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.

摘要。艾滋病毒感染者（PWH）经历更高的癌症死亡率和癌症的可能性增加 与未感染艾滋病毒的癌症患者相比，初始治疗后复发。我们先前的工作表明， 在考虑了已知的风险因素后，艾滋病毒相关的癌症结局差异仍然存在。一种新的方法来 迫切需要找出威尔斯亲王医院癌症预后不佳的目标驱动因素，以改善 预后我们认为PWH的癌症预后受到长期免疫功能障碍的负面影响 导致加速的生物老化。生物老化可以使用基因组生物标志物来量化，例如 随着DNA甲基化转化为表观遗传时钟和年龄相关的克隆造血（CDFI）的存在。 这项提案的首要目标是比较生物年龄，使用基因组生物标志物测量， 感染艾滋病毒的癌症患者与未感染艾滋病毒的癌症患者之间的关系，并量化测量的生物学年龄之间的关联 重要的临床结果。先前对PWH（无癌症）的研究表明， 使用基于血液的表观遗传时钟计算的生物年龄高于实际年龄。 这种加速老化与死亡率增加有关。据报道， PWH。这种疾病的特征是获得性突变，随着时间的推移在血细胞中扩大。积累这些 突变与炎症增加和不良后果有关。数据显示， 与未感染艾滋病毒的人相比，PWH（无癌症）的流行率。因此，有证据表明 在PWH（无癌症）中，HIV和晚期基因组衰老之间的关系，这需要在上下文中进行探索 癌症。为了初步探索我们的假设，我们对30例实体瘤患者（15 PWH和15名HIV未感染者）的实际年龄匹配。我们的初步数据表明基因组老化 在携带艾滋病病毒的癌症患者中更为严重。我们观察到基于表观遗传学的生物学年龄显著较高， 在PWH。我们在3名PWH患者中检测到了突变，但在0名HIV未感染患者中检测到突变。PWH的中位生存期 仅为2年，而未感染HIV的患者为9年;最引人注目的是<1年的中位生存期 在本提案中，我们将利用莫菲特癌症中心的既定方案， 亨斯迈癌症研究所将前瞻性地收集400名癌症患者的生物标本（200名患者和200名 没有艾滋病毒）。考虑到癌症现在是美国人死亡的主要原因， PWH，发病率正在上升。我们提出以下目的：1）比较肿瘤的生物学年龄 使用表观遗传时钟比较HIV感染者与非HIV感染者的基线患病率和治疗相关性 携带和不携带HIV的癌症患者之间的HIV演变;以及3）量化 衰老和临床结果的基因组生物标志物，包括衰老相关的功能评估。本研究 将解决关键的知识差距，即携带艾滋病毒的癌症患者是否在生物学上比年龄大- 匹配没有艾滋病毒的癌症患者，以及这种先进的老龄化是否有助于癌症预后不良。