Radiol Oncol 2024; 58(1): 87-98. doi: 10.2478/raon-2024-0009
87
research article
Telomere length and TERT polymorphisms as 
biomarkers in asbestos-related diseases
Ana Mervic
1
,
 
Katja Goricar
2
, T anja Blagus
2
, Alenka Franko
1,3
, Katarina Trebusak-Podkrajsek
2,4
, 
Metoda Dodic Fikfak
1,3
,
 
Vita Dolzan
1,2*
, Viljem Kovac
1,5*
1 
Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 
2 
Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
3 
Clinical Institute of Occupational Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia
4  
Clinical Institute for Special Laboratory Diagnostics, University Children’s Hospital, University Medical Centre Ljubljana, 
Ljubljana, Slovenia
5 
Institute of Oncology Ljubljana, Ljubljana, Slovenia
Radiol Oncol 2024; 58(1): 87-98.
Received 25 August 2023 
Accepted 13 September 2023
Correspondence to: Assoc. Prof. Viljem Kovač, M.D., Ph.D., Institute of Oncology Ljubljana, Zaloška cesta 2, 1000 Ljubljana, Slovenia; 
Phone: +386 1 5879 622; Email: vkovac@onko-i.si; Prof. Vita Dolžan, M.D., Ph.D., Pharmacogenetics Laboratory, Institute of Biochemistry 
and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia; Phone: +386 1 543 7670; Email: 
vita.dolzan@mf.uni-lj.si
Disclosure: No potential conflicts of interest were disclosed.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background. Asbestos exposure has been proposed as a risk factor for shorter telomere length. The aim of our study 
was to investigate whether telomere length in leukocytes and hTERT genetic polymorphisms may serve as potential 
biomarkers for the risk of developing asbestos-related diseases and as biomarkers of progression and chemotherapy 
response rate in malignant mesothelioma (MM).
Subjects and methods. We conducted two retrospective studies. In the first study, a case-control study, telomere 
length and hTERT polymorphisms were determined in patients with MM, subjects with pleural plaques and controls 
without the asbestos related disease, who were occupationally exposed to asbestos. In the second study, a lon-
gitudinal observational study, telomere length was also determined in samples from MM patients before and after 
chemotherapy. Telomere length was determined by monochromatic multiplex quantitative polymerase chain reac-
tion (PCR), while competitive allele-specific PCR was used to genotype hTERT rs10069690, rs2736100 and rs2736098. 
Logistic regression and survival analysis were used in statistical analysis.
Results. Patients with MM had shorter telomere length than subjects with pleural plaques (p < 0.001). After adjust-
ment for age, rs2736098 CT, and rs10069690 TT and CT+TT genotypes were significantly associated with a higher risk of 
MM (p
adj
 = 0.023; p
adj
 = 0.026 and p
adj
 = 0.017), while rs2736100 AA and CA+AA genotypes conferred to a lower risk for 
MM compared to all other subjects (p
adj 
= 0.017, and p
adj
 = 0.026). Telomere length was not associated with a response 
to chemotherapy (p > 0.05) or time to disease progression (p > 0.05). Carriers of one or two polymorphic rs10069690 
T alleles had a good response to chemotherapy (p = 0.039, and p = 0.048), these associations remained statistically 
significant after adjustment for age (p
adj
 = 0.019; p
adj
 = 0.017). Carriers of two polymorphic rs2736100 A alleles had a 
longer time to disease progression (p = 0.038).
Conclusions. Shorter telomere length and hTERT polymorphisms may serve as a biomarker for the risk of developing 
MM. Additionally, rs10069690 and rs2736100 polymorphisms, but not telomere length, were associated with a chemo-
therapy response or MM progression. 
Key words: malignant mesothelioma; asbestos; telomere length; hTERT polymorphisms 
Introduction
Asbestos consists of mineral fibres with a high ma-
lignant potential, listed among carcinogens by the 
World Health Organisation in 1987 .
1
 The malignant 
potential of asbestos fibres lies within their capa-
bility to deeply infiltrate the respiratory system 

Radiol Oncol 2024; 58(1): 87-98.
Mervic A et al. / Telomeres in asbestos diseases 88
and persist there for extended durations.
2
 There is 
no known safe level of asbestos exposure.
3
Inhaled asbestos fibres induce oxidative stress 
due to the presence of iron as well as frustrated 
phagocytosis by macrophages, what in turn stimu-
lates Fenton and Haber-Weiss reactions, ultimately 
resulting in the generation of reactive oxygen spe-
cies (ROS). Asbestos further elicits the upregulation 
of the heavy chain of ferritin, consequently leading 
to an augmented iron burden and increased pro-
duction of ROS.
5
 Oxidative stress is closely associ-
ated with chronic inflamation. The asbestos depos-
its contribute to the production of iron-rich asbestos 
bodies, that are accountable for sustaining chronic 
inflamation.
4
 The pro-inflamatory microenviron-
ment fosters cell survival by inhibiting apoptosis, 
promoting mesothelial cell proliferation despite 
DNA damage, activating fibroblasts and inducing 
immunosupression.
2,5
 Furthermore, asbestos fibres 
also have a detrimental impact on chromosomes. 
All of these mechanisms eventually contribute to 
the induction of carcinogenesis.
6,7
Asbestos exposure causes several diseases. In 
the lung, asbestosis and lung cancer carcinoma af-
fect the lung parenchyma, while pleural plaques 
(PP) and malignant mesothelioma (MM) affect the 
pleura, but other serous membranes such as peri-
toneum may also be affected.
8
 
Malignant mesothelioma arises from the ma-
lignant transformation of mesothelial cells and is 
a rare, yet highly aggressive cancer with a poor 
prognosis. In over 80% of cases, the development 
of MM is associated with asbestos exposure.
9
 The 
majority of patients who develop MM have been 
exposed to asbestos through occupational expo-
sure; however, para-occupational, domestic and 
environmental exposure have also been associated 
with MM development.
8
 Due to its long latency pe-
riod, which can extend up to 40 years or even long-
er, the MM epidemic continues to rise in Central 
Europe.
8,10,11
 Malignant mesothelioma occurs more 
often in males, with a median age of 70 years.
3
 In 
2018, the incidence of MM in Slovenia was 3.0/100 
000 in males and 1.5/100 000 in females, resulting in 
a total of 45 new cases that year. At the time of di-
agnosis, 31.1% of patients had MM in an early local-
ized stage, 55.6% had cancer spread to lymph nodes 
and in 11.1% it already presented with metastasis.
12
 
Malignant mesothelioma can be histologically clas-
sified into subgroups: epithelioid, biphasic and sar-
comatoid subtypes. The epithelioid subtype is the 
most common and also exhibits the most favour-
able prognosis, while patients with sarcomatoid 
MM tend to have the worst prognosis.
9
 
The diagnosis of MM is accomplished through 
clinical examination, thorax CT or MRI, and PET-
CT. The prevailing clinical presentation often in-
volves progressive dyspnoea, accompanied by 
non-pleuritic chest pain. Additional symptoms in-
clude cough, fever, asthenia, hypoxia, weight loss, 
and night sweats. Typically, the disease is detected 
3-6 months after the initial clinical presentation.
2
 
