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: 8938238
• 负责人: MARK H GREENE
• 金额: $ 45.25万
• 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/8938238
• 关键词: 6p21.3; Acute; Adolescent; Adult; Alleles; Anabolism; BRCA1 gene; Biological; Biological Assay; Biological Availability; Biological Markers; Biology; Birth Weight; Bone neoplasms; Breast; Cancer Etiology; Cancer Intervention; Cancer Prevention Intervention; Canis familiaris; Case-Control Studies; Clinical Trials Cooperative Group; Collaborations; Colorectal Adenoma; Communities; Consensus; CpG Islands; DNA; DNA Repair; Data; Databases; Dental Schools; Descriptive Epidemiology; Disease; Division of Cancer Epidemiology and Genetics; Drug Metabolic Detoxication; Early Diagnosis; Educational workshop; Effectiveness; Evaluation; Event; Exons; Exposure to; Extramural Activities; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Germ Lines; Goals; Growth; Haplotypes; Height; Hereditary Breast and Ovarian Cancer Syndrome; Human; 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; Junk DNA; KRAS2 gene; Lesion; Li-Fraumeni Syndrome; Link; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Manuscripts; Maps; Measurable Disease; Meta-Analysis; Methylation; Modeling; Morbidity - disease rate; Mus; Mutation; Myelosuppression; National Surgical Adjuvant Breast and Bowel Project; Neoplasm Metastasis; Oncogenes; Outcome; Participant; Pathway Analysis; Pathway interactions; Patients; Peer Review; Penetrance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Phenotype; Pilot Projects; Placebos; Population; Predisposition; Process; Protein-Serine-Threonine Kinases; Publications; Publishing; Research Personnel; Resistance; Resources; Risk; Risk Assessment; Risk Factors; Role; SEER Program; Sampling; Screening for cancer; Second Primary Cancers; Series; Signal Pathway; Signaling Pathway Gene; Single Nucleotide Polymorphism; Site; Somatomedins; Stratification; Syndrome; TP53 gene; Tamoxifen; Testing; Therapeutic Agents; Time; Translations; Treatment Efficacy; Update; Validation; Variant; Woman; adenoma; base; cancer epidemiology; cancer risk; cancer therapy; cell growth regulation; chemical carcinogen; clinical decision-making; cohort; design; experience; exposed human population; genetic risk factor; genetic variant; genome wide association study; genome-wide; hormone metabolism; improved; malignant breast neoplasm; meetings; metabotropic glutamate receptor 4; mutation carrier; osteosarcoma; ovarian cancer prevention; pre-clinical; prospective; response; therapeutic target; treatment response

The first project -Genetic Modifiers of Tamoxifen-Related Breast Cancer Risk: NSABP P1G3- 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 published pathway analysis approach generated an allelic signature that has potential as a predictive biomarker of tamoxifen resistance. This project is now complete.Using NCI's 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, 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. 37 SNPs in 7 IGF-related genes (IGF1, IGF-BP3, ALS, IGF-1R, IGF-BP5, IGF2, GH) were genotyped, and circulating levels of IGF-1, IGF-2 and IGFBP-3 were assayed. 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 have been published. We also 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. 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, one in an intron of the oncogene, KRAS, was associated an increased risk of adenoma (OR per allele=1.36, 95% CI =1.13-1.63, P=0.001), and the other in the serine/threonine kinase gene, RPS6KB1, was associated with a reduced risk of adenoma (OR per allele=0.83, 95% CI=0.73-0.95, P=0.006). This project is now complete. 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. We recently published the first multistage GWAS targeting OS consisting of 941 OS subjects and 3,291 cancer-free adult controls. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 10-9) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 10-8 and 2.9 10-7, respectively). A validation OS cohort has been assembled to confirm our observations. In addition, these two loci are now undergoing fine-mapping/re-sequencing to uncover the biological mechanisms underlying susceptibility to osteosarcoma. We contributed to a Workshop that brought together key opinion leaders and experts in the metastasis and osteosarcoma communities and which focussed on developing therapeutics that target metastatic progression. The goal of this meeting was to provide a perspective that would establish a preclinical translational path that could support the early evaluation of potential therapeutic agents that uniquely target the metastatic phenotype. The consensus achieved from the meeting included the following: the biology of metastatic progression is associated with metastasis-specific targets/processes that may not influence grossly detectable lesions; targeting of metastasis-specific processes is feasible; rigorous preclinical data are needed to support translation of metastasis-specific agents into human trials where regression of measurable disease is not an expected outcome; preclinical data should include an understanding of mechanism of action, validation of pharmacodynamic markers of effective exposure and response, the use of several murine models of effectiveness, and where feasible the inclusion of the dog with naturally occurring osteosarcoma to define the activity of new drugs in the micro-metastatic disease setting. Finally, we have contributed more than 1,000 BRCA1/2 mutation carriers accrued from three related studies (Etiologic Studies of Hereditary Breast/Ovarian Cancer [HBOC], Pilot Study of Breast MRI in HBOC, and the National Ovarian Cancer Prevention and Early Detection Study) to identify genetic modifiers of BRCA1/2-related breast and ovarian cancer. This project is a collaboration with the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) which has yielded 32 peer-reviewed publications and an additional 7 manuscripts under review, all focused on detecting common, low-penetrance genetic variants which modify the risk of breast and ovarian cancer in the HBOC context. This project is designed to help develop more precise cancer risk stratification models which might permit more accurate cancer risk assessment in women with HBOC.

