title: Cell-free DNA blood levels in colorectal cancer patients do not correlate with mismatch repair-proficiency.
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.
  
  
  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, paraffin-embedded tissues by immunohistochemistry (IHC) for MLH1/MSH2. CFD plasma levels were measured with SYBR gold nucleic acid gel staining on fluorometry. MMR-proficiency 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 MMR-deficient 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 MMR-deficient patients were 10.4±17.6 μg/l, and 15±48 μg/l, respectively (p=0.46).
  
  
  CONCLUSIONS
  Compared to MMR-proficient 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.
authors.affiliation: Department Oncology, Soroka Medical Center, Beer Sheba, P.O. Box 151, 84101, Israel. AriadS@Clalit.org.il.
authors.forename: Irena
authors.initials: I
authors.lastname: Lazarev
authors.forename: Lital
authors.initials: L
authors.lastname: Leibovitch
authors.forename: David
authors.initials: D
authors.lastname: Czeiger
authors.forename: Neta
authors.initials: N
authors.lastname: Sion-Vardi
authors.forename: David B
authors.initials: DB
authors.lastname: Geffen
authors.forename: Amos
authors.initials: A
authors.lastname: Douvdevani
authors.forename: Samuel
authors.initials: S
authors.lastname: Ariad
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D015179:Colorectal Neoplasms / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D004247:DNA / Q000097:blood* / Q000235:genetics*; D053843:DNA Mismatch Repair; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D000070956:MutL Proteins; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; C088996:PMS1 protein, human; D004247:DNA; D000070956:MutL Proteins
keywords: CFD; CRC; MMR; Mismatch repair; circulating cell-free DNA; colorectal cancer