The therapeutic strategy is tailored based on the 
tumour resectability and the patient’s performance 
status. In resectable disease, the treatment involves 
the combination of surgery, chemotherapy and ra-
diotherapy, while patients with unresectable dis-
ease receive systemic treatment. Chemotherapy 
with pemetrexed/cisplatin doublet has not been 
changed as a standard treatment since 2004 and 
immunotherapy with ipilimumab and nivolumab 
was approved for the first line treatment in late 
2020.
13
 Although different chemotherapy (gem-
citabine/cisplatin, pemetrexed single, vinorelbine 
weekly) and immunotherapy (nivolumab/ipili-
mumab) regimens are used in relapsed MM, there 
is still no standard of care.
2,13,14
The increasing incidence of MM and the poor 
prognosis call for the identification of novel non-
invasive biomarkers that will enable an earlier di-
agnosis, will have a prognostic value and/or will 
predict the response to treatment. Despite the 
growing numbers of potential biomarkers, there 
is no reliable diagnostic or prognostic biomarker 
available yet. Telomerase reactivation may play a 
crucial role in cancer development and progres-
sion, and telomeres could serve both as a potential 
biomarker and as a therapeutic target in cancer. 
In somatic cells telomeres shorten with each cell 
division, ultimately leading to senescence or ap-
optosis.
15,16
 Cancer cells gain the ability to sustain 
their telomere length by reactivating telomerase, a 
process typically suppressed under physiological 
circumstances.
15-18
The regulation of the expression of the human 
telomerase reverse transcriptase (hTERT) subunit 
of telomerase occurs predominantly at the tran-
scriptional level.
19-21
 Numerous single nucleotide 
polymorphisms (SNP) in the hTERT gene may also 
have an impact on telomerase expression levels 
and activity, and may thus play a role in the risk of 
carcenogenesis, as well as the prognosis and sur-
vival of cancer patients.
18,19,22
Telomere length is influenced by cellular senes-
cence, chronic inflammation and oxidative stress. 
Telomere shortening itself serves as one of the 
main markers for senescence, as telomeres typi-
cally shorten by 50−200 base pairs (bp) with each 

Radiol Oncol 2024; 58(1): 87-98.
Mervic A et al. / Telomeres in asbestos diseases 89
cell cycle.
23
 Chronic inflammation is associated 
with elevated hTERT expression, which, in turn, 
maintains telomere length.
7
 On the other hand, the 
celullar turnover stimulated by chronic inflama-
tion leads to an increased number of cell divisions, 
resulting in telomere shortening.
19
 Furthermore, 
oxidative stress causes DNA damage, which sub-
sequently stops telomere elongation.
7,18
 
Cancer cells exhibit shorter, yet stable, telomeres 
compared to non-neoplastic cells.
18,20,21
 Malignant 
mesothelioma is considered to be a telomerase de-
pendant cancer.
22
 The impact of asbestos exposure 
on telomere length was also established in pleural 
effusion cells, showing that non-neoplastic cells 
had longer telomeres than neoplastic MM cells and 
that telomere shortening and genomic instability 
play significant roles in MM pathogenesis, and 
may also serve as biomarkers for disease develop-
ment, treatment response, and prognosis.
23
To the best of our knowledge, the association 
between telomere length and hTERT polymor-
phisms and asbestos-related diseases has not been 
evaluated yet. Thus, the aim of the present study 
was to analyse the role of telomere length in leuko-
cytes and hTERT polymorphisms as a biomarker 
for asbestos-related diseases, in particular MM, its 
response to treatment and prognosis.
Subjects and methods
Subjects
We conducted two retrospective studies. In the 
first study, a case-control study, telomere length 
and hTERT polymorphisms were determined in 
340 patients with MM, 380 subjects with pleural 
plaques and 94 control subjects without any dis-
TABLE 1. Characteristics of subjects included in the study
Characteristics Category/unit
Total participants 
(N = 774)
Control group
(N = 86)
Cases with PP
(N = 386)
Patients with MM
(N = 302)
P
Gender 
Male, N (%) 555 (71.7) 63 (73.3) 269 (69.7) 223 (73.8)
0.467
a
Female, N (%) 219 (28.3) 23 (26.7) 117 (30.3) 79 (26.2)
Age Years, median (25%−75%) 59.1 (51.1−67.5) 53.3 (48.1−59.5) 55.0 (48.8−62.7) 66.0 (59.0−73.0) < 0.001
b
Smoking
No, N (%) 398 (52.0) [8] 47 (54.7) 189 (49.0) 162 (55.1)
0.254
a
Yes, N (%) 368 (48.0) 39 (45.3) 197 (51.0) 132 (44.9)
Number of missing data is presented in [] brackets.
 
Statistically significant values are printed in bold.
a 
Calculated using Fisher exact test; 
b 
Calculated using Kruskal-Wallis test.
MM = malignant mesothelioma; N = number of samples; PP = pleural plaques
TABLE 2. Clinical characteristics of patients with malignant mesothelioma (MM) 
(N = 302) 
Characteristics Category N (%)
Location [1]
Pleura 267 (88,7)
Peritoneum 34 (11,3)
Histology type
Epithelioid 227 (75,2)
Biphasic 27 (8,9)
Sarcomatoid 27 (8,9)
Undifferentiated 21 (6,9)
Stage (pleural MM)
1 20 (7,5)
2 65 (24,3)
3 89 (33,3)
4 93 (34,8)
ECOG performance status [1]
0 18 (6,0)
1 154 (51,2)
2 111 (36,9)
3 18 (6,0)
Asbestos exposure [8]
No 79 (26,9)
Yes 215 (73,1)
Pain [29]
No 114 (41,8)
Yes 159 (58,2)
Weight loss [34]
No 97 (36,2)
Yes 171 (63,8)
CRP [mg/mL] [48] Median (25%−75%) 22 (7−63,5)
Chemotherapy [21]
No chemotherapy 17 (6.1)
Gemcitabine with cisplatin 161 (57.3)
Pemetrexed with cisplatin 92 (31.6)
Other 11 (3.9)
Chemotherapy response [46]
CR 10 (3.9)
PR 73 (28.5)
SD 128 (50.0)
PD 45 (17.6)
Response rate
Poor response (SD+PD) 173 (67.6)
Good response (PR+CR) 83 (32.4)
Number of missing data is presented in [] brackets.
CRP = C-reactive protein; ECOG = Eastern Cooperative Oncology Group; CR = complete 
response; N = number of samples; SD = stable disease; PD = progressive disease; PR = partial 
response

