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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

Serum DNA integrity index as a potential molecular biomarker in endometrial cancer

Authors: Enrico Vizza, Giacomo Corrado, Martina De Angeli, Mariantonia Carosi, Emanuela Mancini, Ermelinda Baiocco, Benito Chiofalo, Lodovico Patrizi, Ashanti Zampa, Giulia Piaggio, Lucia Cicchillitti

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

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Abstract

Background

Circulating cell-free DNA (cfDNA) and its integrity index may represent a rapid and noninvasive “liquid biopsy” biomarker, which gives important complementary information for diagnosis, prognosis, and treatment stratification in cancer patients. The aim of our study was to evaluate the possible role of cfDNA and its integrity index as a complementary tool for endometrial cancer (EC) management.

Methods

Alu-quantitative real-time PCR (qPCR) analysis wasprformed on 60 serum samples from preoperative EC patients randomly recruited. Both cfDNA content and DNA integrity index were measured by qPCR-Alu115 (representing total cfDNA) and qPCR-Alu247 (corresponding to high molecular weight DNA) and correlated with clinicopathologic characteristics. Lymphovascular space invasion (LVSI) was detected by hematoxylin and eosin staining. In case of doubt, LVSI status was further evaluate by immunohistochemistry using anti-CD31 and anti-CD34 antibodies.

Results

Total cfDNA content significantly increases in high grade EC. A significant decrease of DNA integrity index was detected in the subset of hypertensive and obese high grade EC. Serum DNA integrity was higher in samples with LVSI. The ordinal regression analysis predicted a significant correlation between decreased integrity index values and hypertension specifically in tumors presenting LVSI.