第一个项目-他莫昔芬相关乳腺癌风险的遗传修饰因子：NSABP P1G3-是对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的病例/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。这一已发表的通路分析方法产生了一个等位基因标记，有可能作为他莫昔芬耐药性的预测性生物标志物。这个项目现在完成了。使用NCI的PLCO癌症筛查试验，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，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，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、GH）的37个snp进行基因分型，并检测IGF-1、IGF-2、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）。这些数据已经公布。我们还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。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。在基于基因的多重检测校正后，两个SNP关联仍然具有统计学意义，一个在癌基因KRAS内含子中，与腺瘤的风险增加相关（每个等位基因的OR =1.36, 95% CI= 1.13-1.63， P=0.001），另一个在丝氨酸/苏氨酸激酶基因RPS6KB1中，与腺瘤的风险降低相关（每个等位基因的OR =0.83, 95% CI=0.73-0.95， P=0.006）。这个项目现在完成了。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[CAS 10375]。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NCI的SEER项目的美国数据，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，身高是患OS的重要风险因素。与出生体重有关的证据并不确定。我们最近发表了第一个针对OS的多阶段GWAS，包括941名OS受试者和3291名无癌成人对照。两个位点具有全基因组意义：GRM4基因中6p21.3位点（编码谷氨酸受体代谢4；rs1906953; P = 8.1 10-9）和基因沙漠中2p25.2位点（rs7591996和rs10208273； P分别= 1.0 10-8和2.9 10-7）。一个验证OS队列已被组装来证实我们的观察。此外，这两个基因座目前正在进行精细定位/重新测序，以揭示骨肉瘤易感性的生物学机制。我们参与了一个研讨会，该研讨会汇集了转移和骨肉瘤社区的主要意见领袖和专家，并专注于开发针对转移进展的治疗方法。这次会议的目的是提供一个视角，建立一个临床前转化路径，可以支持早期评估潜在的治疗药物，唯一针对转移性表型。会议达成的共识包括：转移进展的生物学与转移特异性靶点/过程有关，这些靶点/过程可能不会影响肉眼可检测的病变；靶向转移特异性过程是可行的；需要严格的临床前数据来支持将转移特异性药物转化为人体试验，其中可测量疾病的回归不是预期结果；临床前数据应包括对作用机制的理解，有效暴露和反应的药效学标记物的验证，几种小鼠有效性模型的使用，以及在可行的情况下纳入患有自然发生的骨肉瘤的狗，以确定新药在微转移疾病环境中的活性。最后，我们贡献了来自三个相关研究（遗传性乳腺癌/卵巢癌病因学研究[HBOC]、乳腺MRI在HBOC中的试点研究和国家卵巢癌预防和早期检测研究）的1000多名BRCA1/2突变携带者，以确定BRCA1/2相关乳腺癌和卵巢癌的遗传修饰因子。该项目是与BRCA1/2修饰剂研究联盟（CIMBA）合作开展的，该联盟已经发表了32篇同行评议的出版物，另外还有7篇手稿正在审查中，所有这些都集中在检测常见的、低外显率的遗传变异，这些变异可以改变HBOC背景下乳腺癌和卵巢癌的风险。该项目旨在帮助开发更精确的癌症风险分层模型，从而可以更准确地评估HBOC妇女的癌症风险。