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.

他莫昔芬相关乳腺癌的第一个项目 - 基因修饰符：NSABP P1G3-是对249名浸润性乳腺癌女性中19个不同基因中39个SNP的病例/病例分析（暴露于他莫昔芬； 165个安慰剂）。这是单个SNP关联和单倍型分析的无效研究。然而，在他莫昔芬（耐药基因型）存在下出现的病例的等位基因的星座与未暴露（安慰剂）病例的情况不同。这种已发表的途径分析方法产生了一种等位基因特征，该标志具有潜在的他莫昔芬抗性的预测生物标志物。该项目现已完成。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）信号传导途径和晚期结直肠腺瘤的风险之间的关系，这表明IGFS可能代表潜在的可修改可修改的癌症风险因素。我们已经分析了800名参与者在基线屏幕时具有晚期结直肠腺瘤，以及800名匹配的非腺瘤受试者。在7个与IGF相关的基因（IGF1，IGF-BP3，ALS，IGF-1R，IGF-BP5，IGF2，GH）中进行了37个SNP，并分析了IGF-1，IGF-1和IGFBP-3的循环水平。后者记录了最高与最低四分位数的腺瘤风险增加1.7倍（95％C.I. 1.2-2.5），该风险对IGF-2，IGF-2，IGF-BP3和许多其他协变量进行了控制。这些数据已发布。我们还证实了IGF-BP3-01（rs2854744）与IGF-BP3-07（rs6413441 rs6413441）与IGF-BP3循环水平之间的新关联。通过添加DCEG罕见癌症研究中的其他基因分型数据扩展了这项研究，该数据偶然地分析了相同的DNA样品。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例晚期结直肠腺瘤病例和1,503个匹配的对照，并在28个IGF途径基因中生成了570个单核苷酸多态性（SNP）的数据。在基于基因的多次测试校正后，两种SNP关联在统计学上具有显着意义，其中一项在癌基因的内含子KRAS的内含子中增加了腺瘤的风险增加（或per aper等位基因= 1.36，95％CI = 1.13-1.63，p = 0.001），p = 0.001），另一个与丝氨酸/硫酶基因的风险相关。等位基因= 0.83，95％CI = 0.73-0.95，p = 0.006）。该项目现已完成。 我们已经开发了一组项目组合，评估了成骨肉瘤的遗传危险因素[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突变中。作为1995年NCI和哈佛牙科学校的OS的前瞻性病例对照研究的一部分，我们研究了许多基因/途径的遗传变异，这些基因/途径与细胞的生长调节有关。我们确定了与IGF2R基因中OS风险相关的小单倍型块。该基因组区域（外显子16附近）由CPG岛组成，该区块中SNP的功能分析表明，与OS风险相关的特定SNP导致该SNP部位的甲基化差异。因为OS是综合征定义的恶性肿瘤之一，在具有种系TP53突变（即Li-Fraumeni综合征）的患者中，我们研究了种系遗传变异在TP53中作为OS风险因素的作用。这些数据并未表明TP53和OS风险之间的变化之间存在牢固的联系，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。我们最近在两个单独的出版物中更新了OS的描述性流行病学：一个基于NCI 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。我们将身高和出生体重作为OS危险因素发表了荟萃分析。数据证实高度是OS的重要危险因素。与出生体重有关的证据不是确定的。我们最近发表了第一个由941位OS受试者和3,291个无癌症的成人对照组成的多阶段GWAS靶向OS。两个基因组在基因组范围内达到了重要性：GRM4基因中的一个基因座，在6p21.3处（编码谷氨酸受体代谢4; rs1906953; rs1906953; p = 8.1 10-9），在2p25.2处的基因沙漠中的一个基因座（RS7591966和RS759196和RS102020202020202020202020202020202020202020202020202.0-10-10-10-10-10-10.0-9.0-10.0-10.0-90;已经组装了验证OS队列以确认我们的观察结果。此外，这两个基因座现在正在进行精细映射/重新测序，以发现对骨肉瘤敏感的生物学机制。我们为一个研讨会做出了贡献，该研讨会汇集了转移和骨肉瘤社区的关键意见领导者和专家，并着重于开发针对转移进展的治疗剂。这次会议的目的是提供一种观点，该观点将建立临床前翻译路径，该路径可以支持对唯一针对转移表型的潜在治疗剂的早期评估。会议中获得的共识包括以下内容：转移性进展的生物学与可能不会影响严重可检测到的病变的转移特异性靶/过程有关；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转移特异性药物转化为人类试验的转化，在这些试验中，可测量疾病的消退不是预期的结果；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志物的验证，使用几种鼠有效性模型以及可行的狗与自然发生的骨肉瘤的可行性，以定义新药物在微型中移位疾病环境中的活性。 最后，我们从三项相关研究（遗传性乳腺/卵巢癌的病因研究[HBOC]，HBOC中的乳腺MRI试验研究以及全国卵巢癌预防和早期检测研究中贡献了1,000多个BRCA1/2突变携带者（病因研究），以鉴定BRCA1/2-估计乳腺癌和卵巢癌的遗传学改性剂。该项目是与BRCA1/2（CIMBA）修饰符的研究人员的合作，该联盟已产生了32份经过同行评审的出版物，并审查了另外7项手稿，所有这些手稿都集中在HBOC环境中检测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，这些模型可能允许患有HBOC女性的癌症风险评估更准确。