Cell-free DNA copy number variations in plasma from colorectal cancer patients

Jian Li, Rachel L. Dittmar, Shu Xia, Huijuan Zhang, Meijun Du, Chiang Ching Huang, Brooke R. Druliner, Lisa Allyn Boardman, Liang Wang

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1099-1111
Number of pages13
JournalMolecular Oncology
Volume11
Issue number8
DOIs
StatePublished - Aug 1 2017

Fingerprint

DNA Copy Number Variations
Colorectal Neoplasms
DNA
Plasma Cells
Colonic Neoplasms
Neoplasms
Serum
Survival
Polyps
DNA Repair
Area Under Curve
Cell Cycle
Genome
Genes

Keywords

  • cell-free DNA
  • colon cancer
  • copy number variation
  • next-generation sequencing
  • survival

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cancer Research

Cite this

Li, J., Dittmar, R. L., Xia, S., Zhang, H., Du, M., Huang, C. C., ... Wang, L. (2017). Cell-free DNA copy number variations in plasma from colorectal cancer patients. Molecular Oncology, 11(8), 1099-1111. https://doi.org/10.1002/1878-0261.12077

Cell-free DNA copy number variations in plasma from colorectal cancer patients. / Li, Jian; Dittmar, Rachel L.; Xia, Shu; Zhang, Huijuan; Du, Meijun; Huang, Chiang Ching; Druliner, Brooke R.; Boardman, Lisa Allyn; Wang, Liang.

In: Molecular Oncology, Vol. 11, No. 8, 01.08.2017, p. 1099-1111.

Research output: Contribution to journalArticle

Li, J, Dittmar, RL, Xia, S, Zhang, H, Du, M, Huang, CC, Druliner, BR, Boardman, LA & Wang, L 2017, 'Cell-free DNA copy number variations in plasma from colorectal cancer patients', Molecular Oncology, vol. 11, no. 8, pp. 1099-1111. https://doi.org/10.1002/1878-0261.12077
Li, Jian ; Dittmar, Rachel L. ; Xia, Shu ; Zhang, Huijuan ; Du, Meijun ; Huang, Chiang Ching ; Druliner, Brooke R. ; Boardman, Lisa Allyn ; Wang, Liang. / Cell-free DNA copy number variations in plasma from colorectal cancer patients. In: Molecular Oncology. 2017 ; Vol. 11, No. 8. pp. 1099-1111.
@article{088e2761066b4eeb9ad466973147a8cf,
title = "Cell-free DNA copy number variations in plasma from colorectal cancer patients",
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.",
keywords = "cell-free DNA, colon cancer, copy number variation, next-generation sequencing, survival",
author = "Jian Li and Dittmar, {Rachel L.} and Shu Xia and Huijuan Zhang and Meijun Du and Huang, {Chiang Ching} and Druliner, {Brooke R.} and Boardman, {Lisa Allyn} and Liang Wang",
year = "2017",
month = "8",
day = "1",
doi = "10.1002/1878-0261.12077",
language = "English (US)",
volume = "11",
pages = "1099--1111",
journal = "Molecular Oncology",
issn = "1574-7891",
publisher = "Elsevier",
number = "8",

}

TY - JOUR

T1 - Cell-free DNA copy number variations in plasma from colorectal cancer patients

AU - Li, Jian

AU - Dittmar, Rachel L.

AU - Xia, Shu

AU - Zhang, Huijuan

AU - Du, Meijun

AU - Huang, Chiang Ching

AU - Druliner, Brooke R.

AU - Boardman, Lisa Allyn

AU - Wang, Liang

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

KW - cell-free DNA

KW - colon cancer

KW - copy number variation

KW - next-generation sequencing

KW - survival

UR - http://www.scopus.com/inward/record.url?scp=85026647192&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85026647192&partnerID=8YFLogxK

U2 - 10.1002/1878-0261.12077

DO - 10.1002/1878-0261.12077

M3 - Article

C2 - 28504856

AN - SCOPUS:85026647192

VL - 11

SP - 1099

EP - 1111

JO - Molecular Oncology

JF - Molecular Oncology

SN - 1574-7891

IS - 8

ER -