Radiol Oncol 2024; 58(1): 87-98.
Mervic A et al. / Telomeres in asbestos diseases 90
eases related to asbestos exposure. The cases with 
PP and controls had a history of occupational 
asbestos exposure while working at the Salonit 
Anhovo factory, Slovenia and were presented 
before the State Board for the Recognition of 
Occupational Asbestos Diseases between January 
1999 and December 2003. The patients with MM 
were treated at the Institute of Oncology Ljubljana 
from 2008 and 2018. Among MM patients, 94 had 
blood samples available from at least two different 
time points during chemotherapy treatment (211 
samples available in total).
The diagnosis of MM, PP, or “no asbestos relat-
ed disease” was confirmed by the experts of the 
State Board for the Recognition of Occupational 
Asbestos Diseases.
24-26 
In all subjects of the study 
high-resolution computed tomography (HRCT) 
was performed. Pleural MM was histologically 
confirmed based on samples obtained through 
thoracoscopy or video-assisted thoracic surgery, 
while samples for confirming peritoneal MM were 
collected via laparascopy . The histopathologic sam-
ples were classified as epithelioid, sarcomatoid, bi-
phasic or undifferentiated types of MM.
2,27,28
 The 
TNM classification was used for staging pleural 
MM.
29
 Additionally, clinical data on MM patients, 
such as a performance status based on The Eastern 
Cooperative Oncology Group (ECOG), weight loss 
and C-reactive protein (CRP) levels were also col-
lected. 
Data on the chemotherapy protocol (gemcit-
abine with cisplatin, pemetrexed with cisplatin, 
other, or no chemotherapy) and chemotherapy re-
sponse (classified as complete response [CR], par-
tial response [PR], stable disease [SD], progressive 
disease [PD]) were collected from patients’ medical 
records at The Institute of Oncology Ljubljana and 
the Cancer Registry of the Republic of Slovenia. 
Data on asbestos exposure were available from 
our previous studies.
30 
A standardized question-
naire-based interview was conducted with cases 
having PP and control group to gather data on 
their smoking status, whereas data for patients 
with MM was extracted from medical records at 
The Institute of Oncology Ljubljana.
31
TABLE 3. Telomere length in patients with malignant mesothelioma (MM) at 
different time points during chemotherapy
Time point N Median (25%−75%) P
N shortens/
N prolongs
A 79 1.23 (1.01−1.37)
B 66 1.23 (1.10−1.38)
C 66 1.27 (1.08−1.36)
Comparison B vs. A 66 0.480
28 shortens
38 prolongs
Comparison C vs. A 66 0.423
32 shortens 
34 prolongs
Comparison C vs. B 53 0.733
26 shortens 
27 prolongs
A = telomere length before first chemotherapy cycle; B = telomere length at third chemotherapy 
cycle; C = telomere length after completed chemotherapy or at disease progression; N = 
number of samples; P = p value
TABLE 4. Comparison of genotype frequencies in control group, cases with pleural plaques (PP) and patients with malignant 
mesothelioma (MM) 
Control group
(N = 86)
Cases with PP
(N = 386)
Patients with MM
(N = 302)
P
SNP Genotype N (%) N (%) N (%)
rs2736098
CC 45 (56.3) 215 (56.3) 139 (46.8)
Padd = 0.018 CT 28 (35.0) 133 (34.8) 140 (47.1)
TT 7 (8.8) 34 (8.9) 18 (6.1)
CT+TT 35 (43.8) 167 (43.7) 158 (53.2) Pdom = 0.039
rs2736100
CC 17 (20.0) 103 (26.8) 93 (30.8)
Padd = 0.362 CA 48 (56.5) 194 (50.4) 147 (48.7)
AA 20 (23.5) 88 (22.9) 62 (20.5)
CA+AA 68 (80.0) 282 (73.2) 209 (69.2) Pdom = 0.127
rs10069690
CC 48 (63.2) 233 (61.0) 160 (54.6)
Padd = 0.107 CT 26 (34.2) 131 (34.3) 107 (36.5)
TT 2 (2.6) 18 (4.7) 26 (8.9)
CT+TT 28 (36.8) 149 (39.0) 133 (45.4) Pdom = 0.178
A = adenine; C = cytosine; N = number of samples; Padd = p value of additive genetic model; Pdom = p value of dominant genetic model; SNP = 
single nucleotide polymorphism; T = thymine. Statistically significant values are printed in bold.

Radiol Oncol 2024; 58(1): 87-98.
Mervic A et al. / Telomeres in asbestos diseases 91
All participants were fully informed about the 
purpose of the study and willingly provided their 
informed written consent to participate. The study 
was part of the comprehensive studies approved 
by the Slovenian Ethics Committee for Research 
in Medicine (KME 41/02/09, 36/02/04 and 31/07/04). 
The study adhered to the principles outlined in the 
Declaration of Helsinki.
Molecular genetic analysis
Peripheral venous blood samples from MM pa-
tients were collected in Tempus tubes and frozen at 
-80⁰C until the analysis. DNA extraction was per-
formed using the MagMax 96DNA Multi Sample 
Kit and the MagMax protocol for stabilized Blood 
Tub RNA isolation (all, Applied Biosystems [ABI]). 
For the purpose of our study, only DNA was ex-
tracted, while the remaining sample was stored 
for later RNA extraction. Genomic DNA of cases 
with PP and control group had been isolated dur-
ing our previous studies from peripheral venous 
blood collected in ethylenediaminetetraacetic acid 
(EDTA) containing tubes and DNA was extracted 
with the QIAmp DNA Mini Kit (QIAGEN). The 
concentration of DNA samples was measured us-
ing the Perkin Elmer Lambda BIO+ UV/VIS spec-
trophotometer. Telomere length was assessed us-
ing monochrome multiplex quantitative polymer-
ase chain reaction (MMQ-PCR), relatively as the 
ratio between the telomere product (Tel) and albu-
min gene product (Alb) as previously described.
32
 
Genotyping of hTERT rs10069690, rs2736100 and 
rs2736098 polymorphisms was performed using 
the competitive allele-specific polymerase chain 
reaction (KASP) SNP Genotyping Assay (LGC 
Group).
Statistics
Descriptive statistics were used to depict the vari-
ables. Continuous variables were described using 
the median and interquartile range, while categor-
ical variables were presented as frequencies. To 
compare the distribution of continuous variables, 
the non-parametric Kruskal-Wallis test was per-
formed; for categorical variables, Fisher’s exact test 
was used.
The association between telomere length and 
categorical variables was analyzed using the 
Mann-Whitney test and the Kruskal-Wallis test. 
The Wilcoxon test for related samples was used 
to evaluate the longitudinal change in telomere 
length. Additionally, the correlation between 
continuous variables and longitudinal telomere 
length change was assessed using Spearman’s Rho 
correlation coefficient.
Minor allele frequency (MAF) was analysed for 
each investigated polymorphism. The deviation 
from the Hardy-Weinberg equilibrium (HWE) was 
TABLE 5. Association between selected polymorphisms and the risk of developing malignant mesothelioma (MM): comparison 
of patients with MM and other participants (control group and cases with pleural plaques [PP])
Patients with 
MM
Others
SNP Genotype N (%) N (%) OR (95% CI) P OR (95% CI)
adj
P
adj
rs2736098
CC 139 (46.8) 260 (56.3) Reference Reference
CT 140 (47.1) 161 (34.8) 1.63 (1.20−2.21) 0.002 1.49 (1.06−2.10) 0.023
TT 18 (6.1) 41 (8.9) 0.82 (0.46−1.48) 0.514 0.78 (0.40−1.54) 0.470
CT+TT 158 (53.2) 202 (43.7) 1.46 (1.09−1.96) 0.011 1.36 (0.98−1.88) 0.070
rs2736100
CC 93 (30.8) 120 (56.3) Reference Reference
CA 147 (48.7) 242 (51.5) 0.78 (0.56−1.10) 0.160 0.71 (0.48−1.04) 0.076
AA 62 (20.5) 108 (23.0) 0.74 (0.49−1.12) 0.155 0.56 (0.35−0.90) 0.017
CA+AA 209 (69.2) 350 (74.5) 0.77 (0.56−1.06) 0.111 0.66 (0.46−0.95) 0.026
rs10069690
CC 160 (54.6) 281 (61.4) Reference Reference
CT 107 (36.5) 157 (34.3) 1.20 (0.88−1.64) 0.261 1.41 (0.99−2.01) 0.058
TT 26 (8.9) 20 (4.4) 2.28 (1.24−4.22) 0.008 2.22 (1.10−4.48) 0.026
CT+TT 133 (45.4) 177 (38.6) 1.32 (0.98−1.78) 0.067 1.52 (1.08−2.12) 0.017
A = adenine; adj = adjustment for age; C = cytosine; CI = confidence interval; OR = odds ratio; Others = control group and cases with pleural 
plaques; SNP = single nucleotide polymorphism; T = thymine. Statistically significant values are printed in bold.

