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Published in: Journal of Translational Medicine 1/2018

Open Access 01-12-2018 | Research

Fragment size and level of cell-free DNA provide prognostic information in patients with advanced pancreatic cancer

Authors: Morten Lapin, Satu Oltedal, Kjersti Tjensvoll, Tove Buhl, Rune Smaaland, Herish Garresori, Milind Javle, Nils Idar Glenjen, Bente Kristin Abelseth, Bjørnar Gilje, Oddmund Nordgård

Published in: Journal of Translational Medicine | Issue 1/2018

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Abstract

Background

It was recently demonstrated that the size of cell-free DNA (cfDNA) fragments that originates from tumor cells are shorter than cfDNA fragments that originates from non-malignant cells. We investigated whether cfDNA fragment size and cfDNA levels might have prognostic value in patients with advanced pancreatic cancer.

Methods

Blood samples were obtained from patients with advanced pancreatic cancer, before (n = 61) initiation of chemotherapy and after the first cycle of chemotherapy (n = 39). Samples were separated with density centrifugation and plasma DNA was isolated. Mode cfDNA fragment size and cfDNA levels were then determined using a 2100 Bioanalyzer. A cohort of partially age-matched healthy volunteers (n = 28) constituted the control group.

Results

Both a pre-treatment cfDNA fragment size of ≤ 167 bp (mode) and high pre-treatment cfDNA levels were associated with shorter progression-free survival (PFS) (p = 0.002 and p < 0.001, respectively) and overall survival (OS) (p = 0.001 and p = 0.001, respectively). Furthermore, multivariable Cox regression analyses demonstrated that pre-treatment cfDNA levels could independently predict prognosis for both PFS (HR = 3.049, p = 0.005) and OS (HR = 2.236, p = 0.028).

