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: 10403025
• 负责人: Anna Coghill
• 金额: $ 77.86万
• 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/10403025
• 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。艾滋病毒感染者 (PWH) 的癌症死亡率较高，患癌症的可能性也较高 与未感染艾滋病毒的癌症患者相比，初始治疗后复发率更高。我们之前的工作表明，这些 考虑到已知的危险因素后，与艾滋病毒相关的癌症结果差异仍然存在。一种新颖的方法 迫切需要确定导致 PWH 所经历的不良癌症结果的有针对性的驱动因素，以改善 预后。我们认为，长期免疫功能障碍会对感染者的癌症结果产生负面影响 这会导致生物衰老加速。生物衰老可以使用基因组生物标志物进行量化，例如 DNA 甲基化转化为表观遗传时钟和年龄相关克隆造血 (ARCH) 的存在。 该提案的总体目标是比较使用基因组生物标记测量的生物年龄， 比较感染艾滋病毒和未感染艾滋病毒的癌症患者，并量化测量的生物年龄之间的关联 具有重要的临床结果。先前对 PWH（无癌症）的研究表明，HIV 感染者 与实际年龄相比，使用基于血液的表观遗传时钟计算出的生物年龄更高。 这种加速的衰老与死亡率的增加有关。据报道 ARCH 也有所增加 王后。 ARCH 的特点是获得性突变会随着时间的推移在血细胞中扩展。这些的积累 突变与炎症增加和不良后果有关。数据表明 ARCH 可能是 与未感染艾滋病毒的人相比，该病在感染者（未患癌症）中普遍存在。因此，有证据表明存在链接 HIV 与 PWH 中的晚期基因组老化（无癌症）之间的关系，值得在这方面进行探索 癌症。为了初步探索我们的假设，我们对 30 名实体瘤患者（15 PWH 和 15 名未感染 HIV 的人）的实际年龄相匹配。我们的初步数据表明基因组老化 感染艾滋病毒的癌症患者的病情更为严重。我们观察到基于表观遗传的生物年龄明显更高 在战俘医院。我们在 3 名 PWH 患者和 0 名未感染 HIV 的患者中检测到 ARCH 突变。 PWH 的中位生存期 仅为 2 年，而未感染 HIV 的患者则为 9 年；最引人注目的是中位生存期<1年 与 ARCH 一起在 PWH 中。在本提案中，我们将利用莫菲特癌症中心的既定方案 亨斯曼癌症研究所将前瞻性地从 400 名癌症患者（200 名癌症患者和 200 名癌症患者）收集生物样本。 没有艾滋病毒）。鉴于癌症现在是导致死亡的主要原因，这项调查是及时且令人信服的。 PWH，且发病率正在增加。我们提出以下目标：1）比较癌症的生物学年龄 使用表观遗传时钟比较感染艾滋病毒和未感染艾滋病毒的患者； 2) 比较基线患病率和治疗相关性 感染和未感染 HIV 的癌症患者之间 ARCH 的演变； 3）量化之间的关联 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 将解决感染艾滋病毒的癌症患者在生物学上是否比年龄更老这一关键知识差距 匹配没有艾滋病毒的癌症患者，以及这种晚期衰老是否会导致不良的癌症结果。