Genomic and epigenomic analysis of plasma cell-free DNA identifies stemness features associated with worse survival in lethal prostate cancer

表观遗传学 DNA甲基化 生物 增强子 表观遗传学 前列腺癌 癌症研究 癌症 基因 遗传学 分子生物学 转录因子 基因表达
作者
Pradeep S. Chauhan,Irfan Alahi,Savar Sinha,Elisa M. Ledet,Ryan Mueller,Jessica Linford,Alexander Shiang,Jace Webster,Lilli Greiner,Breanna Yang,Gabris Ni,Ha X. Dang,Debanjan Saha,Ramandeep K. Babbra,Wenjia Feng,Peter K. Harris,Faridi Qaium,Dzifa Y. Duose,Alexander Sanchez-Espitia,Alexander D. Sherry,Ellen Jaeger,Patrick D. Miller,Sydney Caputo,Jacob J. Orme,Fabrice Lucien,Sean S. Park,Chad Tang,Russell K. Pachynski,Oliver Sartor,Christopher A. Maher,Aadel A. Chaudhuri
出处
期刊:Clinical Cancer Research [American Association for Cancer Research]
标识
DOI:10.1158/1078-0432.ccr-24-1658
摘要

Abstract Purpose: Metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor signaling inhibitors (ARSIs) is often lethal. Liquid biopsy biomarkers for this deadly form of disease remain under investigation, and underpinning mechanisms remain ill-understood. Experimental Design: We applied targeted cell-free DNA sequencing to 126 mCRPC patients from three academic cancer centers, and separately performed genome-wide cell-free DNA methylation sequencing on 43 plasma samples collected prior to the initiation of first-line ARSI treatment. To analyze the genome-wide sequencing data, we performed nucleosome-positioning and differential methylated region analysis. We additionally analyzed single-cell and bulk RNA sequencing data from 14 and 80 mCRPC patients, respectively, to develop and validate a stem-like signature, which we inferred from cell-free DNA. Results: Targeted cell-free DNA sequencing detected AR/enhancer alterations prior to first-line ARSIs which correlated with significantly worse PFS (p = 0.01; HR = 2.12) and OS (p = 0.02; HR = 2.48). Plasma methylome analysis revealed that AR/enhancer lethal mCRPC patients have significantly higher promoter-level hypomethylation than AR/enhancer wild-type mCRPC patients (p < 0.0001). Moreover, gene ontology and CytoTRACE analysis of nucleosomally more accessible transcription factors in cell-free DNA revealed enrichment for stemness-associated transcription factors in lethal mCRPC patients. The resulting stemness signature was then validated in a completely held-out cohort of 80 mCRPC patients profiled by tumor RNA sequencing. Conclusions: We analyzed a total of 220 mCRPC patients, validated the importance of cell-free AR/enhancer alterations as a prognostic biomarker in lethal mCRPC and showed that the underlying mechanism for lethality involves reprogramming developmental states toward increased stemness.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
细心的茗完成签到,获得积分10
1秒前
1秒前
愈加沉稳完成签到,获得积分20
1秒前
Hello应助小何采纳,获得10
1秒前
子墨发布了新的文献求助10
1秒前
小二郎应助小何采纳,获得10
1秒前
Lucas应助Jony采纳,获得10
1秒前
大力初珍完成签到 ,获得积分10
1秒前
2秒前
东子衿完成签到,获得积分20
2秒前
2秒前
maomaoElaine完成签到,获得积分10
3秒前
啾咪完成签到,获得积分10
3秒前
Jiawen完成签到,获得积分10
3秒前
Anserbe发布了新的文献求助10
3秒前
sniffgo完成签到,获得积分20
4秒前
汤一德完成签到,获得积分10
4秒前
实在找不到完成签到,获得积分10
5秒前
乐乐应助KTKT采纳,获得10
5秒前
SUN完成签到,获得积分10
6秒前
6秒前
细心的茗发布了新的文献求助10
6秒前
6秒前
啾咪发布了新的文献求助10
6秒前
大模型应助酷酷冥采纳,获得10
6秒前
王某完成签到,获得积分10
7秒前
大个应助小绵羊采纳,获得10
7秒前
小蘑菇应助wyy采纳,获得30
8秒前
9秒前
bkagyin应助廖小同采纳,获得10
9秒前
可靠代丝完成签到,获得积分10
10秒前
雾海完成签到,获得积分10
10秒前
田様应助科研通管家采纳,获得10
10秒前
共享精神应助科研通管家采纳,获得10
10秒前
Lucas应助科研通管家采纳,获得10
10秒前
Yziii应助科研通管家采纳,获得20
11秒前
赘婿应助科研通管家采纳,获得10
11秒前
完美世界应助科研通管家采纳,获得10
11秒前
科研通AI2S应助科研通管家采纳,获得10
11秒前
高分求助中
Sustainability in ’Tides Chemistry 2000
The ACS Guide to Scholarly Communication 2000
Studien zur Ideengeschichte der Gesetzgebung 1000
TM 5-855-1(Fundamentals of protective design for conventional weapons) 1000
Threaded Harmony: A Sustainable Approach to Fashion 810
Pharmacogenomics: Applications to Patient Care, Third Edition 800
Gerard de Lairesse : an artist between stage and studio 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3074861
求助须知:如何正确求助?哪些是违规求助? 2728212
关于积分的说明 7502977
捐赠科研通 2376311
什么是DOI,文献DOI怎么找? 1259944
科研通“疑难数据库(出版商)”最低求助积分说明 610771
版权声明 597101