The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients

Abstract

Background:Preoperative chemoradiotherapy (CRT) followed by surgery is the standard care for locally advanced rectal cancer, but tumour response to CRT and disease outcome are variable. The current study aimed to investigate the effectiveness of plasma telomerase reverse transcriptase (TERT) levels in predicting tumour response and clinical outcome.Methods:176 rectal cancer patients were included. Plasma samples were collected at baseline (before CRT=T0), 2 weeks after CRT was initiated (T1), post-CRT and before surgery (T2), and 4–8 months after surgery (T3) time points. Plasma TERT mRNA levels and total cell-free RNA were determined using real-time PCR.Results:Plasma levels of TERT were significantly lower at T2 (P<0.0001) in responders than in non-responders. Post-CRT TERT levels and the differences between pre- and post-CRT TERT levels independently predicted tumour response, and the prediction model had an area under curve of 0.80 (95% confidence interval (CI) 0.73–0.87). Multiple analysis demonstrated that patients with detectable TERT levels at T2 and T3 time points had a risk of disease progression 2.13 (95% CI 1.10–4.11)-fold and 4.55 (95% CI 1.48–13.95)-fold higher, respectively, than those with undetectable plasma TERT levels.Conclusions:Plasma TERT levels are independent markers of tumour response and are prognostic of disease progression in rectal cancer patients who undergo neoadjuvant therapy.

Genetic Variants of the TERT Gene, Telomere Length, and Circulating TERT as Prognostic Markers in Rectal Cancer Patients

“…The lack of a strong significant association between TERT polymorphisms and circulating TERT mRNA levels may be explained by the fact that plasma TERT mRNA derives from apoptosis/necrosis of tumor cells, where several other molecular pathways can affect telomerase expression. Nonetheless, as demonstrated previously [24], we found that circulating TERT levels at T2 and ∆TERT levels were predictive of tumor response and prognostic of disease outcome. This is not surprising in light of accumulating evidence suggesting that, besides its canonical role in stabilizing telomeres, TERT may promote tumorigenesis through extra-telomeric functions, including enhancement of proliferation, resistance to apoptosis, inflammation, invasion and metastasis altogether contributing towards the higher resistance of cancer cells [36][37][38].…”

“…Peripheral blood samples were available from all 194 patients at diagnosis, pre-CRT (T0), and for 74 patients at (−2 to 0 day) surgery occurring after CRT (T2). Data on circulating TERT mRNA levels in plasma were partially available from our previous study [24]. The local Ethics Committees approved the study (protocol N. 35333/AO/15), and each patient signed the informed consent.…”

“…The evaluation of pathologic tumor response was assessed as previously described [24,25]. Briefly, the tumors were pathologically staged according to the American Joint Committee on Cancer that established the TNM staging system [39,40].…”

“…To date, there is an essential need for biomarkers that can predict response to CRT at an early time point, allowing the selection of rectal cancer patients who would or would not benefit from CRT, to provide adequate treatment option and to reduce toxicity associated with ineffective CRT. Recently, it has been demonstrated that plasma TERT mRNA levels may serve as a minimally invasive marker for monitoring response to therapy in rectal cancer patients who underwent pre-operative chemoradiotherapy [24,25]; nevertheless, to our knowledge, the role of genetic TERT variants in constitutive telomere length and in TERT mRNA expression, and their associations with response to neoadjuvant therapy and outcome in rectal cancer patients, have not yet been investigated. In the present study, we studied patients with rectal cancer to comprehensively investigate the associations of eight common TERT SNPs with telomere length, circulating TERT mRNA in plasma, response to CRT and disease outcome.…”

Impact of Tumor Regression Grade as a Major Prognostic Factor in Locally Advanced Rectal Cancer after Neoadjuvant Chemoradiotherapy: A Proposal for a Modified Staging System

“…The tumor response to neoadjuvant CRT reflects the underlying tumor biology and might be used as a surrogate for treatment outcome [ 2 , 3 , 4 , 5 ]. In the resected specimen, histological changes caused by CRT in the primary tumor are assessed with the tumor regression grade (TRG), a five-tier grading system initially described by Dworak et al [ 6 ].…”