Novel modalities for prostate cancer screening: mast cells as predictors of disease, disease aggressiveness and marks of disease disparity

总结 前列腺癌（PCa）是美国男性中第二常见的癌症。绝对数量 由于婴儿潮一代人口的老龄化，预计PCa男性的发病率将增加。但缺乏 PCa筛查的可靠生物标志物导致早期检测减少，特别是非洲裔美国人 (AA)与其他种族相比，男性具有最高的PCa发病率、转移风险和死亡率， 美国的种族群体。当怀疑癌症时，患者必须接受多针芯活检 因为前列腺癌的多灶性尽管如此，高达34%的活检男性被告知他们没有癌症 当它们不是时，因为活检错过了癌灶。因此，更好地定义 指示良性前列腺癌发展和侵袭性疾病风险的细胞和分子特征 PCa患者的活检，以提高诊断和筛查。在这一补助金中，我们建议探索一种 PCa中场效应概念的变化，假设组织病理学上看起来良性的前列腺核心 活组织检查实际上可能具有指示PCa和PCa侵袭性的改变， 另一个前列腺部位的患者，使用年龄和种族匹配（AA和高加索美国人（CA））的 样本（每例患者的良性和癌症活检）。前列腺肥大细胞（MC）聚集在 间质、瘤周和/或瘤内区域，但其临床相关性仍有争议。我们的初步 数据提示在PCa患者的良性前列腺组织中建立MC谱的有用性。的 本申请的目的是：研究良性人前列腺组织中的MC功能谱， PCa侵袭性的预测因子和PCa种族差异的候选功能性生物标志物; 验证指示存在于良性人前列腺中的PCa和PCa侵袭性的分子特征 活检并测试其对PCa差异的预测价值以及与MC的关联;并应用我们的新筛查方法 在诊所的模式，取决于成功的验证研究。我们预计，我们的方法可能 改善高风险前列腺癌诊断和筛查，并将MC定位为前列腺癌差异的潜在驱动因素。

SUMMARY Prostate cancer (PCa) is the second most common cancer in men in the United States. The absolute number of men with PCa is projected to increase as a result of the ageing baby boomer population. However, the lack of reliable biomarkers for PCa screening has led to decreased early detection, particularly for African American (AA) men who have the highest PCa morbidity, metastatic risk and mortality rates than any other racial or ethnic group in the US. When cancer is suspected, patients must undergo multiple needle core biopsies because of the multifocal nature of PCa. Nonetheless, up to 34% of biopsied men are told they are cancer-free when they are not, because the biopsies missed the cancer foci. Hence, it is critical to better define the cellular and molecular features indicative of PCa development and risk for aggressive disease in benign biopsies of PCa patients to improve diagnosis and screening. In this grant, we are proposing to explore a variation on the concept of field effect in PCa, postulating that histopathologically benign looking prostate core biopsies may in fact feature alterations indicative of PCa and of PCa aggressiveness present in the same patient at another prostatic site, using age- and race-matched (AA and Caucasian Americans (CA)) sets of samples (benign and cancer-bearing biopsies for each patient). Prostate-resident mast cells (MC) aggregate in stromal, peritumoral and/or intratumoral areas but their clinical relevance remains controversial. Our preliminary data suggests the usefulness of establishing MC profiles in benign prostatic tissues of PCa patients. The objectives of this application are: to investigate MC functional profiles in benign human prostate tissues as predictors of PCa aggressiveness and candidate functional biomarkers of PCa race disparity; to define and validate a molecular signature indicative of PCa and PCa aggressiveness present in benign human prostate biopsies and test its predictive value for PCa disparity and association to MC; and apply our new screening modalities in clinics, contingent upon successful validation studies. We anticipate that our approach may improve diagnosis and screening for high-risk PCa and position MC as potential drivers of PCa disparity.