Faculty Collaboration Database

Cell-free DNA copy number variations in plasma from colorectal cancer patients. Mol Oncol 2017 Aug;11(8):1099-1111

Date

05/16/2017

Pubmed ID

28504856

Pubmed Central ID

PMC5537711

DOI

10.1002/1878-0261.12077

Scopus ID

2-s2.0-85026647192 (requires institutional sign-in at Scopus site)   56 Citations

Abstract

To evaluate the clinical utility of cell-free DNA (cfDNA), we performed whole-genome sequencing to systematically examine plasma cfDNA copy number variations (CNVs) in a cohort of patients with colorectal cancer (CRC, n = 80), polyps (n = 20), and healthy controls (n = 35). We initially compared cfDNA yield in 20 paired serum-plasma samples and observed significantly higher cfDNA concentration in serum (median = 81.20 ng, range 7.18-500 ng·mL^-1 ) than in plasma (median = 5.09 ng, range 3.76-62.8 ng·mL^-1 ) (P < 0.0001). However, tumor-derived cfDNA content was significantly lower in serum than in matched plasma samples tested. With ~10 million reads per sample, the sequencing-based copy number analysis showed common CNVs in multiple chromosomal regions, including amplifications on 1q, 8q, and 5q and deletions on 1p, 4q, 8p, 17p, 18q, and 22q. Copy number changes were also evident in genes critical to the cell cycle, DNA repair, and WNT signaling pathways. To evaluate whether cumulative copy number changes were associated with tumor stages, we calculated plasma genomic abnormality in colon cancer (PGA-C) score by summing the most significant CNVs. The PGA-C score showed predictive performance with an area under the curve from 0.54 to 0.84 for CRC stages I-IV. Locus-specific copy number analysis identified nine genomic regions where CNVs were significantly associated with survival in stage III-IV CRC patients. A multivariate model using six of nine genomic regions demonstrated a significant association of high-risk score with shorter survival (HR = 5.33, 95% CI = 6.76-94.44, P < 0.0001). Our study demonstrates the importance of using plasma (rather than serum) to test tumor-related genomic variations. Plasma cfDNA-based tests can capture tumor-specific genetic changes and may provide a measurable classifier for assessing clinical outcomes in advanced CRC patients.

Author List

Li J, Dittmar RL, Xia S, Zhang H, Du M, Huang CC, Druliner BR, Boardman L, Wang L

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Chromosomes, Human
Circulating Tumor DNA
Colorectal Neoplasms
DNA Copy Number Variations
Female
Gene Amplification
Humans
Male
Middle Aged
Wnt Signaling Pathway