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

• Main Authors: Enrica Rampazzo, Erika Cecchin, Paola Del Bianco, Chiara Menin, Gaya Spolverato, Silvia Giunco, Sara Lonardi, Sandro Malacrida, Antonino De Paoli, Giuseppe Toffoli, Salvatore Pucciarelli, Anita De Rossi
• Format: Article
• Language: English
• Published: MDPI AG 2020-10-01
• Series: Cancers
• Subjects: TERT; telomerase; SNPs; variants; telomere length; circulating <i>TERT</i> mRNA
• Online Access: https://www.mdpi.com/2072-6694/12/11/3115

Single-nucleotide polymorphisms (SNPs) in the <i>TERT</i> gene can affect telomere length and <i>TERT</i> expression and have been associated with risk and/or outcome for several tumors, but very few data are available about their impact on rectal cancer. Eight SNPs (rs2736108, rs2735940, rs2736098, rs2736100, rs35241335, rs11742908, rs2736122 and rs2853690), mapping in regulatory and coding regions of the <i>TERT</i> gene, were studied in 194 rectal cancer patients to evaluate their association with constitutive telomere length, circulating <i>TERT</i> mRNA levels, response to neoadjuvant chemoradiotherapy (CRT) and disease outcome. At diagnosis, the rs2736100CC genotype was associated with longer telomeres measured pre-CRT, while the rs2736100CC, rs2736108TT and rs2735940AA were associated with greater telomere erosion evaluated post-CRT. The rs2736108CC and rs2853690AA/GG genotypes, respectively associated with lower telomere erosion and lower levels of circulating <i>TERT</i> post-CRT, were also independently associated with a better response to therapy [OR 4.6(1.1–19.1) and 3.0(1.3–6.9)]. Overall, post-CRT, low levels (≤ median value) of circulating <i>TERT</i> and its stable/decreasing levels compared to those pre-CRT, were independently associated with a better response to therapy [OR 5.8(1.9–17.8) and 5.3(1.4–19.4), respectively]. Furthermore, post-CRT, patients with long telomeres (>median value) and low levels of circulating <i>TERT</i> had a significantly lower risk of disease progression [HR 0.4(0.1–0.9) and 0.3(0.1–0.8), respectively]. These findings suggest that <i>TERT</i> SNPs could be a useful tool for improving the selection of patients who could benefit from CRT and support the role of telomere length and circulating <i>TERT</i> mRNA levels as useful markers for monitoring the response to therapy and disease outcome in rectal cancer patients.