Perioperative changes in cell-free DNA for patients undergoing surgery for colon cancer

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Abstract

Background

Various conditions with cellular decay are associated with elevated cell-free DNA (cfDNA). This study aimed to investigate if perioperatively measured cfDNA levels were associated with the surgical approach, complications, or recurrence.

Methods

Plasma was obtained from patients who underwent surgery for colon cancer at admission and at the time of discharge. Quantitative measurement of cfDNA was performed by amplifying two amplicons of 102 base pairs (bp) and 132 bp of Beta-2-Microglobulin ( B2M) and Peptidyl-Prolyl cis–trans Isomerase A ( PPIA), respectively.

Results

cfDNA was measured in 48 patients who underwent surgery for colonic cancer. Sixteen patients had recurrence during the follow-up period, fifteen developed a postoperative complication, and seventeen patients developed neither, acting as the control group. Postoperative cfDNA levels were significantly elevated from baseline samples, across all groups, with a median preoperatively B2M level of 48.3 alleles per mL and postoperatively of 220 alleles per mL and a median preoperatively level PPIA of 26.9 alleles per mL and postoperatively of 111.6 alleles per mL ( p < 0.001 for B2M and p < 0.001 for PPIA). Postoperative levels of PPIA, but not B2M, were significantly higher in patients experiencing complications than in the control group ( p = 0.036). However, a tendency towards an association between the surgical approach and the changes in cfDNA levels was found for PPIA ( p = 0.058), and B2M ( p = 0.087).

Conclusions

Plasma cfDNA was increased after surgery in all patients with colon cancer. Postoperative PPIA levels were significantly higher in patients experiencing surgical complications but not in B2M levels.

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Most cited references 27

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Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.

Daniel Dindo, Nicolas Demartines, Pierre-Alain Clavien (2004)

Although quality assessment is gaining increasing attention, there is still no consensus on how to define and grade postoperative complications. This shortcoming hampers comparison of outcome data among different centers and therapies and over time. A classification of complications published by one of the authors in 1992 was critically re-evaluated and modified to increase its accuracy and its acceptability in the surgical community. Modifications mainly focused on the manner of reporting life-threatening and permanently disabling complications. The new grading system still mostly relies on the therapy used to treat the complication. The classification was tested in a cohort of 6336 patients who underwent elective general surgery at our institution. The reproducibility and personal judgment of the classification were evaluated through an international survey with 2 questionnaires sent to 10 surgical centers worldwide. The new ranking system significantly correlated with complexity of surgery (P < 0.0001) as well as with the length of the hospital stay (P < 0.0001). A total of 144 surgeons from 10 different centers around the world and at different levels of training returned the survey. Ninety percent of the case presentations were correctly graded. The classification was considered to be simple (92% of the respondents), reproducible (91%), logical (92%), useful (90%), and comprehensive (89%). The answers of both questionnaires were not dependent on the origin of the reply and the level of training of the surgeons. The new complication classification appears reliable and may represent a compelling tool for quality assessment in surgery in all parts of the world.

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Detection of circulating tumor DNA in early- and late-stage human malignancies.

Chetan Bettegowda, Mark Sausen, Rebecca Leary … (2014)

The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.

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Circulating Mitochondrial DAMPs Cause Inflammatory Responses to Injury

Rui-Qin Zhang, Mustafa Raoof, Yu Chen … (2010)

Injury causes a systemic inflammatory response syndrome (SIRS) clinically much like sepsis 1. Microbial pathogen-associated molecular patterns (PAMPs) activate innate immunocytes through pattern recognition receptors 2. Similarly, cellular injury can release endogenous damage-associated molecular patterns (DAMPs) that activate innate immunity 3. Mitochondria are evolutionary endosymbionts that were derived from bacteria 4 and so might bear bacterial molecular motifs. We show here that injury releases mitochondrial DAMPs (MTD) into the circulation with functionally important immune consequences. MTD include formyl peptides and mitochondrial DNA. These activate human neutrophils (PMN) through formyl peptide receptor-1 and TLR9 respectively. MTD promote PMN Ca2+ flux and phosphorylation of MAP kinases, thus leading to PMN migration and degranulation in vitro and in vivo. Circulating MTD can elicit neutrophil-mediated organ injury. Cellular disruption by trauma releases mitochondrial DAMPs with evolutionarily conserved similarities to bacterial PAMPs into the circulation. These can then signal through identical innate immune pathways to create a sepsis-like state. The release of such mitochondrial ‘enemies within’ by cellular injury is a key link between trauma, inflammation and SIRS.

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Author and article information

Contributors

Mikail Gögenur:

ORCID: http://orcid.org/0000-0001-7768-324X

mgog@regsj.dk

Journal

Journal ID (nlm-ta): BMC Gastroenterol

Journal ID (iso-abbrev): BMC Gastroenterol

Title: BMC Gastroenterology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-230X

Publication date (Electronic): 6 April 2022

Publication date PMC-release: 6 April 2022

Publication date Collection: 2022

Volume: 22

Electronic Location Identifier: 168

Affiliations

[1 ]GRID grid.512923.e, ISNI 0000 0004 7402 8188, Center for Surgical Science, Department of Surgery, , Zealand University Hospital, ; Lykkebækvej 1, 4600 Køge, Denmark

[2 ]GRID grid.512923.e, ISNI 0000 0004 7402 8188, Department of Clinical Immunology, , Zealand University Hospital, ; Ringstedgade 77b, 4700 Næstved, Denmark

[3 ]GRID grid.11702.35, ISNI 0000 0001 0672 1325, Department of Science and Environment, , Roskilde University, ; Universitetsvej 1, 4000 Roskilde, Denmark

[4 ]GRID grid.476266.7, Department of Pathology, , Zealand University Hospital, ; Sygehusvej 9, 4000 Roskilde, Denmark

[5 ]GRID grid.476266.7, Department of Surgery, , Zealand University Hospital, ; Sygehusvej 6, 4000 Roskilde, Denmark

[6 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Faculty of Health and Medical Sciences, , University of Copenhagen, ; Blegdamsvej 3B, 2200 Copenhagen N, Denmark

[7 ]Danish Colorectal Cancer Group, Copenhagen, Denmark

Author information

Mikail Gögenur http://orcid.org/0000-0001-7768-324X

Article

Publisher ID: 2217

DOI: 10.1186/s12876-022-02217-w

PMC ID: 8988386

PubMed ID: 35387596

SO-VID: 9e9a7a17-249c-49e3-9f47-223c68f5c9f6

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 13 December 2021

Date accepted : 17 March 2022

Custom metadata

ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: colon cancer,cell-free dna,perioperative,surgery,complications,surgical stress

Data availability:

ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: colon cancer, cell-free dna, perioperative, surgery, complications, surgical stress

Perioperative changes in cell-free DNA for patients undergoing surgery for colon cancer

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Karger: Gastroenterology

Most cited references 27

Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.

Detection of circulating tumor DNA in early- and late-stage human malignancies.

Circulating Mitochondrial DAMPs Cause Inflammatory Responses to Injury

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