Conclusion

This study demonstrates that cfDNA fragment size and cfDNA levels can be used to predict disease outcome in patients with advanced pancreatic cancer. The described approach, using a rapid, economic and simple test to reveal prognostic information, has potential for future treatment stratification and monitoring.
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Literature
1.
go back to reference Wu TL, Zhang D, Chia JH, Tsao K, Sun CF, Wu JT. Cell-free DNA: measurement in various carcinomas and establishment of normal reference range. Clin Chim Acta. 2002;321(1–2):77–87.CrossRef Wu TL, Zhang D, Chia JH, Tsao K, Sun CF, Wu JT. Cell-free DNA: measurement in various carcinomas and establishment of normal reference range. Clin Chim Acta. 2002;321(1–2):77–87.CrossRef
2.
go back to reference Spindler KL, Appelt AL, Pallisgaard N, Andersen RF, Brandslund I, Jakobsen A. Cell-free DNA in healthy individuals, noncancerous disease and strong prognostic value in colorectal cancer. Int J Cancer. 2014;135(12):2984–91.CrossRef Spindler KL, Appelt AL, Pallisgaard N, Andersen RF, Brandslund I, Jakobsen A. Cell-free DNA in healthy individuals, noncancerous disease and strong prognostic value in colorectal cancer. Int J Cancer. 2014;135(12):2984–91.CrossRef
3.
go back to reference Singh N, Gupta S, Pandey RM, Chauhan SS, Saraya A. High levels of cell-free circulating nucleic acids in pancreatic cancer are associated with vascular encasement, metastasis and poor survival. Cancer Invest. 2015;33(3):78–85.CrossRef Singh N, Gupta S, Pandey RM, Chauhan SS, Saraya A. High levels of cell-free circulating nucleic acids in pancreatic cancer are associated with vascular encasement, metastasis and poor survival. Cancer Invest. 2015;33(3):78–85.CrossRef
4.
go back to reference Shaw JA, Guttery DS, Hills A, Fernandez-Garcia D, Page K, Rosales BM, et al. Mutation analysis of cell-free DNA and single circulating tumor cells in metastatic breast cancer patients with high circulating tumor cell counts. Clin Cancer Res. 2017;23(1):88–96.CrossRef Shaw JA, Guttery DS, Hills A, Fernandez-Garcia D, Page K, Rosales BM, et al. Mutation analysis of cell-free DNA and single circulating tumor cells in metastatic breast cancer patients with high circulating tumor cell counts. Clin Cancer Res. 2017;23(1):88–96.CrossRef
5.
go back to reference Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra24.CrossRef Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra24.CrossRef
6.
go back to reference Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368(13):1199–209.CrossRef Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368(13):1199–209.CrossRef
7.
go back to reference Garcia-Murillas I, Schiavon G, Weigelt B, Ng C, Hrebien S, Cutts RJ, et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med. 2015;7(302):302ra133.CrossRef Garcia-Murillas I, Schiavon G, Weigelt B, Ng C, Hrebien S, Cutts RJ, et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med. 2015;7(302):302ra133.CrossRef
8.
go back to reference Zill OA, Greene C, Sebisanovic D, Siew LM, Leng J, Vu M, et al. Cell-free DNA next-generation sequencing in pancreatobiliary carcinomas. Cancer Discov. 2015;5(10):1040–8.CrossRef Zill OA, Greene C, Sebisanovic D, Siew LM, Leng J, Vu M, et al. Cell-free DNA next-generation sequencing in pancreatobiliary carcinomas. Cancer Discov. 2015;5(10):1040–8.CrossRef
9.
go back to reference Tjensvoll K, Lapin M, Buhl T, Oltedal S, Steen-Ottosen Berry K, Gilje B, et al. Clinical relevance of circulating KRAS mutated DNA in plasma from patients with advanced pancreatic cancer. Mol Oncol. 2016;10(4):635–43.CrossRef Tjensvoll K, Lapin M, Buhl T, Oltedal S, Steen-Ottosen Berry K, Gilje B, et al. Clinical relevance of circulating KRAS mutated DNA in plasma from patients with advanced pancreatic cancer. Mol Oncol. 2016;10(4):635–43.CrossRef
10.
go back to reference Chabon JJ, Simmons AD, Lovejoy AF, Esfahani MS, Newman AM, Haringsma HJ, et al. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun. 2016;7:11815.CrossRef Chabon JJ, Simmons AD, Lovejoy AF, Esfahani MS, Newman AM, Haringsma HJ, et al. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun. 2016;7:11815.CrossRef
11.
go back to reference Heitzer E, Ulz P, Belic J, Gutschi S, Quehenberger F, Fischereder K, et al. Tumor-associated copy number changes in the circulation of patients with prostate cancer identified through whole-genome sequencing. Genome Med. 2013;5(4):30.CrossRef Heitzer E, Ulz P, Belic J, Gutschi S, Quehenberger F, Fischereder K, et al. Tumor-associated copy number changes in the circulation of patients with prostate cancer identified through whole-genome sequencing. Genome Med. 2013;5(4):30.CrossRef
12.
go back to reference Chan KC, Jiang P, Chan CW, Sun K, Wong J, Hui EP, et al. Noninvasive detection of cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing. Proc Natl Acad Sci U S A. 2013;110(47):18761–8.CrossRef Chan KC, Jiang P, Chan CW, Sun K, Wong J, Hui EP, et al. Noninvasive detection of cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing. Proc Natl Acad Sci U S A. 2013;110(47):18761–8.CrossRef
13.
go back to reference Shaw JA, Smith BM, Walsh T, Johnson S, Primrose L, Slade MJ, et al. Microsatellite alterations in plasma DNA of primary breast cancer patients. Clin Cancer Res. 2000;6(3):1119–24.PubMed Shaw JA, Smith BM, Walsh T, Johnson S, Primrose L, Slade MJ, et al. Microsatellite alterations in plasma DNA of primary breast cancer patients. Clin Cancer Res. 2000;6(3):1119–24.PubMed
14.
go back to reference Lui YY, Chik KW, Chiu RW, Ho CY, Lam CW, Lo YM. Predominant hematopoietic origin of cell-free DNA in plasma and serum after sex-mismatched bone marrow transplantation. Clin Chem. 2002;48(3):421–7.PubMed Lui YY, Chik KW, Chiu RW, Ho CY, Lam CW, Lo YM. Predominant hematopoietic origin of cell-free DNA in plasma and serum after sex-mismatched bone marrow transplantation. Clin Chem. 2002;48(3):421–7.PubMed
