Fetal Origins of Testicular Cancer: A Metabolomics Study in Newborns

项目概要/摘要 睾丸癌是最常见的实体瘤，主要包括睾丸生殖细胞肿瘤（TGCT 在青少年和年轻的成年男性中。在过去的40年里，其发病率急剧增加 在世界各地和美国。与其他种族/族裔群体相比，拉丁美洲人的增长率最高， 自2000年以来，发病率和死亡率均有所下降，导致了重大的健康差距。此外，疾病负担 在癌症幸存者中，严重的终身治疗相关并发症的发生率很高， 在这个年轻的群体中失去了生命。因此，TGCT的病因学和预防研究具有重要的公共卫生意义 重要性TGCT发病率的快速增加表明环境在病因学中起重要作用， 然而，迄今尚未发现任何环境风险因素。一些报告表明， 怀孕期间的内分泌干扰物可能与未来的TGCT风险有关，但没有人类 研究直接验证了这一假设。TGCT被认为具有胎儿起源，并从起始的 在子宫内发生的事件，导致几乎所有病例中进展为TGCT的前驱病变; 在从这一关键的发育时期获得前瞻性收集的（诊断前）生物标本时， （产前）对环境风险因素的识别造成了重大限制。“经济学”领域 研究所有相关的化学品暴露;代谢组学平台估计一个人的“内部”环境。 个体可以识别参与疾病发展的两种外源性暴露。通过利用新生儿 加州州对该州出生的所有婴儿的干血斑存档，我们将进行详细的 对胎儿生命的“基因组学”分析，可以识别TGCT病因中的环境触发因素。使用非目标 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 对胎儿暴露和子宫内代谢及生物反应进行推断。此外，我们将申请 新的统计方法，同时检查成千上万的生化签名。使用半- 有针对性的方法，我们还将测试的假设，邻苯二甲酸酯，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， 克服了阻碍以前研究胎儿起源的概念和方法上的挑战， 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）;利用 非靶向和半靶向的方法来鉴定大量相关的生物化学特征， TGCT环境流行病学的当前假设;并使用新的统计方法来研究两个 和三种方式的相互作用，而不需要大的样本量。我们庞大而种族多样的加州- 研究人群将提供机会，填补有关影响因素的重要知识空白 到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.