Genetic Modifiers of Cancer Risk

癌症风险的基因修饰因素

• 批准号: 9339151
• 负责人: Sharon A. Savage
• 金额: $ 51.78万
• 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/9339151
• 关键词: 6p21.3; Acute; Adolescent; Adult; Alleles; Anabolism; BRCA1 gene; BRCA2 Mutation; Biological Assay; Biological Availability; Birth Weight; Bone neoplasms; Breast; Cancer Etiology; Cancer Prevention Intervention; Case-Control Studies; Clinical Trials Cooperative Group; Collaborations; Collection; Colorectal Adenoma; Communities; Counseling; Country; DNA; DNA Repair; Data; Databases; Dental Schools; Descriptive Epidemiology; Diagnosis; Division of Cancer Epidemiology and Genetics; Drug Metabolic Detoxication; Early Diagnosis; Educational workshop; Event; Exposure to; Extramural Activities; Foundations; Frequencies; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Germ-Line Mutation; Goals; Growth; Haplotypes; Height; Hereditary Breast and Ovarian Cancer Syndrome; IGF1 gene; IGF2 gene; Individual; 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; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Manuscripts; Meta-Analysis; Modeling; Morbidity - disease rate; Mutation; Myelosuppression; NFIB gene; National Surgical Adjuvant Breast and Bowel Project; Neoplasm Metastasis; Oncogenes; Outcome; Participant; Pathway Analysis; Pathway interactions; Patients; Peer Review; Penetrance; Pharmaceutical Preparations; Phenotype; Pilot Projects; Placebos; Population; Protein-Serine-Threonine Kinases; Publications; Publishing; Research Personnel; Resistance; Resources; Risk; Risk Assessment; Risk Factors; SEER Program; Sampling; Screening for cancer; Second Primary Cancers; Sequence Analysis; Series; Signal Pathway; Signaling Protein; Single Nucleotide Polymorphism; Somatomedins; Stratification; Tamoxifen; Testing; Time; Treatment Efficacy; Update; Validation; Variant; Woman; Work; 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; metabotropic glutamate receptor 4; mutation carrier; novel; osteosarcoma; ovarian cancer prevention; personalized approach; predictive marker; prospective; 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 Osteosarcoma [CAS 10375]. Osteosarcoma (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 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 also 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 is currently being analyzed. We performed a case-case GWAS of osteosarcoma patients with and without metastases at diagnosis which identified novel functional variants in NFIB as associated with metastasis. Our sequence analysis of TP53in osteosarcoma cases found a higher than expected frequency of germline mutations in individuals with osteosarcoma.We also contributed to a Workshop that brought together key opinion leaders and experts in the metastasis and osteosarcoma communities and which focused on developing therapeutics that target metastatic progression. 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 40 peer-reviewed publications and an additional 8 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. The highest impact publication during the past year has been the massive genotype/phenotype analysis of CIMBA's collection of 20,000 BRCA1 and 12,000 BRCA2 mutation carriers from 55 centers in 33 countries on 6 continents (T Rebbeck et al., JAMA 2015; 313(13):1347-1361) which identified multiple specific regions within each gene that were associated with higher or lower risks of breast or ovarian cancer. This work should form the foundation of being able to counsel patients regarding their cancer risks based on the specific mutation they carry.

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。 我们已经开发了一系列项目组合，这些项目评估了骨肉瘤的遗传危险因素[CAS 10375]。骨肉瘤（OS）是最常见的恶性原发性骨肿瘤，最常见于青少年生长突变中。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。我们还发布了第一个由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;目前正在分析验证OS队列。我们进行了骨肉瘤患者的病例案例GWA，并在诊断时进行转移和没有转移，该患者鉴定了NFIB中的新功能变异与转移有关。我们对TP53IN骨肉瘤病例的序列分析发现，骨肉瘤个体中种系突变的预期频率高于预期的频率。我们还为一个研讨会做出了贡献，该研讨会汇集了转移和骨肉瘤群落的关键意见领导者和专家，并侧重于开发靶向转移性进展的治疗方法。 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40份经过同行评审的出版物和另外的8次手稿，所有这些手稿都侧重于检测HBOC环境中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。过去一年的影响最高的是CIMBA收集的20,000个BRCA1和12,000个BRCA2突变携带者的大量基因型/表型分析，来自6个大洲的33个国家的55个中心（T Rebbeck等人，JAMA 2015; JAMA 2015; 313（13）：1347-1361）在每个基因中均与癌症相关或较低的癌症中有较高的癌症或较低的癌症。这项工作应该构成能够根据他们携带的特定突变来向患者提供癌症风险的基础。