Conclusions

Our study supports the utility of serum DNA integrity index as a noninvasive molecular biomarker in EC. We show that a correlation analysis between cfDNA quantitative and qualitative content and clinicopathologic features, such as blood pressure level, body mass index (BMI) and LVSI status, could represent a potential predictive signature to help stratification approaches in EC.
Appendix
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Literature
1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. Erratum in: CA Cancer J Clin. 2011;61(2):134CrossRefPubMed
2.
Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11(6):426–37.CrossRefPubMed
3.
Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO, Hesch RD, et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res. 2001;61(4):1659–65.PubMed
4.
Thierry AR, El Messaoud S, Gahan PB, Anker P, Stroun M. Origins, structures, and functions of circulating DNA in oncology. Cancer Metastasis Rev. 2016;35(3):347–76.CrossRefPubMedPubMedCentral
5.
Marzese DM, Hirose H, Hoon DS. Diagnostic and prognostic value of circulating tumor-related DNA in cancer patients. Expert Rev Mol Diagn. 2013;13(8):827–44.CrossRefPubMed
6.
Wan JC, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer. 2017;17(4):223–38.CrossRefPubMed
7.
Mandel P, Metais P. Les acides nucleiques du plasma sanguine chez I’homme. C R Seances Soc Biol Fil. 1948;142(3-49):241–3.PubMed
8.
Bendich A, Wilczok T, Borenfreund E. Circulating DNA as a possible factor in oncogenesis. Science. 1965;148(3668):374–6.CrossRefPubMed
9.
Stroun M, Anker P, Maurice P, Lyautey J, Lederrey C, Beljanski M. Neoplastic characteristics of the DNA found in the plasma of cancer patients. Oncology. 1989;46(5):318–22.CrossRefPubMed
10.
Chan KC, Jiang P, Zheng YW, Liao GJ, Sun H, Wong J, et al. Cancer genome scanning in plasma: detection of tumor-associated copy number aberrations, single-nucleotide variants, and tumoral heterogeneity by massively parallel sequencing. Clin Chem. 2013;59(1):211–24.CrossRefPubMed
11.
Rumore P, Muralidhar B, Lin M, Lai C, Steinman CR. Haemodialysis as a model for studying endogenous plasma DNA: oligonucleosome-like structure and clearance. Clin Exp Immunol. 1992;90(1):56–62.CrossRefPubMedPubMedCentral
12.
Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14(9):985–90.
13.
Thierry AR, Mouliere F, El Messaoudi S, Mollevi C, Lopez-Crapez E, Rolet F, et al. Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nat Med. 2014;20(4):430–5.CrossRefPubMed
14.
Holdenrieder S, Stieber P, Bodenmüller H, Busch M, Fertig G, Fürst H, et al. Nucleosomes in serum of patients with benign and malignant diseases. Int J Cancer. 2001;95(2):114–20. Erratum in: Int J Cancer. 2001; 95(6):398CrossRefPubMed
15.
16.
Holdenrieder S, Stieber P. Clinical use of circulating nucleosomes. Crit Rev Clin Lab Sci. 2009;46(1):1–24.CrossRefPubMed
17.
Wang BG, Huang HY, Chen YC, Bristow RE, Kassauei K, Cheng CC, et al. Increased plasma DNA integrity in cancer patients. Cancer Res. 2003;63(14):3966–8.PubMed
18.
19.
Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC MC, Baldwin J, Devon K, Dewar K, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409(6822):860–921. Erratum in: Nature. 2001;411(6838):720. [corrected to J. Szustakowski. Nature 2001;412(6846): 565CrossRefPubMed
20.
Umetani N, Kim J, Hiramatsu S, Reber HA, Hines OJ, Bilchik AJ, et al. Increased integrity of free circulating DNA in sera of patients with colorectal or periampullary cancer: direct quantitative PCR for ALU repeats. Clin Chem. 2006;2(6):1062–9.CrossRef
21.
Walker JA, Kilroy GE, Xing J, Shewale J, Sinha SK, Batzer MA. Human DNA quantitation using Alu element-based polymerase chain reaction. Anal Biochem. 2003;315(1):122–8.CrossRefPubMed
22.
Mangano A, Mangano A, Lianos GD, Cassinotti E, Roukos DH, Dionigi G, et al. Circulating free DNA in plasma or serum as biomarkers of carcinogenesis in colon cancer. Future Oncol. 2015;11(10):1455–8.CrossRefPubMed
23.
van der Vaart M, Pretorius PJ. Characterization of circulating DNA in healthy human plasma. Clin Chim Acta. 2008;395(1–2):186.CrossRefPubMed
24.
Tanaka H, Tsuda H, Nishimura S, Nomura H, Kataoka F, Chiyoda T, et al. Role of circulating free alu DNA in endometrial cancer. Int J Gynecol Cancer. 2012;22(1):82–6.CrossRefPubMed
25.
van der Vaart M, Pretorius PJ. Circulating DNA. Its origin and fluctuation. Ann N Y Acad Sci. 2008;1137:18–26.CrossRefPubMed
26.
Peters DL, Pretorius PJ. Origin, translocation and destination of extracellular occurring DNA--a new paradigm in genetic behaviour. Clin Chim Acta. 2011;412(11-12):806–11.CrossRefPubMed