Radiol Oncol 2024; 58(1): 87-98.
Mervic A et al. / Telomeres in asbestos diseases 92
tested using a chi-square test. A p-value less than 
0.05 indicated that the distribution did not adhere 
to HWE. Both additive and dominant genetic mod-
els were used in statistical analyses. Univariate 
logistic regression was used to assess the associa-
tion between telomere length and polymorphisms 
with asbestos-related diseases and the response to 
chemotherapy.
Cox regression was utilized to evaluate the as-
sociation of telomere length and genotypes with 
progression-free survival (PFS) and overall sur-
vival (OS). Kaplan-Meier method was used to il-
lustrate the PFS function over time.
All statistical analyses were conducted using the 
IBM SPSS Statistics, version 27 .0 (IBM Corporation, 
Armonk, NY, USA). The threshold for statistical 
significance in all tests performed was set at 0.05.
Results
Subjects 
In total, 302 patients with MM, 386 cases with PP 
and 86 controls were included in our study. The 
characteristics of patients with MM, cases with 
PP and the control group are shown in Table 1. 
There were statistically significant differences 
between the groups in respect to age (p < 0.001) 
and asbestos exposure (p < 0.001). Patients with 
MM (66.0 (59.0−73.0) years) were significantly old-
er than cases with PP (55.0 (48.8−62.7) years) and 
control subjects (53.3 (48.1−59.5) years). Asbestos 
exposure was available for the control group, 379 
cases with PP and 42 patients with MM. Among 
subjects with known asbestos exposure, 52.7% of 
patients with MM had medium or high exposure, 
compared to 28.5% of cases with PP and 24.4% 
of the control group. However, the three study 
groups did not differ significantly with regards to 
gender (p = 0.467) and smoking status (p = 0.254) 
(Table 1).
The clinical characteristics of patients with MM 
are summarized in Table 2. The majority had pleu-
ral MM (267; 88.7%) of the epithelioid type (227; 
75.2%) and had stage four (93; 34.8%) or stage three 
(89; 33.3%) of the disease. According to the ECOG 
TABLE 6. Association between selected polymorphisms and risk of developing malignant mesothelioma (MM): comparison of 
patients with MM and cases with pleural plaques (PP) 
SNP Genotype OR (95% CI) P OR (95% CI)
adj
P
adj
rs2736098
CC Reference Reference
CT 1.63 (1.18−2.24) 0.003 1.52 (1.06−2.16) 0.022
TT 0.82 (0.45−1.51) 0.521 0.76 (0.38−1.53) 0.445
CT+TT 1.46 (1.08−1.99) 0.014 1.37 (0.98−1.93) 0.069
rs2736100
CC Reference Reference
CA 0.84 (0.59−1.19) 0.330 0.77 (0.52−1.15) 0.196
AA 0.78 (0.51−1.20) 0.257 0.58 (0.36−0.94) 0.028
CA+AA 0.82 (0.59−1.15) 0.245 0.71 (0.48−1.03) 0.070
rs10069690
CC Reference Reference
CT 1.19 (0.86−1.65) 0.296 1.39 (0.96−2.01) 0.078
TT 2.10 (1.12−3.96) 0.021 2.11 (1.02−4.34) 0.043
CT+TT 1.30 (0.96−1.78) 0.096 1.48 (1.05−2.10) 0.027
A = adenine; C = cytosine; CI = confidence interval; OR = odds ratio; SNP = single nucleotide polymorphism; T = thymine. Statistically significant 
values are printed in bold.
TABLE 7. Association between telomere length and chemotherapy response rate 
in patients with malignant mesothelioma (MM) 
Telomere length
Poor response
Median (25−75%)
Good response
Median (25−75%)
P
A 1.20 (1.01−1.37) 1.28 (1−1.39) 0.576
B 1.21 (1.05−1.37) 1.28 (1.13−1.35) 0.601
C 1.29 (1.07−1.37) 1.23 (1.02−1.34) 0.369
Comparison B vs. A 0.04 (-0.1 to 0.1) -0.01 (-0.11 to 0.07) 0.317
Comparison C vs. A 0.01 (-0.09 to 0.22) -0.04 (-0.16 to 0.15) 0.241
Comparison C vs. B 0.03 (-0.09 to 0.13) -0.01 (-0.12 to 0.07) 0.353
A = telomere length before first chemotherapy cycle; B = telomere length at third chemotherapy 
cycle; C = telomere length after completed chemotherapy or at disease progression

Radiol Oncol 2024; 58(1): 87-98.
Mervic A et al. / Telomeres in asbestos diseases 93
performance status (PS), most patients with MM 
had PS 1 (154; 51.2%) or PS 2 (111; 36.9%).
Telomere length
There was a statistically significant difference in 
telomere length between patients with MM and 
cases with PP (p < 0.001) (Figure 1). Patients with 
MM had shorter median telomere length of 1.23 
(1.01−1.37) compared to 1.43 (1.32−1.56) in cases 
with PP. The difference in telomere length re-
mained statistically significant (p < 0.001) after ad-
justment for age. 
The analysis of the association between tel-
omere length and age revealed a statistically sig-
nificant influence of age on telomere length, in-
dicating that older patients with MM had longer 
telomeres (Spearman’s rho = 0.370; p < 0.001). 
The dynamics of telomere length during 
chemotherapy
Among the patients with MM, no specific trend was 
observed in telomere length changes at different 
time points during chemotherapy. Approximately 
the same number of cases exhibited telomere elon-
gation or shortening (Table 3, Figure 2).
TABLE 8. Association between selected polymorphism and chemotherapy response rate in patients with malignant 
mesothelioma (MM)
SNP Genotype
Poor 
response
N (%)
Good 
response
N (%)
OR (95% CI) P OR (95% CI)
adj
P
adj
rs2736098
CC 81 (68.6) 37 (31.4) Reference Reference
CT 76 (65.5) 40 (34.5) 1.15 (0.67−1.99) 0.611 1.20 (0.67−2.16) 0.542
TT 11 (64.7) 6 (35.3) 1.19 (0.41−3.47) 0.745 1.27 (9.42−3.87) 0.671
CT+TT 87 (65.4) 46 (34.6) 1.16 (0.68−1.96) 0.587 1.21 (0.69−2.14) 0.511
rs2736100
CC 53 (67.1) 26 (32.9) Reference Reference
CA 89 (70.6) 37 (29.4) 0.85 (0.46−1.55) 0.592 0.85 (0.45−1.63) 0.625
AA 31 (60.8) 20 (39.2) 1.32 (0.63−2.74) 0.463 1.16 (0.53−2.57) 0.709
CA+AA 120 (67.8) 57 (32.2) 0.97 (0.55−1.70) 0.911 0.94 (0.51−1.71) 0.831
rs10069690
CC 94(72.9) 35 (27.1) Reference Reference
CT 58 (59.8) 39 (40.2) 1.81 (1.03−3.17) 0.039 2.08 (1.13−3.84) 0.019
TT 14 (66.7) 7 (33.3) 1.34 (0.50−3.60) 0.558 1.85 (0.64−5.31) 0.255
CT+TT 72 (61.0) 46 (39.0) 1.72 (1.00−2.93) 0.048 2.04 (1.13−3.67) 0.017
A = adenine; Adj = adjustment for weight loss and ECOG performance status; C = cytosine; CI = confidence interval; OR = odds ratio; SNP = single 
nucleotide polymorphism; T = thymine. Statistically significant values are printed in bold.
FIGURE 1. Relative telomere length in cases with pleural 
plaques (PP) and patients with malignant mesothelioma 
(MM).
Alb = albumin gene product Tel = telomere product
TABLE 9. Association between telomere length and progression-free survival in 
patients with malignant mesothelioma (MM) 
Telomere length HR (95% CI) P HR (95% CI)
adj
P
adj
A 2.15 (0.69−6.68) 0.185 1.66 (0.50−5.47) 0.408
B 1.02 (0.28−3.76) 0.976 0.92 (0.22−3.76) 0.905
C 1.69 (0.46−6.16) 0.430 1.49 (0.40−5.48) 0.551
Comparison B vs. A 0.16 (0.03−1.01) 0.052 0.23 (0.03−1.67) 0.145
Comparison C vs. A 1.01 (0.25−4.18) 0.985 1.36 (0.31−5.92) 0.682
Comparison C vs. B 1.57 (0.26−9.58) 0.624 2.16 (0.31−14.83) 0.435
Ad = adjustment for C-reactive protein (CRP); CI = confidence interval; HR = hazard ratio 

