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.

项目摘要/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 在青少年和年轻男性中。在过去的40年中，其发病率急剧增加 在全球和美国。与其他种族/种族相比，拉丁美洲人的经历最高 自2000年以来的事件和死亡率都导致了重大的健康分布。此外，伯恩疾病 在癌症存活中与终身治疗相关的严重治疗并发症方面高度很高，潜力多年 在这个年轻人口中丧生。结果，TGCT的病因学和预防研究是高公共卫生的 重要性。 TGCT事件的快速增加表明，环境起着重要的病因学作用， 然而，迄今为止尚未确定环境风险因素。一些报告表明，接触 怀孕期间的内分泌破坏化学物质可能与未来的TGCT风险有关，但没有人类 研究直接检验了这一假设。据信TGCT具有胎儿来源并从开始 在子宫内发生的事件，导致前体病变，几乎在所有情况下都会发展为TGCT；困难 从这个关键的发育时期获得前瞻性收集的（诊断前）生物学标本 （产前）已将确定环境风险因素的识别定位为主要限制。 “杂种学”领域 研究所有相关的化学暴露；代谢组学平台估计 可能识别出疾病发展涉及的两种外源性暴露的人。通过利用新生儿 加利福尼亚州对该州的所有婴儿存档的干血点，我们将进行详细的 对胎儿生活的“外博分析”，可以确定TGCT病因中的环境触发因素。使用不靶向的 测量数千种外源和内源性代谢物的分析只会使我们进入 推断胎儿暴露以及子宫代谢和生物反应。此外，我们将申请 新型统计方法，简单地检查了数千种生化特征。使用半 有针对性的方法，我们还将检验以下假设：邻苯二甲酸盐的出生水平，内分泌干扰器 与男性生殖器异常有关，与TGCT风险有关。我们提出的研究是新颖的 克服了概念和方法论挑战，这些挑战阻碍了先前对胎儿起源的研究 TGCT（尤其是在出生时收集的血液标本以表征胎儿/新生儿时期的血液标本）；利用 未定位和半目标的方法，以识别大量相关的生化特征并进行测试 TGCT环境流行病学中的当前假设；并使用新颖的统计方法检查两种 而三向相互作用，无需大型样本量。我们的大型和种族多样化的加利福尼亚 - 基于的研究人群将提供机会填补有关促成因素的重要知识差距 到TGCT。