Telomere length and TERT polymorphisms as biomarkers in asbestos-related diseases

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
Gender	Female, N (%)	219 (28.3)	23 (26.7)	117 (30.3)	79 (26.2)	0.467^a
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
Smoking	Yes, N (%)	368 (48.0)	39 (45.3)	197 (51.0)	132 (44.9)	0.254^a

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)
Location [1]	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)
Asbestos exposure [8]	Yes	215 (73,1)
Pain [29]	No	114 (41,8)
Pain [29]	Yes	159 (58,2)
Weight loss [34]	No	97 (36,2)
Weight loss [34]	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)
Response rate	Good response (PR+CR)	83 (32.4)

[i] Number of missing data is presented in [] brackets.

[ii] 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

Relative telomere length in cases with pleural plaques (PP) and patients with malignant mesothelioma (MM).
Alb = albumin gene product Tel = telomere product

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
Comparison B vs. A	66		0.480	38 prolongs
Comparison C vs. A	66		0.423	32 shortens
Comparison C vs. A	66		0.423	34 prolongs
Comparison C vs. B	53		0.733	26 shortens
Comparison C vs. B	53		0.733	27 prolongs

[i] 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

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

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
rs2736098	CT	28 (35.0)	133 (34.8)	140 (47.1)	Padd = 0.018
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
rs2736100	CA	48 (56.5)	194 (50.4)	147 (48.7)	Padd = 0.362
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
rs10069690	CT	26 (34.2)	131 (34.3)	107 (36.5)	Padd = 0.107
TT	2 (2.6)	18 (4.7)	26 (8.9)
CT+TT	28 (36.8)	149 (39.0)	133 (45.4)	Pdom = 0.178

[i] 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.

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
rs2736098	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
rs2736100	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
rs10069690	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

[i] 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.

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

[i] 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

[i] A = telomere length before first chemotherapy cycle; B = telomere length at third chemotherapy cycle; C = telomere length after completed chemotherapy or at disease progression

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

[i] 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.

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

[i] Ad = adjustment for C-reactive protein (CRP); CI = confidence interval; HR = hazard ratio

Kaplan Meier survival plot.
Step = disease progression; cross = censored patient; AA = adenine-adenine; CA = cytosineadenine; CC = cytosine-cytosine; hTERT = telomerase reverse transcriptase

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

[i] 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

[i] 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

References

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Articles in this issue

DOI: https://doi.org/10.2478/raon-2024-0009 | Journal eISSN: 1581-3207 | Journal ISSN: 1318-2099

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Language: English

Page range: 87 - 98

Submitted on: Aug 25, 2023

Accepted on: Sep 13, 2023

Published on: Feb 21, 2024

Published by: Association of Radiology and Oncology

In partnership with: Paradigm Publishing Services

Publication frequency: 4 issues per year

Keywords:

malignant mesothelioma,

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© 2024 Ana Mervic, Katja Goricar, Tanja Blagus, Alenka Franko, Katarina Trebusak-Podkrajsek, Metoda Dodic Fikfak, Vita Dolzan, Viljem Kovac, published by Association of Radiology and Oncology
This work is licensed under the Creative Commons Attribution 4.0 License.

Volume 58 (2024): Issue 1 (March 2024)

Telomere length and TERT polymorphisms as biomarkers in asbestos-related diseases

Figures & Tables

TABLE 1.

TABLE 2.

FIGURE 1.

TABLE 3.

FIGURE 2.