15.
go back to reference Chan KC, Zhang J, Hui AB, Wong N, Lau TK, Leung TN, et al. Size distributions of maternal and fetal DNA in maternal plasma. Clin Chem. 2004;50(1):88–92.CrossRef Chan KC, Zhang J, Hui AB, Wong N, Lau TK, Leung TN, et al. Size distributions of maternal and fetal DNA in maternal plasma. Clin Chem. 2004;50(1):88–92.CrossRef
16.
go back to reference Zheng YW, Chan KC, Sun H, Jiang P, Su X, Chen EZ, et al. Nonhematopoietically derived DNA is shorter than hematopoietically derived DNA in plasma: a transplantation model. Clin Chem. 2012;58(3):549–58.CrossRef Zheng YW, Chan KC, Sun H, Jiang P, Su X, Chen EZ, et al. Nonhematopoietically derived DNA is shorter than hematopoietically derived DNA in plasma: a transplantation model. Clin Chem. 2012;58(3):549–58.CrossRef
17.
go back to reference Diehl F, Li M, Dressman D, He Y, Shen D, Szabo S, et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci U S A. 2005;102(45):16368–73.CrossRef Diehl F, Li M, Dressman D, He Y, Shen D, Szabo S, et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci U S A. 2005;102(45):16368–73.CrossRef
18.
go back to reference Mouliere F, Robert B, Arnau Peyrotte E, Del Rio M, Ychou M, Molina F, et al. High fragmentation characterizes tumour-derived circulating DNA. PLoS ONE. 2011;6(9):e23418.CrossRef Mouliere F, Robert B, Arnau Peyrotte E, Del Rio M, Ychou M, Molina F, et al. High fragmentation characterizes tumour-derived circulating DNA. PLoS ONE. 2011;6(9):e23418.CrossRef
19.
go back to reference Jiang P, Chan CW, Chan KC, Cheng SH, Wong J, Wong VW, et al. Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients. Proc Natl Acad Sci U S A. 2015;112(11):E1317–25.CrossRef Jiang P, Chan CW, Chan KC, Cheng SH, Wong J, Wong VW, et al. Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients. Proc Natl Acad Sci U S A. 2015;112(11):E1317–25.CrossRef
20.
go back to reference Underhill HR, Kitzman JO, Hellwig S, Welker NC, Daza R, Baker DN, et al. Fragment length of circulating tumor DNA. PLoS Genet. 2016;12(7):e1006162.CrossRef Underhill HR, Kitzman JO, Hellwig S, Welker NC, Daza R, Baker DN, et al. Fragment length of circulating tumor DNA. PLoS Genet. 2016;12(7):e1006162.CrossRef
21.
go back to reference Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.CrossRef Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.CrossRef
22.
go back to reference Yamamoto Y, Uemura M, Nakano K, Hayashi Y, Wang C, Ishizuya Y, et al. Increased level and fragmentation of plasma circulating cell-free DNA are diagnostic and prognostic markers for renal cell carcinoma. Oncotarget. 2018;9(29):20467–75.CrossRef Yamamoto Y, Uemura M, Nakano K, Hayashi Y, Wang C, Ishizuya Y, et al. Increased level and fragmentation of plasma circulating cell-free DNA are diagnostic and prognostic markers for renal cell carcinoma. Oncotarget. 2018;9(29):20467–75.CrossRef
23.
go back to reference Sun K, Jiang P, Wong AIC, Cheng YKY, Cheng SH, Zhang H, et al. Size-tagged preferred ends in maternal plasma DNA shed light on the production mechanism and show utility in noninvasive prenatal testing. Proc Natl Acad Sci U S A. 2018;115(22):E5106-e14.CrossRef Sun K, Jiang P, Wong AIC, Cheng YKY, Cheng SH, Zhang H, et al. Size-tagged preferred ends in maternal plasma DNA shed light on the production mechanism and show utility in noninvasive prenatal testing. Proc Natl Acad Sci U S A. 2018;115(22):E5106-e14.CrossRef
24.
go back to reference Swystun LL, Mukherjee S, Liaw PC. Breast cancer chemotherapy induces the release of cell-free DNA, a novel procoagulant stimulus. J Thromb Haemost. 2011;9(11):2313–21.CrossRef Swystun LL, Mukherjee S, Liaw PC. Breast cancer chemotherapy induces the release of cell-free DNA, a novel procoagulant stimulus. J Thromb Haemost. 2011;9(11):2313–21.CrossRef
25.
go back to reference Kwee S, Song MA, Cheng I, Loo L, Tiirikainen M. Measurement of circulating cell-free DNA in relation to 18F-fluorocholine PET/CT imaging in chemotherapy-treated advanced prostate cancer. Clin Transl Sci. 2012;5(1):65–70.CrossRef Kwee S, Song MA, Cheng I, Loo L, Tiirikainen M. Measurement of circulating cell-free DNA in relation to 18F-fluorocholine PET/CT imaging in chemotherapy-treated advanced prostate cancer. Clin Transl Sci. 2012;5(1):65–70.CrossRef
26.
go back to reference Pietrasz D, Pecuchet N, Garlan F, Didelot A, Dubreuil O, Doat S, et al. Plasma circulating tumor DNA in pancreatic cancer patients is a prognostic marker. Clin Cancer Res. 2017;23(1):116–23.CrossRef Pietrasz D, Pecuchet N, Garlan F, Didelot A, Dubreuil O, Doat S, et al. Plasma circulating tumor DNA in pancreatic cancer patients is a prognostic marker. Clin Cancer Res. 2017;23(1):116–23.CrossRef
27.
go back to reference Kim MK, Woo SM, Park B, Yoon KA, Kim YH, Joo J, et al. Prognostic implications of multiplex detection of KRAS mutations in cell-free DNA from patients with pancreatic ductal adenocarcinoma. Clin Chem. 2018;64(4):726–34.CrossRef Kim MK, Woo SM, Park B, Yoon KA, Kim YH, Joo J, et al. Prognostic implications of multiplex detection of KRAS mutations in cell-free DNA from patients with pancreatic ductal adenocarcinoma. Clin Chem. 2018;64(4):726–34.CrossRef
Metadata
Title
Fragment size and level of cell-free DNA provide prognostic information in patients with advanced pancreatic cancer
Authors
Morten Lapin
Satu Oltedal
Kjersti Tjensvoll
Tove Buhl
Rune Smaaland
Herish Garresori
Milind Javle
Nils Idar Glenjen
Bente Kristin Abelseth
Bjørnar Gilje
Oddmund Nordgård
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2018
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-018-1677-2

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