THE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANT

肛门癌作为HIV感染者（PWH）中第二常见的实体恶性肿瘤导致显著的发病率，每年新发病例> 2，000例。我们的数据显示，肛门癌的发病率在美国迅速增长。这一趋势在男男性行为的艾滋病毒感染者中更为明显，其终生风险为10%，尽管在早期发现和预防方面取得了进展，但预计还会增加。肛门癌在50岁以上的PWH中比50岁以下的PWH更普遍。肛门癌的预防主要是识别和消融高度鳞状上皮内病变（HSIL），即癌的直接前体。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患者将在同一解剖象限中检测到高级别病变。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，并且可能依赖于年龄。目的：该项目的目标是了解年龄差异是否与HSIL攻击性相关，并确定攻击性的生物标志物。具体目标：（1）确定治疗失败率随年龄增长;（2）确定不同年龄组肛门高度鳞状上皮内病变（HSIL）的克隆性程度，并检测HIV感染者中克隆性与病变侵袭性的相关性。研究设计：我们建议研究和测序来自一个组织库的HSIL，该组织库包含来自一个种族多样的携带HPV相关HSIL的PWH队列的> 2，000个标本。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中发现的病变频率。这将确定治疗是否随着年龄的增长而失败，以及是否与复发病灶的数量相关。我们将按年龄随机选择200例HSIL患者，用于预测消融术后复发的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.