Novel Prognostic Biomarkers in Metastatic and Locally Advanced Colorectal Cancer: Micronuclei Frequency and Telomerase Activity in Peripheral Blood Lymphocytes

Abstract

PurposeDue to the current practice on colorectal cancer (CRC) management, chemoresistance is most often recognized at the end of the treatment. Therefore, effective and easy-to-use prognostic biomarkers are needed.Experimental DesignWe evaluated the prognostic significance of two novel CRC biomarkers: a) micronuclei frequency (MNf) in 55 metastatic CRC (mCRC) and 21 locally advanced rectal cancer (laRC) patients using cytokinesis block micronucleus assay (CBMN assay) and b) telomerase activity (TA) in 23 mCRC and five laRC patients using TRAP-ELISA. Both biomarkers were evaluated in peripheral blood lymphocytes (PBLs) before, at the middle, and at the end of the therapy (approximately 0, 3, and 6 months) for mCRC patients before, at the end of the therapy, and after surgery for laRC patients.ResultsOverall, MNf demonstrated significant prognostic value since a decrease of MNf less than 29% between middle and initial MNf measurements can discriminate between progressive and stable/responsive disease with sensitivity of 36% and specificity of 87.0% while being able to identify responsive disease with sensitivity of 72.7% and specificity of 59.3%. On the other hand, TA presented a significant trend of increase (p = 0.07) in patients with progressive disease at the middle measurement.ConclusionsThe findings of this study suggest that the MN frequency may serve as a promising prognostic biomarker for the monitoring of the treatment response of patients with CRC, while TA should be evaluated in a larger group of patients to further validate its significance.

Micronuclei in Circulating Tumor Associated Macrophages Predicts Progression in Advanced Colorectal Cancer

“…Numerous studies have shown that MN presence in certain populations of cWBCs are indicative of cancer presence and patients with worse clinical outcomes including in CRC, though the origin and specific subtype of these cells is unknown [ 11 , 17 ]. As CAMLs are a specific circulating stromal cell population that has been shown to be highly prognostic for patient outcomes [ 19 , 20 , 23 , 24 , 25 , 27 , 28 , 29 ], we evaluated the CAML population based on MN presence.…”

“…This is much lower than the rate of MN formation listed in prior publications, which averaged 61 MN per 186 baseline peripheral blood lymphocytes in CRC, and other solid tumor cancers [ 30 ]. However, this rarity is likely a result of the cancer specificity of CAMLs, which are an established cancer specific cWBC subtype, versus other groups studying MN formation with general blood lymphocytes which are more ubiquitous [ 11 , 17 , 19 , 27 , 30 , 31 ]. As MN presence has been previously associated with activation of the innate immune system, we examined the potential effects of MN formation on the number of CAMLs in circulation [ 16 , 20 , 21 , 29 ], finding no significant correlation between the presence of MN and the number of CAMLs found in circulation ( Figure 2 ).…”

“…The presence of MN in the cytoplasm of certain populations of cWBCs has been shown to indicate both cancer presence and cancers with higher rates of progression and with poorer outcomes [ 11 , 17 ]. This has largely been hypothesized resulting from a person’s overall cellular response to an exposure to genotoxins, not specific to tumorigenesis itself [ 18 ].…”

Τelomerase inhibitors and activators in aging and cancer: A systematic review

“…In another study, it was found that the highest telomerase activity occurred ovarian, adrenal cortical, esophageal and lung cancer ( 54 ). In addition, it has been found that hTERT expression is increased in the early stages of colorectal cancer ( 55 ).…”

Biomarkers for Predicting the Response to Radiation-Based Neoadjuvant Therapy in Rectal Cancer

“…Recent studies have suggested that micronuclei frequency (MNf) in peripheral blood lymphocytes may be a prognostic biomarker for monitoring the response of RC patients who undergo induction chemotherapy and then operation. However, it is not known whether MNf could also serve as a predictive biomarker of the response to chemoradiotherapy [126]. Other indexes based on changes to circulating lymphocytes have also been suggested as potential biomarkers of the response to nCRT.…”