Cell-free DNA blood levels in colorectal cancer patients do not correlate with mismatch repair-proficiency

Irena Lazarev, Lital Leibovitch, David Czeiger, Neta Sion-Vardi, David B. Geffen, Amos Douvdevani, Samuel Ariad

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

While sporadic cases of colorectal cancer (CRC) most commonly arise via the well-characterized chromosomal instability pathway (CIN), most other cases develop via a serrated neoplasia pathway (CIMP), in which methylation of CpG islands results in silencing of DNA nucleotide mismatch repair (MMR)-related genes, and a high level of microsatellite instability (MSI). MSI-high tumors typically show proximal location, mucinous histology, poor differentiation, and lymphocytic infiltration. Cell-free circulating DNA (CFD) may become elevated in CRC patients compared to healthy individuals. Because of these biological differences, we hypothesized that compared to MMR-proficient tumors MMR-deficient CRCs may produce higher CFD blood levels. Patients and Methods: Forty-one patients with newly-diagnosed CRC from all stages were studied for MMR-proficiency status, and CFD and carcinoembryonic antigen (CEA) blood levels. MMR proficiency was evaluated in formalin-fixed, paraffinembedded tissues by immunohistochemistry (IHC) for MLH1/MSH2. CFD plasma levels were measured with SYBR gold nucleic acid gel staining on fluorometry. MMRproficiency status was studied by clinicopathological parameters, CFD and CEA blood levels. Results: Tumors were MMR-proficient, and -deficient in 16 patients (39%), and 25 patients (61%), respectively. The mean age of MMRdeficient patients was approximately 10 years higher than that of MMR-proficient patients (61.2±8.4 years versus 71.9±9.7 years, p=0.07). MMR-deficient tumors were more often proximally-located, (p=0.018). The mean CFD plasma levels in MMR-proficient, and MMR-deficient patients were 795±431 ng/ml, and 906±494 ng/ml, respectively (p=0.68). The mean CEA serum levels in MMR-proficient and MMRdeficient patients were 10.4±17.6 μg/l, and 15±48 μg/l, respectively (p=0.46). Conclusion: Compared to MMRproficient CRCs, MMR-deficient tumors occurred in older patients, and were more commonly proximally-located. Despite the presence of distinct biological and histopathological characteristics, both tumor types produced similar CFD blood levels.

Original languageEnglish
Pages (from-to)349-354
Number of pages6
JournalIn Vivo
Volume28
Issue number3
StatePublished - 1 Jan 2014
Externally publishedYes

Keywords

  • CFD
  • CRC
  • Circulating cell-free DNA
  • Colorectal cancer
  • MMR
  • Mismatch repair

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • Pharmacology

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