Perinatal hormonal biomarkers and risk of testicular germ cell tumors

描述(申请人提供)：睾丸癌(TC)是青少年和年轻人中最常见的癌症，而在婴儿中很少见。在过去的40年里，TC在美国的发病率急剧上升。与非西班牙裔白人相比，拉美裔美国人的发病率和死亡率上升得更快，加剧了少数族裔的健康差距。TC多为生殖细胞肿瘤(TGCT)，其组织学类型(精原细胞瘤与非精原细胞瘤)随年龄而异。TGCT的危险因素知之甚少。一些疾病，如隐睾症，导致了TGCT的风险，最近发现了遗传因素。环境因素仍然是TGCT的重要决定因素，发病率的上升证明了这一点。雌激素和雄激素(也称为类固醇性激素)在睾丸发育中起核心作用，并可能直接或通过暴露于杀虫剂中存在的有机氯等内分泌干扰物而在TGCT的病因学中发挥主导作用。由于发病早，TGCT很可能在怀孕期间发生，这段时间男性胎儿暴露在高水平的类固醇性激素中。TGCT发展的另一个关键窗口可能是从宫内生活向宫外生活的过渡，这一转变的特点是母体激素突然停止，新生儿自身的类固醇性激素和其他调节激素如促性腺激素在出生后激增。评估围产期性激素在TGCT中的潜在作用，包括暴露的时间，已被证明具有挑战性，主要是因为在获得产前诊断、围产期生物检疫方面存在困难。我们建议的探索性研究的目的是提供1988年和2009年加州出生的男性TGCT患者(150例15-19岁和50例0-4岁)和200名年龄/种族匹配的对照组的出生激素水平的初步数据。我们将使用出生时收集的干燥血斑(DBS)存档样本，并通过加州儿童癌症记录链接项目(CCRLP)向我们提供。可用于检测DBS标本中的类固醇性激素(即雌酮、雌二醇、雌三醇、睾酮和脱氢表雄酮)和促性腺激素(即促黄体激素和卵泡刺激素)的可靠实验室方法(即液-质联用和免疫分析)。荷尔蒙水平将在病例和对照组之间进行总体比较，并按年龄、组织学和种族进行比较。我们提出的探索性生物标记物研究将是填补目前非西班牙裔白人和西班牙裔TGCT病因学知识空白的关键一步，以及量化出生时可能与包括不育症在内的其他睾丸疾病有关的性激素水平。

DESCRIPTION (provided by applicant): Testicular cancers (TC) are the most common cancers in adolescents and young adults, while rare in infants. TC incidence increased dramatically in the US the past 40 years. Compared to non-Hispanic Whites, the incidence and mortality rates are increasing more rapidly in Hispanics, worsening minority health disparities. TC is mostly germ cell tumors (TGCT) and the histologic types (seminomas vs. nonseminomas) vary with age. The risk factors of TGCT are poorly understood. A few conditions such as cryptorchidism contribute to TGCT risk, and genetic factors have been recently identified. Environmental factors remain important determinants of TGCT, as evidenced by the raise in incidence rates. Estrogens and androgens (also called steroid sex hormones) have a central role on the development of the testis, and may play a dominant role in the etiology of TGCT, either directly or via mediation by exposure to endocrine disrupting chemicals such as organochlorines present in pesticides. Because of its early onset, TGCT are likely to develop during pregnancy, a period when the male fetus is exposed to high levels of steroid sex hormones. Another critical window for the development of TGCT may be the transition from intra-uterine to extra-uterine life, which is marked by an abrupt withdrawal of maternal hormones and a postnatal surge of the newborns' own steroid sex hormones and other regulatory hormones such as gonadotropins. Assessing the potential role of perinatal sex hormones, including the timing of exposure, in TGCT has proven challenging, mainly due to difficulties in obtaining pre-diagnosis, perinatal biospecimens. The objective of our proposed exploratory study is to provide preliminary data on birth hormone levels in California-born males diagnosed with TGCT from 1988 and 2009 (150 cases aged 15-19 years and 50 cases aged 0-4 years) and 200 age/ethnicity-matched controls. We will use archived dried bloodspot (DBS) specimens collected at birth and available to us through the California Childhood Cancer Record Linkage Project (CCRLP). Robust laboratory methods (i.e., liquid chromatography- mass spectrometry and immunoassays) are available to measure steroid sex hormones (i.e., estrone, estradiol, estriol, testosterone, and dehydroepiandrosterone) and gonadotropins (i.e., luteinizing hormone and follicle-stimulating hormone) in DBS specimens. Hormone levels will be compared between cases and controls overall, and by age, histologic, and ethnic group. Our proposed exploratory biomarker study will be a key step towards filling gaps in the current knowledge of TGCT etiology in non-Hispanic Whites and Hispanics, as well as quantifying sex hormone levels at birth that may be involved in other testicular conditions including infertility.