THE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANT

肛门癌是人类免疫缺陷病毒(HIV)患者中第二常见的实体恶性肿瘤，每年新增病例2,000例。我们的数据显示，在美国，肛门癌的发病率正在迅速增长。这一趋势在与男性发生性行为的艾滋病毒感染者中更加明显，尽管在早期发现和预防方面取得了进展，但终生风险为10%，而且预计还会增加。与50岁以下的人相比，50岁以上的女性更容易患上肛门癌。肛门癌的预防集中在高度鳞状上皮内病变(HSIL)的识别和消融，HSIL是癌症的直接前驱。HSIL在PWH中具有高度侵袭性，每年有1%进展为浸润性癌。然而，对于PWH的治疗效果是有限的，因为50%接受治疗的HSIL患者将在同一解剖象限检测到高度级别的病变。有迹象表明，治疗失败率随着年龄的增长而增加，但数据有限，需要预测治疗失败的生物标记物，而且可能与年龄有关。目的：本项目的目的是了解年龄差异是否与HSIL侵袭性相关，并识别侵袭性的生物标志物。具体目标：(1)确定随年龄增长的治疗失败率；(2)确定不同年龄组的肛门高级别鳞状上皮内病变(HSIL)中克隆的程度，并测试克隆与HIV感染者病变侵袭性的关联。研究设计：我们建议从人乳头瘤病毒相关的HSIL的不同种族的PWH队列中提取2,000份标本，对HSIL进行研究和测序。我们将首先确定50岁以上和50岁以下的人在同一解剖象限内消融后发现病变的频率。这将确定治疗是否随着年龄的增长而失败，以及是否与复发病变的数量有关。我们将按年龄随机选择200例HSIL，用于预测消融后复发的HSIL，以改善危险分层。

Anal cancer causes significant morbidity as the second most common solid malignancy in People with HIV (PWH) with >2,000 new cases per year. Our data show that anal cancer incidence is rapidly growing in the US. This trend is even more pronounced in HIV infected men who have sex with men where the lifetime risk is 10% and is projected to increase despite advances in early detection and prevention. Anal Cancer is more prevalent in PWH above 50 years of age compared to those under 50. Prevention of anal cancer centers around identification and ablation of high-grade squamous intraepithelial lesions (HSIL), the immediate precursors of carcinoma. HSIL are highly aggressive in PWH, with 1% per year progressing to invasive carcinoma. Treatment efficacy is limited for PWH, however, as 50% of patients with treated HSIL will have high-grade lesions detected in the same anatomic quadrant. There are indications that treatment failure rates increase with age, but the data is limited and biomarkers for predicting treatment failure are needed and may be age dependent. Objective: The goal of this project is to understand whether age disparities are associated with HSIL aggressiveness and to identify biomarkers of aggressiveness. Specific Aims: (1) To determine the failure rate of treatment with increasing age; (2) and to determine the extent of clonality in anal high-grade squamous intraepithelial lesions (HSIL) across age groups and test the association of clonality with lesion aggressiveness in people with HIV. Study Design: We propose to study and sequence HSIL from a tissue bank of >2,000 specimens from an ethnically diverse cohort of PWH harboring HPV-associated HSIL. We will first determine the frequency of lesions found in the same anatomic quadrant after ablation in people above 50 years of age and those below 50. This will establish if treatment is failing with age and if it is correlated to the number of recurrent lesions. We will randomly select 200 HSIL unselected to outcome by age to use for the prediction of HSIL that will recur after ablation to improve risk stratification.