27.
Hefeneider SH, Cornell KA, Brown LE, Bakke AC, McCoy SL, Bennett RM. Nucleosomes and DNA bind to specific cell-surface molecules on murine cells and induce cytokine production. Clin Immunol Immunopathol. 1992;63(3):245–51.CrossRefPubMed
28.
Frank MO. Circulating cell-free DNA differentiates severity of inflammation. Biol Res Nurs. 2016;18(5):477–88.CrossRefPubMed
29.
Jeong DW, Moon JY, Choi YW, Moon H, Kim K, Lee YH, et al. Effect of blood pressure and glycemic control on the plasma cell-free DNA.In hemodialysis patients. Kidney Res Clin Pract. 2015;34(4):201–6.CrossRefPubMedPubMedCentral
30.
Aune D, Sen A, Vatten LJ. Hypertension and the risk of endometrial cancer: a systematic review and meta-analysis of case-control and cohort studies. Sci Rep. 2017;7:44808.CrossRefPubMedPubMedCentral
31.
Kitahara M, Hazama S, Tsunedomi R, Takenouchi H, Kanekiyo S, Inoue Y, et al. Prediction of the efficacy of immunotherapy by measuring the integrity of cell-free DNA in plasma in colorectal cancer. Cancer Sci. 2016;107(12):1825–9.CrossRefPubMedPubMedCentral
32.
Holdenrieder S, Burges A, Reich O, Spelsberg FW, Stieber P. DNA integrity in plasma and serum of patients with malignant and benign diseases. Ann N Y Acad Sci. 2008;1137:162–70.CrossRefPubMed
33.
Ellinger J, Bastian PJ, Haan KI, Heukamp LC, Buettner R, Fimmers R, et al. Noncancerous PTGS2 DNA fragments of apoptotic origin in sera of prostate cancer patients qualify as diagnostic and prognostic indicators. Int J Cancer. 2008;122(1):138–43.CrossRefPubMed
34.
O'Hanlan KA, Kargas S, Schreiber M, Burrs D, Mallipeddi P, Longacre T, et al. Ovarian carcinoma metastases to gastrointestinal tract appear to spread like colon carcinoma: implications for surgical resection. Gynecol Oncol. 1995;59(2):200–6.CrossRefPubMed
35.
Paladini D, Cross P, Lopes A, Monaghan JM. Prognostic significance of lymph node variables in squamous cell carcinoma of the vulva. Cancer. 1994;74(9):2491–6.CrossRefPubMed
36.
Roman LD, Felix JC, Muderspach LI, Varkey T, Burnett AF, Qian D, et al. Influence of quantity of lymph-vascular space invasion on the risk of nodal metastases in women with early-stage squamous cancer of the cervix. Gynecol Oncol. 1998;68(3):220–5.CrossRefPubMed
37.
Yu H, Zhang S, Zhang R, Zhang L. The role of VEGF-C/D and Flt-4 in the lymphatic metastasis of early-stage invasive cervical carcinoma. J Exp Clin Cancer Res. 2009;9(28):98.CrossRef
38.
Talbot IC, Ritchie S, Leighton MH, Hughes AO, Bussey HJ, Morson BC. Spread of rectal cancer within veins. Histologic features and clinical significance. Am J Surg. 1981;141(1):15–7.CrossRefPubMed
39.
Katz A, Strom EA, Buchholz TA, Theriault R, Singletary SE, McNeese MD. The influence of pathologic tumor characteristics on locoregional recurrence rates following mastectomy. Int J Radiat Oncol Biol Phys. 2001;50(3):735–42.CrossRefPubMed
40.
Sun JG, Wang Y, Chen ZT, Zhuo WL, Zhu B, Liao RX, Zhang SX. Detection of lymphangiogenesis in non-small cell lung cancer and its prognostic value. J Exp Clin Cancer Res. 2009;16(28):21.CrossRef
41.
Mariani A, Webb MJ, Keeney GL, Aletti G, Podratz KC. Predictors of lymphatic failure in endometrial cancer. Gynecol Oncol. 2002;84(3):437–42.CrossRefPubMed
42.
Silvestris N, Ciliberto G, De Paoli P, Apolone G, Lavitrano ML, Pierotti MA, Stanta G; On the behalf of the “dynamic medicine OECI group”. Liquid dynamic medicine and N-of-1 clinical trials: a change of perspective in oncology research. J Exp Clin Cancer Res 2017;13;36(1):128.
43.
Deng L, Gao Y, Li X, Cai M, Wang H, Zhuang H, et al. Expression and clinical significance of annexin A2 and human epididymis protein 4 in endometrial carcinoma. J Exp Clin Cancer Res. 2015;34:96.CrossRefPubMedPubMedCentral
44.
Cicchillitti L, Corrado G, Carosi M, Dabrowska ME, Loria R, Falcioni R, Cutillo G, Piaggio G, Vizza E. Prognostic role of NF-YA splicing isoforms and Lamin a status in low grade endometrial cancer. Oncotarget. 2017;8(5):7935–45.CrossRefPubMed
45.
Cancer Genome Atlas Research Network, Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73. Erratum in: Nature. 2013;500(7461):242CrossRef
Metadata
Title
Serum DNA integrity index as a potential molecular biomarker in endometrial cancer
Authors
Enrico Vizza
Giacomo Corrado
Martina De Angeli
Mariantonia Carosi
Emanuela Mancini
Ermelinda Baiocco
Benito Chiofalo
Lodovico Patrizi
Ashanti Zampa
Giulia Piaggio
Lucia Cicchillitti
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0688-4

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