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

Ana Mervic
Ana Mervic
, 
Katja Goricar
Katja Goricar
, 
Tanja Blagus
Tanja Blagus
, 
Alenka Franko
Alenka Franko
, 
Katarina Trebusak-Podkrajsek
Katarina Trebusak-Podkrajsek
, 
Metoda Dodic Fikfak
Metoda Dodic Fikfak
, 
Vita Dolzan
Vita Dolzan
 und 
Viljem Kovac
Viljem Kovac
   | 21. Feb. 2024
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Article Category: Research Article
Online veröffentlicht: 21. Feb. 2024
Seitenbereich: 87 - 98
Eingereicht: 25. Aug. 2023
Akzeptiert: 13. Sept. 2023
DOI: https://doi.org/10.2478/raon-2024-0009
Schlüsselwörter
© 2024 Ana Mervic et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

FIGURE 1.

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

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

Association between telomere length and progression-free survival in patients with malignant mesothelioma (MM)

Telomere length HR (95% CI) P HR (95% CI)adj Padj
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

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

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

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) 0.467a
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) < 0.001b
Smoking No, N (%) 398 (52.0) [8] 47 (54.7) 189 (49.0) 162 (55.1) 0.254a
Yes, N (%) 368 (48.0) 39 (45.3) 197 (51.0) 132 (44.9)

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)

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

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 Padj
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

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 Padj
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

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 Padj
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

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 Padj
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

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 Padj
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
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