Association of inflammatory genes and prostate cancer

描述(申请人提供)：前列腺癌对公众健康具有重要意义，因为它是美国最常见的癌症，也是男性癌症死亡的第二大原因。虽然前列腺癌的病因仍不清楚，但流行病学研究一直表明这种疾病的遗传易感性。到目前为止，识别易感基因的努力主要集中在与雄激素生物合成和生长因子有关的基因上。然而，仍有几条候选途径尚未得到充分研究。众所周知，慢性或复发性炎症在许多人类癌症的发展中起着致病作用。多年来，人们一直在前列腺组织中发现炎性变化，这导致了人们猜测炎症可能导致前列腺癌的发生。炎症在肿瘤发生和发展中可能起作用的确切机制仍有待阐明，而且很可能是复杂的。炎症相关的DNA损伤、细胞凋亡减少(绕过P53)、生长和生存因素、血管生成、侵袭和转移都可能在前列腺癌的发生发展中发挥作用。我们假设，许多炎症基因的序列变异与前列腺癌风险有关。为了验证这一假设，我们建议1)在瑞典收集的前列腺癌病例对照人群中进行前列腺癌风险与炎症基因序列变异的关联的探索性测试，2)在第二个新收集的瑞典前列腺癌病例对照人群中对第一个人群中涉及的炎症基因序列变异的子集进行确认性测试，以及3)探索htSNPs和htSNP单倍型对两个研究人群中都涉及的炎症基因子集的血清和/或前列腺组织中相应蛋白水平的功能影响。对这些问题的回答将大大提高我们对炎症在前列腺癌中的作用的认识，并将指导我们识别更多的前列腺癌基因。

DESCRIPTION (provided by applicant): Prostate cancer is of significant public health importance because it is the most common cancer and the second leading cause of cancer death among men in the United States. Although the etiology of prostate cancer remains unknown, epidemiologic studies have consistently demonstrated genetic susceptibility to this disease. To date, efforts to identify susceptibility genes have primarily focused on genes involved in androgen biosynthesis and growth factors. However, there remain several candidate pathways that have yet to be adequately studied. Chronic or recurrent inflammation is known to play a causative role in the development of many human cancers. Inflammatory changes have been recognized in prostate tissues for many years, leading to speculation that inflammation might contribute to prostate cancer development. The exact mechanism by which inflammation might act in tumor development and progression remains to be elucidated and is likely to be complex. Inflammation-associated DNA damage, decreased apoptosis (bypassing p53), growth and survival factors, angiogenesis, invasion and metastasis may all play a role in the development and progression of prostate cancer. We hypothesize that sequence variants in a number of inflammatory genes are associated with prostate cancer risk. To test this hypothesis, we propose to 1) perform exploratory tests for association of Prostate cancer risk with inflammatory gene sequence variants in an established Prostate cancer case-control population that was collected in Sweden, 2) perform confirmatory tests for association of Prostate cancer risk with a subset of inflammatory gene sequence variants that have been implicated in the first population in a second newly collected Swedish Prostate cancer case-control population and 3) explore the functional impact of htSNPs and htSNP-haplotypes on the corresponding protein levels in serum and/or prostate tissue for a subset of inflammatory genes that have been implicated in both study populations. Answers to these questions will significantly improve our knowledge of the role of inflammation in prostate cancer and will guide our efforts in identifying additional prostate cancer genes.