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

		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)	-

[i] Data are missing for: ^a 6 patients, ^b 11 patients, ^c 1 patient and ^d 2 patients. ECOG = Eastern Cooperative Oncology Group

Table 2

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

			Patients			Controls
SNP	Role	Genotype	N (%)	MAF	P_HWE	N (%)	MAF	P_HWE	OR (95% CI)	P	OR (95% CI)_adj	P_adj
rs28362731^a	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)
rs1049305^b	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)
rs1476597^c	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)

[i] Data are missing for: ^a2 controls and 3 patients, ^b2 controls and 1 patient, ^c2 controls. _adj = adjusted by gender and age; MAF = minor allele frequency; P_HWE = P for Hardy-Weinberg equilibrium; Ref. = reference genotype

Table 3

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 response^a	Stable disease (SD)	92 (49.5)
	Progressive disease (PD)	27 (14.5)
Progression of disease^b	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)
Pain^b	No	79 (41.4)
	Yes	112 (58.6)
	No	68 (35.8)
Weight loss^c	Yes	122 (64.2)

[i] Data are missing for: ^a8 patients, ^b3 patients, ^c4 patients. CRP = C reactive protein; LDH = lactate dehydrogenase; OS = overall survival; PFS = progression free survival

Table 4

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

[i] SNP = single nucleotide polymorphisms; OS = overall survival; PFS = progression free survival; Ref. = reference genotype

Table 5

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

			Anemia grade ≥ 2^a					Thrombocytopenia^b			Leukopenia grade ≥ 2^c		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	P_adj2	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

[i] Data are missing for: ^a2 patients, ^b4 patients, ^c7 patients. _adj1 = adjusted by CRP; _adj2 = adjusted by pain at diagnosis; SNP = single nucleotide polymorphisms

Table 6

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

			Alopecia^a			Nephrotoxicity^b			Nausea/Vomiting^c
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

[i] Data are missing for: ^a 33 patients, ^b 4 patients and ^c 28 patients. SNP = single nucleotide polymorphisms

Table 7

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 ≥ 2^a	1.84 (0.10–32.37)	0.676	-	0.999	0.34 (0.10–1.16)	0.085
Leukopenia grade ≥ 2^b	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
Thrombocytopenia^c	1.73 (0.11–26.38)	0.693	3.06 (0.20–46.56)	0.422	0.95 (0.16–5.66)	0.955
Nephrotoxicity^c	0.68 (0.04–11.98)	0.794	-	0.999	1.01 (0.30–3.43)	0.982
Alopecia^d	2.06 (0.11–40.01)	0.633	-	0.999	0.60 (0.16–2.29)	0.453
Nausea/Vomiting^e	2.12 (0.11–40.98)	0.620	6.83 (0.35–132.4)	0.204	0.71 (0.19–2.64)	0.608

[i] Data are missing for: ^a 2 patients, ^b 7 patients, ^c 4 patients, ^d 33 patients and ^e 28 patients. Interaction 1: interaction between rs28362731 and rs1049305. Interaction 2: interaction between rs28362731 and smoking. Interaction 3: interaction between rs1049305 and smoking.

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DOI: https://doi.org/10.2478/raon-2019-0009 | Journal eISSN: 1581-3207 | Journal ISSN: 1318-2099

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Language: English

Page range: 96 - 104

Submitted on: Jan 9, 2019

Accepted on: Jan 25, 2019

Published on: Mar 3, 2019

Published by: Association of Radiology and Oncology

In partnership with: Paradigm Publishing Services

Publication frequency: 4 issues per year

Keywords:

malignant mesothelioma,

AQP1,

Related subjects:

© 2019 Barbara Senk, Katja Goricar, Viljem Kovac, Vita Dolzan, Alenka Franko, published by Association of Radiology and Oncology
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Volume 53 (2019): Issue 1 (March 2019)