Rapid, ultra low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy

被引：37

作者：

Hovelson, Daniel H. ^{[1
,2
]}

Liu, Chia-Jen ^{[3
]}

Wang, Yugang ^{[4
]}

Kang, Qing ^{[5
]}

Henderson, James ^{[4
]}

Gursky, Amy ^{[4
]}

Brockman, Scott

Ramnath, Nithya ^{[5
]}

Krauss, John C. ^{[5
]}

Talpaz, Moshe ^{[5
]}

Kandarpa, Malathi ^{[5
]}

Chugh, Rashmi ^{[5
]}

Tuck, Missy ^{[5
]}

Herman, Kirk ^{[5
]}

Grasso, Catherine S. ^{[10
,11
,12
]}

Quist, Michael J. ^{[10
,11
,12
]}

Feng, Felix Y. ^{[13
,14
,15
]}

Haakenson, Christine ^{[16
]}

Langmore, John ^{[16
]}

Kamberov, Emmanuel ^{[16
]}

Tesmer, Tim

Husain, Hatim ^{[17
,18
]}

Lonigro, Robert J. ^{[1
,3
]}

Robinson, Dan ^{[1
,3
,8
]}

Smith, David C. ^{[5
,8
]}

Alva, Ajjai S. ^{[5
,8
]}

Hussain, Maha H. ^{[5
,8
]}

Chinnaiyan, Arul M. ^{[1
,3
,8
,10
,11
]}

Tewari, Muneesh ^{[2
,5
,6
,7
,8
,9
]}

Mills, Ryan E. ^{[2
,7
]}

Morgan, Todd M. ^{[1
,4
,8
]}

Tomlins, Scott A. ^{[1
,3
,4
,8
]}

机构：

[1] Univ Michigan, Sch Med, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Sch Med, Dept Computat Med & Bioinformat, Ann Arbor, MI USA

[3] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Sch Med, Dept Urol, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Sch Med, Dept Internal Med Hematol Oncol, Ann Arbor, MI USA

[6] Univ Michigan, Sch Med, Dept Biomed Engn, Ann Arbor, MI USA

[7] Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI USA

[8] Univ Michigan, Sch Med, Dept Comprehens Canc Ctr, Ann Arbor, MI 48109 USA

[9] Univ Michigan, Sch Med, Dept Biointerfaces Inst, Ann Arbor, MI USA

[10] Univ Calif Los Angeles, Div Hematol Oncol, Los Angeles, CA USA

[11] Jonsson Comprehens Canc Ctr, Los Angeles, CA 90034 USA

[12] Parker Inst Canc Immunotherapy, San Francisco, CA USA

[13] Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA USA

[14] Univ Calif San Francisco, Dept Urol, San Francisco, CA USA

[15] Univ Calif San Francisco, Dept Med, San Francisco, CA USA

[16] Takara Bio USA, Ann Arbor, MI USA

[17] Univ Calif San Diego, Moores Canc Ctr, Med Oncol, San Diego, CA 92103 USA

[18] Northwestern Univ, Feinberg Sch Med, Div Hematol Oncol, Chicago, IL 60611 USA

来源：

ONCOTARGET | 2017年 / 8卷 / 52期

基金：

美国国家卫生研究院;

关键词：

cell-free DNA; precision oncology; prostate cancer; whole genome sequencing; copy-number analysis; INTEGRATIVE CLINICAL GENOMICS; PROSTATE-CANCER; PLASMA DNA; ACTIONABLE MUTATIONS; TUMOR SAMPLES; RESISTANCE; IDENTIFICATION; VALIDATION; HETEROGENEITY; ABERRATIONS;

D O I：

10.18632/oncotarget.21163

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Current cell-free DNA (cfDNA) next generation sequencing (NGS) precision oncology workflows are typically limited to targeted and/or disease-specific applications. In advanced cancer, disease burden and cfDNA tumor content are often elevated, yielding unique precision oncology opportunities. We sought to demonstrate the utility of a pan-cancer, rapid, inexpensive, whole genome NGS of cfDNA approach (PRINCe) as a precision oncology screening strategy via ultra-low coverage (similar to 0.01x) tumor content determination through genome-wide copy number alteration (CNA) profiling. We applied PRINCe to a retrospective cohort of 124 cfDNA samples from 100 patients with advanced cancers, including 76 men with metastatic castration-resistant prostate cancer (mCRPC), enabling cfDNA tumor content approximation and actionable focal CNA detection, while facilitating concordance analyses between cfDNA and tissue-based NGS profiles and assessment of cfDNA alteration associations with mCRPC treatment outcomes. Therapeutically relevant focal CNAs were present in 42 (34%) cfDNA samples, including 36 of 93 (39%) mCRPC patient samples harboring AR amplification. PRINCe identified pre-treatment cfDNA CNA profiles facilitating disease monitoring. Combining PRINCe with routine targeted NGS of cfDNA enabled mutation and CNA assessment with coverages tuned to cfDNA tumor content. In mCRPC, genome-wide PRINCe cfDNA and matched tissue CNA profiles showed high concordance (median Pearson correlation = 0.87), and PRINCe detectable AR amplifications predicted reduced time on therapy, independent of therapy type (Kaplan-Meier log-rank test, chi-square = 24.9, p < 0.0001). Our screening approach enables robust, broadly applicable cfDNA-based precision oncology for patients with advanced cancer through scalable identification of therapeutically relevant CNAs and pre-/post-treatment genomic profiles, enabling cfDNA-or tissue-based precision oncology workflow optimization.

引用

页码：89848 / 89866

页数：19

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