HIV Genomic Aging Project in Oncology (HIV-GAP)

肿瘤学中的 HIV 基因组衰老项目 (HIV-GAP)

• 批准号: 10491212
• 负责人: Anna Coghill
• 金额: $ 75.77万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491212
• 关键词: AIDS related cancer; Accounting; Address; Age; Aging; Biological; Biological Aging; Biological Markers; Blood; Blood Cells; Cancer Burden; Cancer Center; Cancer Patient; Cancer Relapse; Cardiovascular Diseases; Cause of Death; Cessation of life; Chronic Disease; Chronology; Clinical; Clinical Management; Consent; DNA; DNA Methylation; Data; Development; Diagnosis; Disease; Ensure; Epigenetic Process; Evaluation; Evolution; Female; Future; Gait speed; Gastrointestinal Neoplasms; Gender; General Population; Genomics; Goals; Gynecologic; Gynecologic Oncology; HIV; HIV Seronegativity; Hematopoiesis; Hematopoietic stem cells; Immune System Diseases; Incidence; Individual; Inferior; Inflammation; Institutes; Institution; Investigation; Knowledge; Lead; Life Expectancy; Link; Malignant Neoplasms; Measures; Modification; Monitor; Mutation; Neoplasm Metastasis; Oncology; Outcome; Patients; Persons; Prevalence; Process; Prognosis; Protocols documentation; Race; Recurrent disease; Refractory; Risk Factors; Role; Sample Size; Sampling; Selection for Treatments; Site; Solid Neoplasm; Time; Translating; Tumor Tissue; Vital Status; Work; adverse outcome; age group; age related; anti aging; antiretroviral therapy; base; bead chip; cancer complication; cancer diagnosis; cancer therapy; cohort; experience; follow-up; functional status; gastrointestinal; genomic biomarker; improved; instrumental activity of daily living; male; men; mortality; mortality risk; next generation sequencing; novel; novel strategies; programs; prospective; sample collection; tool; translational impact; tumor

ABSTRACT. People with HIV (PWH) experience higher cancer mortality and increased likelihood of cancer relapse after initial therapy compared to HIV-uninfected cancer patients. Our prior work demonstrated that these HIV-associated cancer outcome disparities persist after accounting for known risk factors. A novel approach to identify targetable drivers of the poor cancer outcomes experienced by PWH is urgently needed to improve prognosis. We posit that cancer outcomes in PWH are negatively impacted by prolonged immune dysfunction that results in accelerated biological aging. Biological aging can be quantified using genomic biomarkers, such as DNA methylation translated into epigenetic clocks and presence of age-related clonal hematopoiesis (ARCH). The overarching goal of this proposal is to compare biological age, measured using genomic biomarkers, between cancer patients with versus without HIV and to quantify associations between measured biological age with important clinical outcomes. Previous studies in PWH (without cancer) indicate that HIV-infected individuals have higher biological age, calculated using blood-based epigenetic clocks, compared to their chronological age. This accelerated aging was associated with increased mortality. ARCH has also been reportedly increased in PWH. ARCH is characterized by acquired mutations that expand over time in blood cells. Accumulation of these mutations is linked to increased inflammation and adverse outcomes. Data suggest that ARCH may be twice as prevalent in PWH (without cancer) compared to HIV-uninfected persons. Thus, there is evidence for a link between HIV and advanced genomic aging in PWH (without cancer), which warrants exploration in the context of cancer. To preliminarily explore our hypothesis, we sequenced blood DNA from 30 solid tumor patients (15 PWH and 15 HIV-uninfected) matched on chronological age. Our preliminary data indicate that genomic aging is more advanced in cancer patients with HIV. We observed significantly higher epigenetic-based biological age in the PWH. We detected ARCH mutations in 3 PWH but 0 HIV-uninfected patients. The median survival in PWH was only 2 years, compared to 9 years in HIV-uninfected patients; most striking was the <1-year median survival in the PWH with ARCH. In this proposal, we will utilize an established protocol at Moffitt Cancer Center and Huntsman Cancer Institute to prospectively collect biospecimens from 400 cancer patients (200 with and 200 without HIV). The investigation is timely and compelling given that cancer is now a leading cause of death in PWH, and incidence is increasing. We propose the following aims: 1) Compare the biological age of cancer patients with versus without HIV using epigenetic clocks; 2) Compare baseline prevalence and therapy-related evolution of ARCH between cancer patients with and without HIV; and 3) Quantify the association between genomic biomarkers of aging and clinical outcomes, including aging-related functional assessments. This study will address the critical knowledge gap of whether cancer patients with HIV are biologically older than age- matched cancer patients without HIV, and whether this advanced aging contributes to poor cancer outcomes.

抽象的。艾滋病毒（PWH）患者的癌症死亡率更高，癌症的可能性增加 与HIV未感染的癌症患者相比，初始治疗后的复发。我们先前的工作证明了这些 在考虑已知危险因素后，与HIV相关的癌症结果差异持续存在。一种新颖的方法 迫切需要确定PWH所经历的癌症不良结局的目标驱动因素以改善 预后。我们认为，PWH中的癌症结局受到长期免疫功能障碍的负面影响 这导致了加速的生物衰老。可以使用基因组生物标志物来定量生物衰老，例如 随着DNA甲基化转化为表观遗传时钟和与年龄相关的克隆造血作用（ARCH）的存在。 该建议的总体目标是比较使用基因组生物标志物测量的生物年龄， 在患有HIV与无HIV的癌症患者之间，并量化测得的生物年龄之间的关联 具有重要的临床结果。先前在PWH（无癌症）的研究表明，感染了HIV的个体 与年代年龄相比，使用基于血液的表观遗传时钟计算的生物年龄更高。 这种加速的衰老与死亡率的增加有关。据报道，拱门也有所增加 PWH。弓的特征是获得的突变，这些突变会随着时间的流逝而在血细胞中膨胀。这些积累 突变与炎症增加和不良结局有关。数据表明拱门可能是两倍 与艾滋病毒未感染的人相比，PWH（无癌症）的普遍。因此，有链接的证据 在PWH（无癌症）中的艾滋病毒和高级基因组衰老之间，这值得探索。 癌症。为了初步探索我们的假设，我们对30名实体瘤患者的血液DNA进行了测序（15例 PWH和15 HIV未直发的）按年代年龄匹配。我们的初步数据表明基因组衰老 在艾滋病毒癌症患者中更为先进。我们观察到基于表观遗传学的生物年龄明显更高 在PWH中。我们在3个PWH中检测到ARCH突变，但是0例HIV未感染的患者。 PWH中的中位生存 仅2年，而艾滋病毒未感染的患者为9年；最惊人的是<1年的中位生存期 在PWH中与拱门。在此提案中，我们将在莫菲特癌症中心使用既定的方案，并 亨斯曼癌症研究所（Huntsman Cancer Institute 没有艾滋病毒）。鉴于癌症现在已成为死亡的主要原因，这项调查是及时而令人信服的 PWH，发病率正在增加。我们提出以下目的：1）比较癌症的生物年龄 使用表观遗传时钟的患者与无艾滋病毒的患者； 2）比较基线患病率和与治疗有关 癌症患者和患有艾滋病毒的癌症患者之间的弓形演变； 3）量化 衰老和临床结果的基因组生物标志物，包括与衰老相关的功能评估。这项研究 将解决艾滋病毒癌症患者是否在生物学上年龄超过年龄的关键知识差距 - 与没有HIV的癌症患者相匹配，以及这种高级衰老是否有助于癌症不良的结局。