Fetal Origins of Testicular Cancer: A Metabolomics Study in Newborns

睾丸癌的胎儿起源：新生儿代谢组学研究

• 批准号: 10426083
• 负责人: Catherine Metayer
• 金额: $ 18.94万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-10 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426083
• 关键词: Accounting; Address; Adolescent and Young Adult; Archives; Biochemical; Biological; Biological Assay; Biological Markers; Birth; Blood; Blood specimen; California; Cancer Survivor; Chemical Exposure; Chemicals; Clinical; Data; Deltastab; Development; Diagnosis; Diagnostic; Disease; Endocrine Disruptors; Environment; Environmental Epidemiology; Environmental Risk Factor; Ethnic Origin; Ethnic group; Etiology; Event; Exposure to; Future; Goals; Health; Human; Incidence; Individual; Infant; Informatics; Knowledge; Latino Population; Lead; Lesion; Life; Link; Male Adolescents; Male Genital Organs; Malignant Neoplasms; Malignant neoplasm of testis; Measurement; Measures; Metabolic; Metabolism; Methodology; Neonatal; Nested Case-Control Study; Newborn Infant; Onset of illness; Phenotype; Play; Population; Population Study; Pregnancy; Prevention; Prevention Research; Process; Public Health; Questionnaires; Race; Records; Reporting; Resources; Risk; Risk Factors; Role; Sample Size; Sampling; Solid Neoplasm; Specimen; Spottings; Statistical Methods; Suggestion; Sum; Technology; Testicular Germ Cell Tumor; Testing; Work; aged; biobank; biomarker discovery; burden of illness; cancer risk; case control; critical period; early onset; ethnic diversity; experience; fetal; health disparity; high dimensionality; in utero; insight; liquid chromatography mass spectrometry; male; metabolomics; mortality; multidimensional data; neglect; neonatal period; neoplasm registry; novel; phthalates; population based; predictive marker; prenatal; prenatal exposure; programs; prospective; racial and ethnic; repository; reproductive system disorder; response; screening; statistics; targeted biomarker; tumor initiation; tumorigenic

PROJECT SUMMARY/ABSTRACT Testicular cancer, mainly comprised of testicular germ cell tumors (TGCT), is the most common solid tumor among adolescent and young adult males. Its incidence has increased dramatically during the past 40 years worldwide and in the US. Compared to other racial/ethnic groups, Latinos experience the highest increase in both incidence and mortality rates since 2000, leading to major health disparities. In addition, the disease burden is high in terms of serious life-long treatment-related complications in cancer survivors, and years of potential life lost in this young population. As a result, etiologic and prevention research of TGCT is of high public health importance. The rapid increase in TGCT incidence suggests that environment plays an important etiology role, yet no environmental risk factors to date have been identified. Some reports have suggested that exposure to endocrine disrupting chemicals during pregnancy may be associated with future risk of TGCT, but no human studies have directly tested this hypothesis. TGCT is believed to have fetal origin and to develop from an initiating event occurring in utero, resulting in a precursor lesion that progresses to TGCT in nearly all cases; the difficulty in obtaining prospectively collected (pre-diagnosis) biological specimens from this critical period of development (prenatal) has posed a major limitation to the identification of environmental risk factors. The field of “exposomics” studies all relevant chemical exposures; metabolomics platforms estimate the “internal” environment of an individual that may identify both exogenous exposures involved in disease development. By leveraging newborn dried blood spots archived by the state of California on all infants born in the state, we will conduct a detailed “exposomic” analysis of fetal life that could identify environmental triggers in TGCT etiology. Using an untargeted analysis which measures thousands of exogenous and endogenous metabolites simultaneously permits us to make inference on fetal exposure and in utero metabolism and biologic response. Additionally, we will apply novel statistical methods that simultaneously examine thousands of biochemical signatures. Using a semi- targeted approach, we will also test the hypothesis that birth levels of phthalates, an endocrine disruptor associated with male genital anomalies, is associated with TGCT risk. Our proposed study is novel in that it overcomes conceptual and methodological challenges that have hindered previous studies of the fetal origin of TGCT (especially access to blood specimens collected at birth to characterize the fetal/neonatal periods); utilizes untargeted and semi-targeted approaches to identify a large number relevant biochemical signatures and to test current hypotheses in TGCT environmental epidemiology; and uses novel statistical methods to examine two and three way interactions without the need for large sample sizes. Our large and ethnically diverse California- based study population will provide the opportunity to fill important knowledge gaps about the factors contributing to TGCT.

项目概要/摘要 睾丸癌，主要由睾丸生殖细胞肿瘤（TGCT）组成，是最常见的实体瘤 过去 40 年来，青少年和年轻成年男性的发病率急剧增加。 在全球和美国，与其他种族/族裔群体相比，拉丁美洲人的增长最快。 自 2000 年以来，发病率和死亡率均呈上升趋势，导致健康状况出现重大差异。此外，疾病负担也有所增加。 癌症幸存者中严重的终生治疗相关并发症很高，并且潜在的年数 因此，TGCT 的病因学和预防研究具有很高的公共卫生意义。 TGCT 发病率的迅速增加表明环境起着重要的病因作用， 但迄今为止，尚未发现任何环境风险因素。一些报告表明，暴露于环境风险因素。 怀孕期间的内分泌干扰化学物质可能与未来 TGCT 的风险相关，但没有人类 研究直接检验了这一假设，认为 TGCT 具有胎儿起源并从初始阶段发展而来。 子宫内发生的事件，几乎在所有情况下都会导致先兆病变进展为 TGCT； 从这个发育的关键时期获得前瞻性收集（诊断前）的生物标本 （产前）对环境风险因素的识别造成了重大限制“暴露组学”领域。 研究所有相关的化学暴露；代谢组学平台估计一个人的“内部”环境 通过利用新生儿，可以识别与疾病发展有关的两种外源性暴露。 加利福尼亚州存档的所有在该州出生的婴儿的干血斑，我们将进行详细的调查 使用非针对性的方法对胎儿生命进行“暴露组学”分析，可以识别 TGCT 病因中的环境触发因素。 同时测量数千种外源性和内源性代谢物的分析使我们能够 此外，我们还将应用对胎儿暴露以及子宫内代谢和生物反应的推断。 使用半同步检查数千个生化特征的新颖统计方法。 通过有针对性的方法，我们还将检验以下假设：邻苯二甲酸盐（一种内分泌干扰物）的出生水平 与男性生殖器异常相关，与 TGCT 风险相关。我们提出的研究是新颖的。 克服了阻碍先前胎儿起源研究的概念和方法学挑战 TGCT（特别是获取出生时采集的血液样本以表征胎儿/新生儿时期）； 非靶向和半靶向方法来识别大量相关的生化特征并进行测试 TGCT 环境流行病学的当前假设；并使用新颖的统计方法来检验两个 以及不需要大样本量的三向互动。 基于研究人群将提供机会来填补有关影响因素的重要知识空白 到TGCT。