Fetal Origins of Testicular Cancer: A Metabolomics Study in Newborns

项目摘要/摘要 睾丸癌是最常见的实体肿瘤，主要包括睾丸生殖细胞肿瘤(TGCT)。 在青春期和年轻成年男性中。在过去的40年里，它的发病率急剧上升。 在世界各地和美国。与其他种族/民族相比，拉美裔经历了最高的增长 自2000年以来，发病率和死亡率都很高，导致了严重的健康差距。此外，疾病负担 癌症幸存者的严重终身治疗相关并发症的发生率很高，而且有多年的潜在 在这些年轻的人群中失去了生命。因此，TGCT的病原学和预防研究具有很高的公共卫生性。 重要性。TGCT发病率的快速上升表明环境在病因中起着重要作用， 然而，到目前为止，还没有确定任何环境风险因素。一些报告表明，接触到 怀孕期间的内分泌干扰化学物质可能与TGCT的未来风险有关，但人类 研究已经直接验证了这一假设。TGCT被认为起源于胎儿，并从一开始 发生在子宫内的事件，导致前驱病变，几乎在所有病例中都进展为TGCT；困难 在这一发育的关键时期获得预期收集的(诊断前)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 可识别与疾病发展有关的两种外源性暴露的个人。通过利用新生儿 加利福尼亚州存档的干血点对所有在该州出生的婴儿，我们将进行详细的 对胎儿生命的“暴露”分析可以确定TGCT病因学中的环境触发因素。使用未定向的 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 对胎儿暴露、宫内代谢和生物反应作出推断。此外，我们将申请 新颖的统计方法，可以同时检查数千个生化信号。使用半- 有针对性的方法，我们还将测试出生时邻苯二甲酸盐水平的假说，邻苯二甲酸酯是一种内分泌干扰物 与男性生殖器畸形相关，与TGCT风险相关。我们提议的研究是新颖的，因为它 克服了概念和方法上的挑战，这些挑战阻碍了以前对胎儿起源的研究 TGCT(特别是获取出生时采集的血液样本以确定胎儿/新生儿时期的特征)；利用 非目标和半目标的方法，以识别大量相关的生化特征并测试 TGCT环境流行病学的当前假设；并使用新的统计方法检验两个 以及无需大样本容量的三向交互作用。我们幅员辽阔、种族多样的加利福尼亚州- 基于研究群体的研究将提供机会来填补有关促成因素的重要知识空白 致TGCT。

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.