PO.PS01.08 · 人群科学
ARIC研究中的克隆性造血与血液系统及髓系恶性肿瘤的发生
Clonal hematopoiesis and incident hematologic and myeloid malignancy in ARIC
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：克隆性造血（CH）指以髓系谱系驱动基因（N=74[经典]，Bick等，Nature 2020）的突变来定义，是血液系统恶性肿瘤（HM）的一个危险因素。Bernstein等（Nature Genetics 2024）另外鉴定出17个基因，其突变在人群中受到正向选择，并记录了其与HM的正相关。持续完善能够传递风险的CH突变，对于临床应用以及研究从CH到HM的可干预驱动因素至关重要。因此，我们开发了一套CH检出流程，利用扩展的基因列表以及基于Google AlphaFold 3的变异致病性评分，从基于人群的测序数据中检测CH。我们在一个具有长期随访的社区队列中，研究了由该新流程检出的CH与HM风险之间的关联。
方法：我们对社区动脉粥样硬化风险研究（Atherosclerosis Risk in Communities）中9,365名参与者进行了前瞻性分析，这些参与者年龄44-80岁、无癌症史，并具有全外显子组测序数据。在中位随访21年期间，主要通过与癌症登记处的链接确认了410例HM（其中147例为髓系）。该随访时间长于最初广为人知的CH研究。在平均测序深度100x下，变异等位基因频率（VAF）>3.8%的突变被纳入CH考虑。我们将经典CH基因中的突变以及Bernstein等另外鉴定的基因中的截短突变归类为确定性CH。对于这些另外鉴定基因中的错义突变，我们应用AlphaFold 3预测致病性，若评分≥0.9则判定为可能性CH。我们估计了小型（3.8<VAF<10%）和大型（VAF≥10%）CH（均与无CH对照相比）与HM及髓系恶性肿瘤发生相关的风险比（HR）和95%置信区间（CI），并对年龄、性别和种族进行了校正。作为比较，我们采用经典CH（Bick等定义，VAF≥2%）进行了相同的分析。
查看英文原文 English abstract
Background: Clonal hematopoiesis (CH), defined using mutations in myeloid-lineage driver genes (N=74 [classic], Bick et al. Nature 2020), is a risk factor for hematologic malignancy (HM). Bernstein et al. ( Nature Genetics 2024) identified 17 additional genes with mutations that are positively selected in the population, and documented a positive association with HM. Continuing to refine CH mutations that convey risk is critical for clinical use and research on modifiable drivers of CH to HM. Thus, we developed a CH-calling pipeline that detects CH from population-based sequencing data using an expanded gene list as well as a variant pathogenicity score based on Google AlphaFold 3. We investigated associations between CH called by the new pipeline and HM risk in a community-based cohort with long follow up.
Methods: We conducted a prospective analysis of 9,365 participants in the Atherosclerosis Risk in Communities study aged 44-80 years, without a cancer history, and with whole exome sequencing data. 410 HMs (147 myeloid) were ascertained mainly by cancer registry linkage in a median follow up of 21 years. Follow up is longer than in the original well-known CH studies. With a mean depth of 100x, mutations with a variant allele frequency (VAF)>3.8% were considered for CH. We classified definitive CH as mutations in classic CH genes and truncating mutations in genes additionally identified by Bernstein et al. For missense mutations in the additional genes, we applied AlphaFold 3 to predict pathogenicity and called probable if score≥0.9. We estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association of small (3.8<vaf<10%) and="" large="" (vaf≥10%)="" ch="" (both="" vs="" no="" ch)="" with="" incident="" hm="" myeloid="" malignancy="" adjusting="" for="" age,="" sex,="" race.="" comparison,="" we="" ran="" the="" same="" analyses="" using="" classic="" (bick="" et="" al.="" defined="" vaf≥2%).</vaf<10%)>
利益披露 Disclosure
E. A. Platz, None..
H. Uryu, None..
V. A. Burk, None..
M. Ru, None..
S. Pasca, None..
L. P. Gondek, None..
K. Y. King, None..
C. E. Joshu, None.
P. Natarajan,
Allelica, Amgen, Apple, Boston Scientific, Cleerly, Genentech / Roche, Ionis, Novartis, and Silence Therapeutics ).
AIRNA, Allelica, Apple, AstraZeneca, Bain Capital, Blackstone Life Sciences, Bristol Myers Squibb, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Esperion Therapeutics, Foresite Ca Other, personal fees.
Bolt, Candela, Mercury, MyOme, Parameter Health, Preciseli, and TenSixteen Bio Other, Equity.
Recora Other, Royalties.
Vertex Pharmaceuticals Other, Spousal employment.
C. M. Ballantyne,
89Bio Other, Personal fees.
Abbott Diagnostics Personal fees.
Amgen Personal fees.
Arrowhead Personal fees.
AstraZeneca Personal fees.
Denka Seiken Personal fees.
Esperion Personal fees.
Genentech Personal fees.
Heartflow Personal fees.
Ionis Personal fees.
Eli Lilly Personal fees.
Merck Personal fees.
NewAmsterdam Pharma Personal fees.
Novartis Personal fees.
Novo Nordisk Personal fees.
Roche Diagnostic Personal fees.
K. Takahashi, None.