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Genetic polymorphisms in aquaporin 1 as risk factors for malignant mesothelioma and biomarkers of response to cisplatin treatment

Barbara Senk
Barbara Senk
, 
Katja Goricar
Katja Goricar
, 
Viljem Kovac
Viljem Kovac
, 
Vita Dolzan
Vita Dolzan
 et 
Alenka Franko
Alenka Franko
   | 03 mars 2019
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Article Category: Research Article
Publié en ligne: 03 mars 2019
Pages: 96 - 104
Reçu: 09 janv. 2019
Accepté: 25 janv. 2019
DOI: https://doi.org/10.2478/raon-2019-0009
© 2019 Barbara Senk, Katja Goricar, Viljem Kovac, Vita Dolzan, Alenka Franko, published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Associations between AQP1 SNPs and non-haematological side effects of cisplatin based treatment (N = 176)

Alopeciaa Nephrotoxicityb Nausea/Vomitingc
SNP Genotype N (%) OR (95% CI) P N (%) OR (95% CI) P N (%) OR(95% CI) P
GG 60 (45.8) Ref. - 74 (46.8) Ref. - 73 (53.7) Ref. -
rs28362731 GA 5 (55.6) 1.48 (0.38–5.76) 0.572 3 (27.3) 0.43 (0.11–1.66) 0.219 5 (55.6) 1.08 (0.28–4.19) 0.913
GG 30 (46.2) Ref. - 35 (43.8) Ref. - 36 (52.9) Ref. -
GC 20 (35.7) 0.65 (0.31–1.35) 0.246 34 (50.0) 1.29 (0.67–2.46) 0.448 26 (44.8) 0.72 (0.36–1.46) 0.364
rs1049305 CC 15 (71.4) 2.92 (1.00–8.46) 0.049 10 (43.5) 0.99 (0.39–2.52) 0.982 15 (71.4) 2.22 (0.77–6.41) 0.140
GC+CC 35 (45.5) 0.97 (0.50–1.89) 0.934 44 (48.4) 1.20 (0.66–2.20) 0.547 41 (51.9) 0.96 (050–1.84) 0.900

Clinical characteristics of MM patients treated with cisplatin based chemotherapy (N = 194)

Characteristic N (%)
Gemcitabine and cisplatin 132 (68.0)
Chemotherapy type Pemetrexed and cisplatin 62 (32.0)
Complete response (CR) 6 (3.2)
Partial response (PR) 61 (32.8)
Chemotherapy responsea Stable disease (SD) 92 (49.5)
Progressive disease (PD) 27 (14.5)
Progression of diseaseb No 20 (10.5)
Yes 171 (89.5)
No 58 (29.9)
Death Yes 136 (70.1)
PFS Median (25%–75%) (month) 7.8 (5.3–13.8)
OS Median (25%–75%) (month) 18.1 (9.4–28.7)
Follow-chemotherapy up from the start of Median (25%–75%) (month) 49.2 (18.9–75.5)
CRP Median (25%–75%) 20.5 (9–58)
LDH Median (25%–75%) 2.67 (2.26–3.11)
Painb No 79 (41.4)
Yes 112 (58.6)
No 68 (35.8)
Weight lossc Yes 122 (64.2)

Influence of interactions on the risk of occurrence of side effects

Interaction 1rs28362731 Interaction 2 Interaction 3
Side effect -rs1049305 P1 rs28362731 - smoking P2 rs1049305 - smoking P3
OR (95% CI) OR (95% CI) OR (95% CI)
Anemia grade ≥ 2a 1.84 (0.10–32.37) 0.676 - 0.999 0.34 (0.10–1.16) 0.085
Leukopenia grade ≥ 2b 0.95 (0.04–23.07) 0.974 - 0.999 0.92 (0.21–4.02) 0.915
Neutropenia grade ≥ 2 0.55 (0.03–9.76) 0.686 7.55 (0.39–145.1) 0.180 0.67 (0.19–2.35) 0.526
Thrombocytopeniac 1.73 (0.11–26.38) 0.693 3.06 (0.20–46.56) 0.422 0.95 (0.16–5.66) 0.955
Nephrotoxicityc 0.68 (0.04–11.98) 0.794 - 0.999 1.01 (0.30–3.43) 0.982
Alopeciad 2.06 (0.11–40.01) 0.633 - 0.999 0.60 (0.16–2.29) 0.453
Nausea/Vomitinge 2.12 (0.11–40.98) 0.620 6.83 (0.35–132.4) 0.204 0.71 (0.19–2.64) 0.608

Influence of AQP1 SNP on survival and chemotherapy response in MM patients

Progress free survival Overall survival Chemotherapy response
SNP Genotype PFS median (25%–75%) month HR (95% CI) P OS median (25%–75%) month HR (95% CI) P Poor response N (%) Good response N (%) OR (95% CI) P
GG 7.7 (5.2–13.6) Ref. - 18.1 (9.1–28.0) Ref. - 112 (65.1) 60 (34.9) Ref. -
rs28362731 GA 11.1 (7.0–14.7) 0.72 (0.39–1.33) 0.299 26.5 (14.4–47.8) 0.56 (0.26–1.19) 0.130 6 (54.5) 5 (45.5) 1.56 (0.46–5.31) 0.481
GG 7.9 (5.4–12.1) Ref. - 18.1 (9.0–26.8) Ref. - 55 (64.7) 30 (35.3) Ref. -
GC 7.8 (5.2–15.0) 0.80 (0.58–1.11) 0.187 22.1 (10.1–29.7) 0.72 (0.50–1.05) 0.091 43 (58.1) 31 (41.9) 1.32 (0.70–2.51) 0.394
rs1049305 CC 7.4 (4.8–14.1) 0.92 (0.59–1.46) 0.736 13.3 (8.1–25.4) 1.10 (0.67–1.80) 0.712 20 (76.9) 6 (23.1) 0.55 (0.20–1.52) 0.248
GC+CC 7.8 (4.9–15.0) 0.83 (0.62–1.13) 0.233 18.2 (9.5–28.7) 0.81 (0.58–1.14) 0.220 63 (63.0) 37 (37.0) 1.08 (0.59–1.97) 0.810