Radiol Oncol 2024; 58(1): 87-98.
Mervic A et al. / Telomeres in asbestos diseases 94
hTERT polymorphisms and the risk for 
asbestos-related diseases
We investigated three hTERT polymorphisms: 
rs2736098, rs2736100 and rs10069690. The distribu-
tion of all genotypes followed the Hardy-Weinberg 
equilibrium (HWE) (pHWE > 0.05). Genotype fre-
quencies in different study groups are presented 
in Table 4.
For further analysis, the most common CC gen-
otype was used as the reference.
For rs2736098, the genotype distribution dif-
fered significantly between groups association 
with MM (P value of additive genetic model 
[Padd] = 0.018; P value of dominant genetic model 
[Pdom] = 0.039). Carries of polymorphic rs2736098 
T alleles were more common among patients with 
MM compared to cases with PP and control sub-
jects. There were no significant differences in the 
distribution of other investigated polymorphisms 
among the groups (Table 4).
When MM patients were compared to all other 
subjects combined, polymorphic rs2736098 T allele 
was statistically significantly associated with an 
increased risk of developing MM (CT genotype: 
odds ratio [OR] = 1.63; 95% confidence interval [CI] 
= 1.20-2.21; p = 0.002; CT+TT genotype: OR = 1.46; CI 
= 1.09-1.96; p = 0.011) (Table 5). After adjustment for 
age, only the association of CT genotype remained 
significant (OR
adj
 = 1.49; CI
adj
 = 1.06-2.10; p
adj
 = 0.023). 
The presence of at least one polymorphic rs2736100 
A allele was associated with a lower risk for de-
veloping MM after age adjustment (AA genotype: 
OR
adj
 = 0.56; CI
adj
 = 0.35-0.90; p
adj
 = 0.017; CA+AA 
genotype: OR
adj
 = 0.66; CI
adj
 = 0.46-0.95; p
adj
 = 0.026). 
Carriers of two polymorphic rs10069690 T alleles 
had a higher risk of MM development (TT geno-
type: OR = 2.28; CI = 1.24-4.22; p = 0.008). After ad-
justment for age, the risk for MM was significantly 
higher in carriers of at least one polymorphic allele 
(CT+TT genotype: OR
adj
 = 1.52; CI
adj
 = 1.08-2.12; p
adj
 
= 0.017) as well as in carriers of two polymorphic 
alleles (TT genotype: OR
adj
 = 2.2; CI
adj
 = 1.10-4.48; 
p
adj
 = 0.026) (Table 5).
When the group of MM patients was compared 
with the cases with PP, polymorphic rs2736098 T 
allele remained statistically significantly associ-
ated with an increased risk of developing MM 
(CT genotype: OR = 1.63; CI = 1.18-2.24; p = 0.003; 
CT+TT genotype: OR = 1.46; CI = 1.08-1.99; p = 
0.014) (Table 6). After adjustment for age, only CT 
genotype remained associated with significantly 
higher MM risk (OR
adj
 = 1.52; CI
adj
 = 1.06-2.16; p
adj
 = 
0.022). Carriers of two polymorphic rs2736100 A al-
leles had a lower risk for developing MM, but only 
after adjustment for age (OR
adj
 = 0.58; CI
adj
 = 0.36-
0.94; p
adj
 = 0.028). On the other hand, carriers of two 
polymorphic rs10069690 T alleles had a higher risk 
of MM development (OR = 2.10; CI = 1.12-3.96; p = 
0.021). After adjustment for age, the risk for MM 
remained significant in carriers of two polymor-
phic alleles (OR
 adj
 = 2.11; CI
 adj
 = 1.02-4.34; p
 adj
 = 
0.043). Additionally, in the multivariable analysis 
FIGURE 2. Relative telomere length at different time points A, B and C.
A = telomere length before first chemotherapy cycle: B = telomere length at third chemotherapy 
cycle; C = telomere length after completed chemotherapy or at disease progression
FIGURE 3. Kaplan Meier survival plot. 
Step = disease progression; cross = censored patient; AA = adenine-adenine; CA = cytosine- 
adenine; CC = cytosine-cytosine; hTERT = telomerase reverse transcriptase

Radiol Oncol 2024; 58(1): 87-98.
Mervic A et al. / Telomeres in asbestos diseases 95
the association was also significant in the domi-
nant model (CT+TT genotype: OR
 adj
 = 1.48; CI
 adj
 = 
1.05-2.10; p
 adj
 = 0.027) (Table 6). 
Treatment response rate in patients 
with malignant mesothelioma
The data on chemotherapy treatment and response 
are presented in Table 2. The majority of patients 
with MM received chemotherapy based on gemcit-
abine with cisplatin (N = 161; 57.3%). Complete and 
partial responses were achieved only in 3.9% and 
28.5% of patients, respectively, while in 50.0% of 
patients, the disease was stable. Disease progres-
sion occurred in 17.6% of patients. The majority of 
patients thus had a poor chemotherapy response 
rate (N = 173; 67.6%).
We observed no significant associations be-
tween telomere length or their dynamics with a 
chemotherapy response rate (p > 0.05) (Table 7).
TABLE 10. Association between selected polymorphisms and progression−free survival in patients with malignant mesothelioma 
(MM)
SNP Genotype PFS Median (25%−75%) HR (95% CI) P HR (95% CI)
adj
P
adj
rs2736098
CC 10.2 (6.5−18.9) Reference Reference
CT 9.4 (6.1−14.5) 1.21 (0.93−1.57) 0.163 1.31 (0.98−1.76) 0.073
TT 10.0 (6.6−14.2) 1.32 (0.79−2.20) 0.294 1.46 (0.82−2.59) 0.194
CT+TT 9.7 (6.3−14.3) 1.22 (0.95−1.57) 0.127 1.33 (1.00−1.77) 0.051
rs2736100
CC 9.4 (5.9−13.4) Reference Reference
CA 9.7 (6.4−14.9) 0.98 (0.74−1.30) 0.879 0.83 (0.60−1.14) 0.250
AA 12.2 (7.1−20.1) 0.68 (0.47−0.98) 0.038 0.68 (0.45−1.03) 0.070
CA+AA 10.2 (6. 5−17.6) 0.87 (0.67−1.15) 0.328 0.78 (0.57−1.06) 0.113
rs10069690
CC 10.7 (6.3−16.5) Reference Reference
CT 9.3 (6.1−15.0) 1.09 (0.83−1.42) 0.552 1.06 (0.79−1.43) 0.699
TT 11. 8 (7.3−13.4) 0.85 (0.52−1.38) 0.502 0.81 (0.48−1.38) 0.443
CT+TT 9.4 (6.6−15.0) 1.04 (0.80−1.34) 0.791 1.01 (0.76−1.33) 0.963
A = adenine; Adj = adjustment for smoking, asbestos exposure, weight loss, C-reactive protein (CRP), and histology type of MM; C = cytosine; CI = 
confidence interval; HR = hazard ratio; PFS = progression free survival: SNP = single nucleotide polymorphism; T = thymine. Statistically significant 
values are printed in bold.
TABLE 11. Association between selected polymorphisms and overall survival in patients with malignant mesothelioma (MM) 
SNP Genotype OS Median (25%−75%) HR (95% CI) P HR (95% CI)
adj
P
adj
rs2736098
CC 18.2 (10.1−28.6) Reference Reference
CT 19.3 (9.6−31.4) 1.01 (0.76−1.35) 0.944 1.02 (0.75−1.39) 0.899
TT 24.4 (22.0−31.1) 0.84 (0.46−1.54) 0.573 0.94 (0.48−1.83) 0.859
CT+TT 20.3 (9.9−31.2) 0.99 (0.75−1.31) 0.924 1.01 (0.75−1.36) 0.945
rs2736100
CC 17. 5 (11.6−28.1) Reference Reference
CA 19.3 (10.7−32.5) 0.87 (0.64−1.20) 0.404 0.88 (0.62−1.24) 0.460
AA 20.6 (9.6−31.4) 0.79 (0.53−1.17) 0.229 0.86 (0.56−1.31) 0.478
CA+AA 19.5 (10.0−32.5) 0.85 (0.63−1.14) 0.270 0.87 (0.63−1.21) 0.410
rs10069690
CC 20.3 (9.6−31.4) Reference Reference
CT 19.3 (11.1−25.9) 1.09 (0.81−1.47) 0.578 1.13 (0.82−1.55) 0.455
TT 16.0 (13.1−29.0) 1.01 (0.60−1.72) 0.958 0.74 (0.41−1.35) 0.321
CT+TT 18.5 (11.4−29.0) 1.08 (0.81−1.43) 0.619 1.04 (0.77−1.41) 0.780
A = adenine; Adj = adjustment for asbestos exposure, ECOG performance status, C-reactive protein (CRP), histology type of MM; C = cytosine; CI 
= confidence interval; HR = hazard ratio; OS = overall survival; SNP = single nucleotide polymorphism; T = thymine   

