MOLECULAR BIOMARKERS FOR PROSTATE CANCER SUSCEPTIBILITY

前列腺癌是一个重大的公共健康问题，大约五分之一的美国男性受其影响。然而，人们对前列腺癌的病因知之甚少。除了确定的风险因素（年龄、种族和家族史）外，膳食脂肪摄入的暗示证据是存在的，但尚不确定。前列腺癌的发病率随着年龄的增长而增加，因此我们必须提高对前列腺疾病发展和进展的潜在机制的理解。由于缺乏与前列腺癌发生、肿瘤进展和转移相关的足够的分子和遗传标记，理解这种机制的努力受到阻碍。在这项初步研究中，我们将在前列腺癌患者和对照组的外周血淋巴细胞中使用暴露（DNA加合物）、效应（细胞遗传学终点）和易感性（DNA修复能力的个体间差异）的互补分子生物标志物，以更好地了解前列腺癌的发展机制。我们的假设是，DNA修复能力改变和DNA加合物水平升高的个体，将会有足够数量的数字和结构染色体损伤，从而允许肿瘤转化。我们将在100例前列腺癌患者和100例健康对照中验证我们的假设。在这项研究中，我们将1)描述染色体不稳定性的作用，2)获取DNA损伤和修复能力，3)比较背景和诱变剂诱导的前列腺癌患者和对照组血液培养中的DNA加合物水平。我们还将确定这些生物标志物与前列腺癌风险之间的关系，并调整其他已知的流行病学风险因素，这些因素可能对背景遗传不稳定性有影响。这项初步研究的结果将有助于验证这种综合方法在未来大规模流行病学研究中的实用性。

Prostate cancer is a major public health problem, affecting an estimated one in five American men. However, little is known about the causes of prostate cancer. Aside from the well established risk factors (age, race and family history) suggestive evidence for dietary fat intake exists but is yet inconclusive. Prostate cancer incidence increases with advancing age, it is imperative therefore that we improve our understanding of the underlying mechanisms that dictate the development and progression of prostatic disease. Efforts to understand such mechanisms are hampered by the lack of adequate molecular and genetic markers associated with prostate carcinogenesis, tumor progression and metastasis. In this pilot study we will use complementary molecular biomarkers of exposure (DNA adducts), effect (cytogenetic end-points) and susceptibility (interindividual variation in DNA repair capacity) in the peripheral blood lymphocytes of patients with prostate cancer and controls in an attempt to better understand the mechanism of development of prostate cancer. Our hypothesis is that individuals with altered DNA repair capacity and for elevated levels of DNA adducts, will harbor sufficient amount of numerical and structural chromosome damage that will allow the neoplastic transformation. We will test our hypothesis in 100 cases with prostate cancer and 100 healthy matched controls. In this study we will 1) characterize the role of chromosomal instability, 2) access the DNA damage and repair capacity and 3) compare the DNA adduct levels in background and mutagen induced blood cultures from the prostate cancer patients and controls. We will also determine the association between these biomarkers and the risk to prostate cancer with adjustment for other known epidemiological risk factors, which may have an effect on the background genetic instability. The results of this pilot study will help validate the usefulness of this comprehensive approach in large scale epidemiological studies in the future.