Association between AQP1 SNPs and haematological side effects of cisplatin based treatment (N = 176)

Anemia grade ≥ 2a Thrombocytopeniab Leukopenia grade ≥ 2c Neutropenia grade ≥ 2
SNP Genotype N (%) OR (95% CI) P OR (95% CI)adj1 P adj1 N (%) OR P (95% CI) OR (95% CI)adj2 Padj2 N OR (%) (95% CI) P N (%) OR P (95% CI)
rs28362731 GG 79 (49.4) Ref. - Ref. - 21 (13.3) Ref. - Ref. - 39 Ref. (25.2) - 59 (36.4) Ref. -
GA 3 (27.3) (0.100.38 –1.50) 0.169 (0.130.53 –2.12) 0.370 (36.44 ) (1.003.73 –13.84) 0.049 (1.134.63 –19.05) 0.034 (18.22 ) (0.140.66 –3.19) 0.606 3 (27.3) (0.170.66 –2.56) 0.543
GG (56.846 ) Ref. - Ref. - (12.510 ) Ref. - Ref. - (14 17.5) Ref. - 25 (30.9) Ref. -
GC (34.323 ) (0.200.40 –0.78) 0.007 (0.230.46 –0.92) 0.029 (11.88 ) (0.350.93 –2.52) 0.892 (0.240.71 –1.08) 0.529 (18 27.7) (0.821.81 –3.99) 0.144 26 (37.1) (0.671.32 –2.60) 0.416
rs1049305 CC (52.013 ) (0.340.82 –2.03) 0.674 (0.280.74 –1.94) 0.536 (30.47 ) (1.013.06 –9.28) 0.048 (0.692.18 –6.94) 0.185 (36.19 ) (1.103.03 –8.38) 0.033 11 (45.8) (0.751.90 –4.81) 0.178
GC +CC (39.136 ) (0.270.49 –0.90) 0.021 (0.270.52 –0.99) 0.046 (16.515 ) (0.581.38 –3.28) 0.463 (0.431.07 –2.69) 0.885 (30.727 ) (1.002.09 –4.35) 0.049 37 (39.4) (0.781.45 –2.72) 0.242

Description of all malignant mesothelioma (MM) patients (N = 231) and MM patients treated with cisplatin based chemotherapy (N = 194)

All MM patients MM patients cisplatin treated based with chemotherapy
Characteristic Characteristic type N (%) N (%)
Age Median (25%–75%) 66 (58–73) 65 (58–71.3)
Gender Men 170 (73.6) 146 (75.3)
Women 61 (26.4) 48 (24.7)
I 18 (7.8) 15 (7.7)
II 57 (24.7) 48 (24.7)
MM stage III IV 69 (29.9) 66 (28.6) 62 (32.0) 50 (25.8)
Peritoneal MM 20 (8.7) 18 (9.3)
Undefined 1 (0.4) 1 (0.5)
Epithelioid 167 (72.3) 147 (75.8)
Histological Biphasic 26 (11.3) 21 (10.8)
type Sarcomatoid 24 (10.4) 21 (10.8)
Undefined 14 (6.0) 5 (2.6)
0 15 (6.5) 15 (7.7)
ECOG 1 111 (48.1) 100 (51.5)
performance status 2 90 (39.0) 76 (39.2)
3 15 (6.5) 3 (1.5)
Exposure to No 59 (26.6)a 45 (23.3)c
asbestos Yes 166 (73.8) 148 (76.7)
No 120 (53.3)a 101(52.6)d
Smoking Yes 105 (46.7) 91(47.4)
Gemcitabine/ Cisplatin 132 (60.0)b 132 (68.0)
Pemetrexed/Cisplatin 62 (28.2) 62 (32.0)
Treatment chemotherapy Without 16 (7.3) -
Other forms of chemotherapy 10 (4.5) -

Distribution of AQP1 genotypes in MM patients and controls and risk of MM

Patients Controls
SNP Role Genotype N (%) MAF PHWE N (%) MAF PHWE OR (95% CI) P OR (95% CI)adj Padj
rs28362731a p.Gly165Asp GG 210 (92.1) 0.039 0.535 288 (91.7) 0.041 0.444 Ref. - Ref. -
GA 18 (7.9) 26 (8.3) 0.95 0.871 0.94 0.885
(0.51–1.78) (0.38–2.30)
rs1049305b c.*578G>C GG 107 (46.5) 0.337 0.082 128 (40.8) 0.373 0.288 Ref. - Ref. -
GC 91 (39.6) 138 (43.9) 0.79 0.207 0.59 0.039
(0.55–1.14) (0.35–0.97)
CC 32 (13.9) 48 (15.3) 0.80 0.390 0.63 0.199
(0.48–1.13) (0.32–1.27)
GC+CC 123 (53.5) 186 (59.2) 0.79 0.181 0.60 0.033
(0.56–1.12) (0.37–0.96)
rs1476597c c.-783G>C GG 157 (68.0) 0.255 <0.001 220 (70.1) 0.247 <0.001
GC 30 (13.0) 33 (10.5)
CC 44 (19.0) 61 (19.4)
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