Radiol Oncol 2024; 58(1): 87-98.
Mervic A et al. / Telomeres in asbestos diseases 96
When we analysed the associations between 
hTERT polymorphisms and a chemotherapy re-
sponse rate, only rs10069690 influenced the chem-
otherapy response rate in MM patients. Carriers 
of at least one polymorphic rs10069690 allele had 
a significantly better response rate to chemo-
therapy (CT genotype: OR = 1.18; CI = 1.03-3.17; p 
= 0.039; CT+TT genotype: RO = 1.72; CI = 1.00-2.93; 
p = 0.048). Both associations became even stronger 
after adjustment for weight loss and ECOG per-
formance status (CT genotype: OR
 adj
 = 2.08; CI
 adj
 = 
1.13-3.84; p
 adj
 = 0.019; CT+TT genotype: RO
 adj
 = 2.04; 
CI
 adj
 = 1.13-3.67; p
 adj
 = 0.017) (Table 8).
Survival of patients with malignant 
mesothelioma
Within the median follow-up time of the patients 
of 41.7 (22.8−77.3) months, median PFS was 10.0 
(6.3−16.4) months and the median overall survival 
(OS) was 19.3 (10.0−30.3) months.
Telomere length or their dynamics were not as-
sociated with PFS, even after adjustment for CRP 
(all p > 0.05) (Table 9).  
In Cox regression analysis (Table 10), patients 
with the rs2736100 AA genotype had significantly 
longer PFS compared to patients with the refer-
ence CC genotype (hazard ratio [HR] = 0.68; CI = 
0.47-0.98; p = 0.038). The association of rs2736100 
with PFS in patients with MM is illustrated as a 
function of time (Kaplan Meier plot) in Figure 3. 
None of other investigated polymorphisms were 
associated with PFS, not even after the adjustment 
for smoking status, asbestos exposure, weight loss, 
CRP level and histology type (p > 0.05) (Table 10).
Additionally, the investigated polymorphisms 
were not associated with OS of patients with 
MM neither in univariable analysis, nor after the 
adjustment for asbestos exposure, ECOG perfor-
mance status, CRP level, and histologic type (all p 
> 0.05) (Table 11).
Discussion
In our study, we evaluated whether telomere 
length or their dynamics and hTERT polymor-
phisms could serve as a biomarker for the risk of 
developing asbestos-related diseases, chemother-
apy response, and progression in MM patients. 
Consistent with previous studies, we observed 
that patients with MM had shorter telomeres com-
pared to cases with PP . Previous studies stated that 
the telomeres in cancer patients are shorter but sta-
ble when compared to healthy individuals.
18,20,21
 
Also, a study analysing telomere length in pleural 
effusion cells reported shorter telomeres in 12 MM 
patients compared to 35 cases with non-neoplastic 
disease.
23 
Interestingly, older patients with MM had 
longer telomeres than younger patients with MM. 
According to our knowledge, telomere shorten-
ing is one of the most important markers of age-
ing.
19,33,34
 Furthermore, cancer cells have typically 
short telomeres
18,20,21
, as also shown for MM.
23
 
However, the presence of telomerase reactivation 
in MM
22
 allows for an unlimited cell division po-
tential and telomere length maintenance, which, 
on the contrary, does not occur in non-neoplastic 
cells,
35
 potentially contributing to the observed re-
sults.
In the first part of the study, we evaluated the 
association of TERT SNPs with a risk for MM. We 
observed rather consistent associations of the pol-
ymorphic rs2736098 T allele with an increased risk 
of MM in the additive or in the dominant genetic 
model. Although no specific studies on this associ-
ation with MM have been conducted, recent stud-
ies have shown associations between rs2736098 
and lung cancers
36,37
 as well as an increased risk 
for bladder cancer, while the risk was decreased 
for breast and colon cancers.
36
Another important finding of this study was 
the decreased risk of MM associated with homozy-
gosity for polymorphic rs2736100 A allele after 
adjustment for age. This observation emphasizes 
the importance of age as a contributing factor to 
carcinogenesis, although further investigation is 
needed to determine whether this association is 
coincidental. Our results are in agreement with 
previous studies indicating that carriers of two ref-
erence rs2736100 C alleles generally have a higher 
risk of developing idiopathic lung fibrosis, chroni-
cal obstructive pulmonary disease (COPD) and la-
ryngeal cancer.
18,39,40
Furthermore, we observed a significantly high-
er risk for MM in carriers of two polymorphic 
rs10069690 T alleles. To our knowledge, there are 
no other studies investigating this association in 
MM; however, rs10069690 has been linked to a 
higher overall cancer risk, specifically in breast, 
ovarian, lung and thyroid cancers.
41
In the second part of the study, we evaluated 
the association of telomere length and TERT SNPs 
with a treatment outcome in MM. We did not find 
any associations between telomere length and 
MM chemotherapy response. While studies on 
breast cancer reported that chemotherapy can lead 

Radiol Oncol 2024; 58(1): 87-98.
Mervic A et al. / Telomeres in asbestos diseases 97
to telomere shortening in the short term, telomere 
length was shown to return to its pre-treatment 
level after two years.
42
 Given that our findings are 
based on a limited number of participants and 
that studies in MM patients are lacking, further 
analyses and investigations are necessary to gain a 
deeper understanding of the relationship between 
telomere length and a chemotherapy response in 
MM.
In our study, polymorphic rs10069690 T allele 
was associated with a good chemotherapy re-
sponse. Moreover, this association became even 
more statistically significant after adjustment for 
age. Interestingly, our findings differ from a previ-
ous study in breast cancer, which is also telomer-
ase-dependent cancer, where rs10069690 was asso-
ciated with poor chemotherapy outcome.
43
 As there 
are currently no studies specifically exploring this 
relationship in MM, further studies are required 
to fully understand the impact of rs10069690 on a 
chemotherapy response in MM.
No significant associations were identified be-
tween telomere length and PFS in patients with 
MM. To our knowledge, there are no other stud-
ies that investigated the association between tel-
omere length and survival in MM, and the exist-
ing survival analyses conducted for other cancer 
types yield contradictory results. An extensive 
study examining the effect of telomere length on 
survival in various benign and malignant diseases 
found no influence on cancer patients’ survival.
44
 
