个单核苷酸多态性（snp）的数据。两个SNP关联在多次测试的基因校正后仍然具有统计学意义。rs12305513的G等位基因位于癌基因KRAS的内含子中，与腺瘤的风险增加相关（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上，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）。我们已经开发了一系列评估成骨肉瘤遗传风险因素的项目[CAS10375]。骨源性肉瘤（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年由NCI和哈佛牙科学院发起的一项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（近外显子16）由CpG岛组成，该区域SNP的功能分析表明，与OS风险相关的特定SNP导致该SNP位点的差异甲基化。由于OS是种系TP53突变（即Li-Fraumeni综合征）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。这些数据并没有表明TP53变异和OS风险之间有很强的联系，尽管它们确实提供了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NCIs 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。目前正在审查一项荟萃分析；它的目的是澄清身高和出生体重是OS的风险因素。数据证实，身高是患OS的重要风险因素。与出生体重有关的证据并不确定。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小组，以及欧洲和澳大利亚的多名研究人员。GWAS将包括大约2000个操作系统案例；对照将来自现有的NCI研究。

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..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. 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). We have developed a portfolio of projects evaluating Genetic Risk Factors for Osteogenic Sarcoma [CAS10375]. 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 NCIs SEER program, and the other based on multiple international cancer epidemiology databases. A meta-analysis is currently under review; it was aimed at clarifying height and birth weight as OS risk factors. The data confirm 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 Childrens 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.