THE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANT

肛门癌是艾滋病毒感染者（PWH）中第二大常见的实体恶性肿瘤，每年新发病例约2000例。我们的数据显示，美国的肛门癌发病率正在迅速增长。这一趋势在感染艾滋病毒的男男性行为者中更为明显，其终生风险为10%，尽管在早期发现和预防方面取得了进展，但预计这一风险还会增加。肛门癌在50岁以上的PWH患者中比在50岁以下的PWH患者中更为普遍。肛门癌的预防主要围绕高级别鳞状上皮内病变（HSIL）的识别和消融，这是癌症的直接前兆。HSIL在PWH中具有高度侵袭性，每年有1%进展为浸润性癌。然而，PWH的治疗效果有限，因为50%接受治疗的HSIL患者在同一解剖象限检测到高级别病变。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志物，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，并确定侵袭性的生物标志物。具体目的：(1)确定随年龄增长的治疗失败率；(2)确定不同年龄组肛门高级鳞状上皮内病变（HSIL）的克隆程度，并检测HIV感染者中克隆与病变侵袭性的关系。研究设计：我们建议对来自不同种族的携带hpv相关HSIL的PWH患者的2000个标本组织库中的HSIL进行研究和测序。我们将首先确定50岁以上和50岁以下人群消融后在同一解剖象限发现病变的频率。这将确定治疗是否随着年龄的增长而失败，以及它是否与复发病变的数量相关。我们将按年龄随机选择200例未选择预后的HSIL，用于预测消融后复发的HSIL，以改善风险分层。

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.