Conversely, an American study on pancreatic can-
cer observed that shorter telomeres were linked to 
poorer OS, while hTERT polymorphisms had no 
statistically significant impact on OS.
45
 Similarly, 
our study showed no significant associations be-
tween the investigated hTERT polymorphisms 
and overall survival of MM patients. Due to the 
inconsistent knowledge in this field, further stud-
ies should be performed to better define the factors 
influencing the outcome of MM. 
Finally, our study has shown that carriers of 
two polymorphic rs2736100 A alleles had a lower 
risk for MM progression. However, this area of 
research is still limited, and our finding con-
trasts with a kidney cancer study that identified 
rs2736100 as an independent factor associated 
with a poor prognosis.
46
 Similarly, an Indian study 
reported  that rs2736100 contributes to a poorer 
prognosis of glioma patients.
47
 On the other hand, 
a Chinese study did not seem to validate the rela-
tionship between this polymorphism and a poor 
prognosis in papillary thyroid carcinoma.
48
 It is 
essential to consider that the mentioned studies 
did not focus on MM and were not conducted on 
Caucasians, thus caution should be applied when 
interpreting the data. Therefore, future studies in-
vestigating these associations with a specific focus 
on MM are required.
In conclusion, our results suggest that tel-
omere length and genetic polymorphisms in the 
hTERT gene have a limited role as a biomarker for 
the risk of developing asbestos-related diseases. 
Collectively, our study did not demonstrate the 
role of telomere length as a biomarker for a MM 
chemotherapy response; however, with a cautious 
interpretation, hTERT polymorphisms may repre-
sent a biomarker for the chemotherapy outcome in 
MM. Similarly, telomere length does not seem to 
impact PFS, while hTERT polymorphisms may be 
used as a biomarker for the risk of MM progres-
sion. So far, our findings have been encouraging, 
yet further studies are necessary to validate these 
associations in independent patient cohorts and 
elucidate the role of telomere length and genetic 
variants of the hTERT gene in MM.
Acknowledgements
This work was financially supported by the 
Slovenian Research and Innovation Agency (ARIS 
Grants No. P1-0170 and L3-2622).
References
1. Toyokuni S. Commentary on “mechanisms of asbestos-induced carcinogen-
esis” published in 2009. Nagoya J Med Sci 2023; 85: 13-5. doi: 10.18999/
nagjms.85.1.13
2. Hajj GNM, Cavarson CH, Pinto CAL, Venturi
 
G, Navarro
 
JR, de Lima VCC.
. 
Malignant pleural mesothelioma: an update. J Bras Pneumol 2021; 47: 
e20210129. doi: 10.36416/1806-3756/e20210129 
3. Brims F. Epidemiology and clinical aspects of malignant pleural mesothe-
lioma. Cancers 2021; 13: 4194. doi: 10.3390/cancers13164194.
4. Gaudino G, Xue J, Yang H. How asbestos and other fibers cause mesothe-
lioma. Transl Lung Cancer Res 2020; 9(Suppl 1): S39-46. doi: 10.21037/
tlcr.2020.02.01
5. Tallet A, Nault JC, Renier A Hysi
 
I, Galateau-Sallé
 
F, A Cazes A, et al. 
Overexpression and promoter mutation of the TERT gene in malignant pleu-
ral mesothelioma. Oncogene 2014; 33: 3748-52. doi: 10.1038/onc.2013.351
6. Rossiello F, Jurk D, Passos JF, di Fagagna FA. Telomere dysfunction in age-
ing and age-related diseases. Nat Cell Biol 2022; 24: 135-47. doi: 10.1038/
s41556-022-00842-x
7. Lin J, Epel E. Stress and telomere shortening: insights from cellular mecha-
nisms. Ageing Res Rev 2022; 73: 101507. doi: 10.1016/j.arr.2021.101507
8. Wadowski B, De Rienzo A, Bueno R. The molecular basis of malignant 
pleural mesothelioma. Thorac Surg Clin 2020; 30: 383-93. doi: 10.1016/j.
thorsurg.2020.08.005
9. Berry TA, Belluso E, Vigliaturo R, Gieré
 
R, Emmett
 
EA, Testa JR, et al. Asbestos 
and other hazardous fibrous minerals: potential exposure pathways and 
associated health risks. Int J Environ Res Public Health 2022; 19: 4031. doi: 
10.3390/ijerph19074031

Radiol Oncol 2024; 58(1): 87-98.
Mervic A et al. / Telomeres in asbestos diseases 98
10. Pouliquen DL, Kopecka J. Malignant mesothelioma. Cancers 2021; 13: 3447. 
doi: 10.3390/cancers13143447
11. Zhu W, Liu J, Li Y, Shi Z, Wei S. Global, regional, and national trends in 
mesothelioma burden from 1990 to 2019 and the predictions for the 
next two decades. SSM Popul Health 2023; 23: 101441. doi: 10.1016/j.
ssmph.2023.101441
12. Cancer in Slovenia 2018. Annual report. Zadnik V, Gašljević G, Hočevar 
M, Jarm K, Pompe-Kirn V, Strojan P, et al, editors. Ljubljana: Institute of 
Oncology Ljubljana, Epidemiology and Cancer Registry, Slovenian Cancer 
Registry; 2020. 
13. Štrbac, D, Dolžan V. Novel and future treatment options in mesothelioma: a 
systematic review. Int J Mo Sci 2022; 23: 1975. doi: 10.3390/ijms23041975
14. Guo X, Lin L, Zhu J. Immunotherapy vs. chemotherapy in subsequent treat-
ment of malignant pleural mesothelioma: which is better? J Clin Med 2023; 
12: 2531. doi:10.3390/jcm12072531
15. Okamoto K, Seimiya H. Revisiting telomere shortening in cancer. Cells 2019; 
8: 107. doi: 10.3390/cells8020107
16. Razgonova MP, Zakharenko AM, Golokhvast KS, Thanasoula M,
 
Sarandi 
E,
 
Nikolouzakis K, et al. Telomerase and telomeres in aging theory and 
chronographic aging theory (review). Mol Med Rep 2020; 22: 1679-94. doi: 
10.3892/mmr.2020.11274
17. Rampazzo E, Cecchin E, Del Bianco P , Menin C,
 
Spolverato G,
 
Giunco S, et al. 
Genetic variants of the TERT gene. telomere length, and circulating TERT as 
prognostic markers in rectal cancer patients. Cancers 2020; 12: 3115. doi: 
10.3390/cancers12113115
18. Yuan X, Dai M, Xu D. Telomere-related markers for cancer. Curr Top Med 
Chem 2020; 20: 410-32. doi: 10.2174/1568026620666200106145340
19. Levstek T, Redenšek S, Trošt M,  Dolžan
 
V , Trebušak Podkrajšek K. Assessment 
of the telomere length and its effect on the symptomatology of parkinson’s 
disease. Antioxidants 2021; 10: 137. doi: 10.3390/antiox10010137
20. Borges G, Criqui M, Harrington L. Tieing together loose ends: telomere 
instability in cancer and aging. Mol Oncol 2022; 16: 3380-96. doi: 10.3390/
antiox10010137
21. Cigan SS, Meredith JJ, Kelley AC, Yang
 
T, Langer
 
EK, Hooten AJ, et al. 
Predicted leukocyte telomere length and risk of germ cell tumours. Br J 
Cancer 2022; 127: 301-12. doi: 10.1038/s41416-022-01798-3
22. Au AY, Hackl T, Yeager TR, Cohen SB,
 
