Genetic Variants of the TERT Gene, Telomere Length, and Circulating TERT as Prognostic Markers in Rectal Cancer Patients
by
, , , , , , ,
Enrica Rampazzo
1,*
,
Erika Cecchin
2
,
Paola Del Bianco
3
,
Chiara Menin
4,
Gaya Spolverato
5, 
Silvia Giunco
1
,
Sara Lonardi
6,
Sandro Malacrida
7,
Antonino De Paoli
8, 
Giuseppe Toffoli
2,
Salvatore Pucciarelli
5 and
Anita De Rossi
1,4
1
Section of Oncology and Immunology, Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Gattamelata 64, 35128 Padova, Italy
2
Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico (CRO)-IRCCS, Via Franco Gallini 2, 33081 Aviano (PN), Italy
3
Clinical Research Unit, Veneto Institute of Oncology (IOV)-IRCCS, Via Gattamelata 64, 35128 Padova, Italy
4
Immunology and Molecular Oncology Unit, Veneto Institute of Oncology (IOV)-IRCCS, Via Gattamelata 64, 35128 Padova, Italy
5
Section of Surgery, Department of Surgery, Oncology and Gastroenterology, Via Giustiniani 1, University of Padova, 35128 Padova, Italy
6
Medical Oncology Unit 1, Veneto Institute of Oncology (IOV)-IRCCS, Via Gattamelata 64, 35128 Padova, Italy
7
Eurac Research, Institute of Mountain Emergency Medicine, Viale Druso Drususallee 1, 39100 Bolzano, Italy
8
Radiation Oncology, Centro di Riferimento Oncologico (CRO)-IRCCS, Via Franco Gallini 2, 33081 Aviano (PN), Italy
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(11), 3115; https://doi.org/10.3390/cancers12113115
Submission received: 23 September 2020
/
Revised: 22 October 2020
/
Accepted: 23 October 2020
/
Published: 25 October 2020
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
Simple Summary
Single nucleotide polymorphisms (SNPs) in the TERT gene, which encode the catalytic component of telomerase, can affect TERT expression and constitutive telomere length and have been associated with risk and/or outcome for several human cancers, but very few data are available about their impact on rectal cancer. The aim of our study was to comprehensively investigate the associations of eight common TERT SNPs with telomere length, circulating TERT mRNA in plasma, response to neoadjuvant therapy (CRT) and disease outcome in rectal cancer patients. Our findings indicate that the TERT variants can differently contribute to telomere erosion during CRT, circulating TERT levels and response to CRT. Thus, they could be a useful tool for improving the selection of patients who might benefit from CRT. Furthermore, circulating TERT variation during CRT and its level post-CRT are independent markers of response to CRT and disease progression.
Abstract
Single-nucleotide polymorphisms (SNPs) in the TERT gene can affect telomere length and TERT 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 TERT gene, were studied in 194 rectal cancer patients to evaluate their association with constitutive telomere length, circulating TERT 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 TERT 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 TERT 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 TERT 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 TERT 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 TERT mRNA levels as useful markers for monitoring the response to therapy and disease outcome in rectal cancer patients.
