Genetic variability of HIF1A and response to treatment with cisplatin in combination with pemetrexed or gemcitabine in patients with malignant mesothelioma

Association between investigated single nucleotide polymorphisms with response and chemotherapy (N = 226)

SNP	Genotype	SD/PD N (%)	CR/PR N (%)	OR (95% CI)	P	ORadj (95% CI)adj	Padj
rs11549465	CC	92 (62.2)	56 (37.8)	Ref.		Ref.
	CT	31 (77.5)	9 (22.5)	0.48 (0.21–1.08)	0.074	0.37 (0.14–0.97)	0.044
	TT	10 (62.5)	6 (37.5)	0.99 (0.34–2.86)	0.979	1.55 (0.48–4.98)	0.464
	CT+TT	41 (73.2)	15 (26.8)	0.60 (0.31–1.18)	0.141	0.60 (0.28–1.30)	0.194
rs11549467	GG	126 (65.6)	66 (34.4)	Ref.		Ref.
	GA+AA	14 (66.7)	7 (33.3)	0.96 (0.37–2.48)	0.924	1.06 (0.38–2.98)	0.906
rs2057482	CC	95 (63.3)	55 (36.7)	Ref.		Ref.
	CT	41 (66.1)	21 (33.9)	0.89 (0.48–1.65)	0.699	0.92 (0.45–1.85)	0.806
	TT	7 (70.0)	3 (30.0)	0.74 (0.18–2.98)	0.672	0.61 (0.11–3.39)	0.574
	CT+TT	48 (66.7)	24 (33.3)	0.86 (0.48–1.56)	0.627	0.87 (0.45–1.71)	0.689

Clinical characteristics of patients with malignant mesothelioma (N = 234)

Characteristic	Category/Unit	N (%) [N]
Sex	Man, N (%)	176 (75.2)
	Woman, N (%)	58 (24.8)
Age	Age, median (25%– 75%)	66 (58–72)
Stage	I	15 (6.4) [1]
	II	53 (22.7)
	III	75 (32.2)
	IV	62 (26.6)
	Peritoneal MM	28 (12.0)
Histological type	Epithelioid	183 (78.2)
	Biphasic	20 (8.5)
	Sarcomatoid	22 (9.4)
	Not specified	9 (3.8)
ECOG performance status	0	15 (6.4)
	1	126 (53.8)
	2	90 (38.5)
	3	3 (1.3)
C-reactive protein (CRP)	Median (25%–75%)	21 (8–59) [19]
Asbestos exposure	No, N (%)	60 (25.8) [1]
	Yes, N (%)	173 (74.2)
Smoking	No, N (%)	129 (55.6) [2]
	Yes, N (%)	103 (44.4)
Pain	No, N (%)	99 (43.4) [6]
	Yes, N (%)	129 (56.6)
Weight loss	No, N (%)	76 (34.4) [13]
	Yes, N (%)	145 (65.6)
Type of chemotherapy	Gemcitabine/cisplatin	152 (65.0)
	Pemetreksed/cisplatin	82 (35.0)
Response to chemotherapy	SD+PD	147 (65.0) [8]
	CR+PR	79 (35.0)
Disease progression	No, N (%)	21 (9.1) [3]
	Yes, N (%)	210 (90.9)
Death	No, N (%)	65 (27.8)
	Yes, N (%)	169 (72.2)
Progression-free survival	Months, median value (25%–75%)	7.9 (5.3–13.8)
Overall survival	Months, median value (25%–75%)	18.2 (9.7–28.0)
Follow-up duration	Months, median valu (25%–75%)	44.4 (20.4–75.5)

Association between investigated polymorphisms and progression-free survival (N = 231)

SNP	Genotype	PFS median (25–75%)	HR (95% CI)	P	HRadj (95% Cl)adj	Padj
rs11549465	CC	7.8 (5.6–13.0)	Ref.		Ref.
	CT	8.9 (5.3–16.2)	0.92 (0.64–1.33)	0.665	0.79 (0.52–1.20)	0.271
	TT	5.6 (3.5–17.4)	1.1 (0.69–1.90)	0.608	0.98 (0.55–1.72)	0.932
	CT+TT	8.5 (4.8–16.2)	0.98 (0.71–1.35)	0.912	0.84 (0.59–1.21)	0.354
rs11549467	GG	7.7 (5.2–13.1)	Ref.		Ref.
	GA+AA	11.2 (7.7–16.0)	0.74 (0.46–1.19)	0.220	0.67 (0.40–1.11)	0.119
rs2057482	CC	8.9 (5.5–16.0)	Ref.		Ref.
	CT	7.9 (5.3–12.4)	1.21 (0.89–1.65)	0.223	1.35 (0.95–1.92)	0.099
	TT	7.6 (5.5–8.3)	1.63 (0.83–3.21)	0.158	1.41 (0.65–3.07)	0.390
	CT+TT	7.6 (5.3–11.9)	1.25 (0.93–1.68)	0.131	1.35 (0.97–1.89)	0.076

Association between investigated polymorphisms and overall survival (N = 234)

SNP	Genotype	OS median (25%–75%)	HR (95% CI)	P	HRadj (95% CI)adj	Padj
rs11549465	CC	18.1 (9.9–28.0)	Ref.		Ref.
	CT	21.0 (6.8–29.8)	0.85 (0.56–1.30)	0.451	0.75 (0.47–1.19)	0.217
	TT	20.3 (9.1–32.5)	1.00 (0.56–1.77)	0.994	0.85 (0.46–1.59)	0.610
	CT+TT	21.0 (8.7–29.8)	0.89 (0.62–1.28)	0.542	0.78 (0.52–1.16)	0.215
rsll549467	GG	18.1 (9.2–28.7)	Ref.		Ref.
	GA+AA	22.2 (12.6–29.6)	0.90 (0.55–1.48)	0.687	0.95 (0.56–1.60)	0.847
rs2057482	CC	19.6 (9.8–27.9)	Ref.		Ref.
	CT	18.0 (9.8–29.7)	1.07 (0.76–1.50)	0.694	1.07 (0.74–1.52)	0.729
	TT	11.6 (9.4–22.1)	1.44 (0.70–2.95)	0.325	1.43 (0.66–3.10)	0.366
	CT+TT	15.6 (9.8–29.7)	1.11 (0.81–1.53)	0.529	1.10 (0.78–1.55)	0.573