Pass HI,
 
Harris CC, et al. Telomerase 
activity in pleural malignant mesotheliomas. Lung Cancer 2011; 73: 283-8. 
doi: 10.1016/j.lungcan.2010.12.023
23. Aida S, Aida J, Naoi M, Kato M, Tsuura Y , Natsume I, et al. Measurement of 
telomere length in cells from pleural effusion: asbestos exposure causes 
telomere shortening in pleural mesothelial cells. Pathol Int 2018; 68: 503-8. 
doi: 10.1111/pin.12710
24. Alfudhili KM, Lynch DA, Laurent F, Ferretti GR,
 
Dunet V, Beigelman-Aubry C. 
et al. Focal pleural thickening mimicking pleural plaques on chest computed 
tomography: tips and tricks. Br J Radiol 2016; 89: 20150792. doi: 10.1259/
bjr.20150792
25. Kim Y , Myong JP , Lee JK, Kim
 
JS, Kim YK, Jung SH, et al. CT characteristics of 
pleural plaques related to occupational or environmental asbestos exposure 
from South Korean asbestos mines. Korean J Radiol 2015; 16: 1142-52. doi: 
10.3348/kjr.2015.16.5.1142 
26. Wolff H, Vehmas T, Oksa P, Rantanen J, Vainio H. Asbestos, asbestosis, and 
cancer, the Helsinki criteria for diagnosis and attribution 2014: recom-
mendations. Scand J Work Environ Health 2015; 41: 5-15. doi: 10.5271/
sjweh.3462
27. Chapel DB, Schulte JJ, Husain AN, Krausz T. Application of immunohisto-
chemistry in diagnosis and management of malignant mesothelioma. Transl 
Lung Cancer Res 2020; 9(Suppl 1): S3-27. doi: 10.21037/tlcr.2019.11.29
28. Munkholm-Larsen S, Cao CQ, Yan TD. Malignant peritoneal mesothelioma. 
World J Gastrointest Surg 2009; 1: 38-48. doi: 10.4240/wjgs.v1.i1.38
29. Berzenji L, Van Schil PE, Carp L. The eighth TNM classification for malig-
nant pleural mesothelioma. Transl Lung Cancer Res 2018; 7: 543-9. doi: 
10.21037/tlcr.2018.07.05
30. Franko A, Goricar K, Kovac V, Dodic-Fikfak M,
 
Dolzan V. NLRP3 and CARD8 
polymorphisms influence risk for asbestos-related diseases. J Med Biochem 
2020; 39: 91-9. doi: 10.2478/jomb-2019-0025
31. Klebe S, Leigh J, Henderson DW, Nurminen M. Asbestos. smoking and 
lung cancer: an update. Int J Environ Res Public Health 2019; 17: 258. doi: 
10.3390/ijerph17010258
32. Levstek
 
T, Redenšek
 
S, Trošt
 
M, Dolžan
 
V, Trebušak Podkrajšek
 
K. Assessment 
of the telomere length and its effect on the symptomatology of Parkinson’s 
disease. Antioxidants 2021; 10: 137. doi: 10.3390/antiox10010137. 
33. Lulkiewicz M, Bajsert J, Kopczynski P, Barczak W, Rubis B. Telomere length: 
how the length makes a difference. Mol Biol Rep 2020; 47: 7181-8. doi: 
10.1007/s11033-020-05551-y
34. Havas A, Yin S, Adams PD. The role of aging in cancer. Mol Oncol 2022; 16: 
3213-9. doi: 10.1002/1878-0261.13302
35. Kusamura S, Baratti D, De Simone M, Pasqual EM,
 
Ansaloni L,
 
 Marrelli D, 
et al. Diagnostic and therapeutic pathway in diffuse malignant peritoneal 
mesothelioma. Cancers 2023; 15: 662. doi: 10.3390/cancers15030662
36. Zhou M, Jiang B, Xiong M, Zhu X. Association between TERT rs2736098 
polymorphisms and cancer risk-a meta-analysis. Front Physiol 2018; 9: 377. 
doi: 10.3389/fphys.2018.00377
37. Wang M, Sun Y . Telomerase reverse transcriptase rs2736098 polymorphism 
is associated with lung cancer: a meta-analysis. J Int Med Res 2020; 48: 
300060520936173. doi: 10.1177/0300060520936173
38. Holesova Z, Krasnicanova L, Saade R, Pös O, Budis J, Gazdarica J, et al. 
Telomere length changes in cancer: insights on carcinogenesis and potential 
for non-invasive diagnostic strategies. Genes 2023; 14: 715. doi: 10.3390/
genes14030715
39. Arimura-Omori M, Kiyohara C, Yanagihara T, Yamamoto Y, Ogata-Suetsugu 
S, Harada E, et al. Association between telomere-related polymorphisms 
and the risk of IPF and COPD as a precursor lesion of lung cancer: findings 
from the Fukuoka tobacco-related lung disease (FOLD) registry. Asian Pac J 
Cancer Prev 2020; 21: 667-73. doi: 10.31557/APJCP .2020.21.3.667
40. Cornean CI, Catana A, Maniu AA, Do polymorphisms of the TERT, GSTM1, 
and GSTT1 genes increase laryngeal cancer susceptibility in smokers of 
Romanian descent? Medicina (Kaunas) 2022; 58: 1106. doi: 10.3390/
medicina5808110
41. He G, Song T, Zhang Y , Chen X, W, Chen H,  et al. TERT rs10069690 polymor-
phism and cancers risk: a meta-analysis. Mol Genet Genomic Med 2019; 7: 
e00903. doi: 10.1002/mgg3.903
42. Benitez-Buelga C, Sanchez-Barroso L, Gallardo M, Apellániz-Ruiz M, Inglada-
Pérez L, Yanowski K, et al. Impact of chemotherapy on telomere length in 
sporadic and familial breast cancer patients. Breast Cancer Res Treat 2015; 
149: 385-94. doi: 10.1007/s10549-014-3246-6
43. Zins K, Peka E, Miedl H, Ecker S, Abraham D, Schreiber M. Association of 
the telomerase reverse transcriptase rs10069690 polymorphism with the 
risk, age at onset and prognosis of triple negative breast cancer . Int J Mol Sci 
2023; 24: 1825. doi: 10.3390/ijms24031825
44.  Schneider CV, Schneider KM, Teumer A, Rudolph KL, Hartmann D, Rader DJ, 
et al. Association of telomere length with risk of disease and mortality. JAMA 
Intern Med 2022; 182: 291-300. doi: 10.1001/jamainternmed.2021.7804
45. Hamada T, Yuan C, Bao Y, Mingfeng Zhang, Natalia Khalaf, Ana Babic, et al. 
Prediagnostic leukocyte telomere length and pancreatic cancer survival. 
Cancer Epidemiol Biomarkers Prev 2019; 28: 1868-75. doi: 10.1158/1055-
9965.EPI-19-0577
46. Ma R, Liu C, Lu M, Yuan X, Cheng G, Kong F, et al. The TERT locus geno-
types of rs2736100-CC/CA and rs2736098-AA predict shorter survival in 
renal cell carcinoma. Urol Oncol 2019; 37: 301.e1-10. doi: 10.1016/j.uro-
lonc.2019.01.014
47. Pandith AA, Wani ZA, Qasim I, Afroze D, Manzoor U, Amin I, et al. 
Association of strong risk of hTERT gene polymorphic variants to malignant 
glioma and its prognostic implications with respect to different histo-
logical types and survival of glioma cases. J Gene Med 2020; 22: e3260. doi: 
10.1002/jgm.3260
48. Nie X, Shang J, Wang W. TERT genetic polymorphism rs2736100 is associ-
ated with an aggressive manifestation of papillary thyroid carcinoma. Front 
Surg 2022; 9: 1019180. doi: 10.3389/fsurg.2022.1019180