HIV Genomic Aging Project in Oncology (HIV-GAP)

抽象的。艾滋病毒携带者(PWH)经历更高的癌症死亡率和更高的癌症可能性 与未感染艾滋病毒的癌症患者相比，初次治疗后复发。我们之前的工作表明，这些 在考虑了已知的风险因素后，与艾滋病毒相关的癌症结果差异仍然存在。一种新的方法来 迫切需要找出导致威斯康星患者癌症预后不良的目标驱动因素 预后。我们假设长期免疫功能障碍对PWH患者的癌症预后有负面影响。 这导致了生物衰老的加速。生物老化可以使用基因组生物标记物来量化，例如 随着DNA甲基化转化为表观遗传时钟和年龄相关克隆性造血(ARCH)的存在。 这项建议的首要目标是比较使用基因组生物标记物测量的生物年龄， HIV携带者和未携带HIV的癌症患者之间的关系以及测量的生物年龄之间的关联 具有重要的临床结果。之前在PWH(非癌症)上的研究表明，艾滋病毒感染者 使用基于血液的表观遗传学时钟计算的生物学年龄比他们的实际年龄更高。 这种加速的衰老与死亡率的增加有关。据报道，ARCH在#年也有所增加 威尔斯亲王医院。ARCH的特征是获得性突变，随着时间的推移，这些突变会在血细胞中扩大。这些东西的积累 突变与炎症增加和不良后果有关。数据表明，拱门可能是 与未感染艾滋病毒的人相比，在PWH(无癌症)中流行。因此，有证据表明两者之间存在联系 HIV与PWH(非癌症)的晚期基因组老化之间的关系，值得在此背景下进行探索 癌症的威胁。为了初步验证我们的假设，我们对30名实体肿瘤患者(15名)的血液DNA进行了测序 威斯康星医院和15名未感染艾滋病毒的人)在时间上年龄匹配。我们的初步数据表明基因组老化 在携带艾滋病毒的癌症患者中更为晚期。我们观察到显著更高的基于表观遗传学的生物学年龄 在威尔斯亲王医院。我们在3例PWH患者中检测到ARCH突变，但在未感染HIV的患者中未检测到ARCH突变。威尔斯亲王医院的中位生存期 只有两年，相比之下，未感染艾滋病毒的患者为九年；最令人震惊的是中位生存期为一年。 在有拱门的威斯康星医院里。在这份提案中，我们将利用莫菲特癌症中心的既定方案，并 亨斯迈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)中收集生物标本 没有艾滋病毒)。考虑到癌症现在是#年的主要死亡原因，这项调查是及时和令人信服的。 PWH，发病率呈上升趋势。我们提出了以下目标：1)比较癌症的生物学年龄 使用表观遗传学时钟比较HIV携带者和非HIV携带者；2)比较基线患病率和治疗相关 癌症患者与HIV携带者之间ARCH的演变；以及3)量化两者之间的关联 衰老和临床结果的基因组生物标记物，包括与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在生物学上是否比年龄更大- 匹配没有艾滋病毒的癌症患者，以及这种高龄是否导致较差的癌症结果。

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.