Caspase 8 polymorphisms contribute to the prognosis of advanced lung adenocarcinoma patients after platinum-based chemotherapy

Figures & data

Table 1. The clinical characteristics of 555 advanced adenocarcinoma patients treated with platinum-based chemotherapy.

Variables	N = 555	mOS (95%CI)	χ^2	p
Median age, y (range)	57(26–80)
<60	309 (55.8%)	24.1 (21.4–26.8)	9.12	3E-3^*
≥ 60	245 (44.2%)	17.4 (15.3–19.6)
Sex
Male	340 (61.3%)	18.7 (16.5–20.9)	6.76	9E-3^*
Female	215 (38.7%)	24.9 (20.7–29.1)
Smoking status
Nonsmoker	290 (52.3%)	22.5 (19.1–25.9)	3.76	0.052
Ever Smoker	264 (47.7%)	18.7 (15.7–21.6)
Clinical stage
IIIa	22 (4.0%)	27.9 (16.6–39.2)	3.32	0.190
IIIb	148 (26.7%)	20.3 (17.3–23.3)
IV	384 (69.3%)	19.9 (17.3–22.5)
Doublet regimen
DNA damaging agents	153 (27.6%)	21.0 (17.1–24.9)	3.10	0.213
Platinum-tubulin-targeting drugs^b	384 (69.2%)	19.6 (17.1–22.1)
Other combination^c	18 (3.2%)	30.5(14.6–46.4)

^a Others NSCLC included mixed-cell, neuroendocrine carcinoma, or undifferentiated carcinoma.

^b Tubulin-targeting drugs includes paclitaxel (n = 267), docetaxel (n = 74) or navelbine (n = 284).

^c Other combination included etoposide or bevacizumab.

* p < 0.05. Abbreviations: mOS: median overall survival, CI: confidence interval

Table 2. Genotype frequencies and MAF of CASP8 tag SNPs in current data, or in CHB, CEU and YRI from HapMap SNP database.

		Allele frequencies
Tag SNPs	Location	Current Data	CHB	CEU	YRI	p
Rs1049454	3′ UTR
MAF		0.212 (G)	0.199 (G)	0.022 (G)	0.322(G)	<0.0001
A/A		330 (61.8%)	85 (63.9%)	107 (95.5%)	68 (46.6%)
A/G		181 (33.9%)	43 (32.3%)	5 (4.5%)	63 (42.5%)
G/G		23 (4.3%)	5 (3.8%)	0	16 (11.0%)
Rs3769827	intron
MAF		0.211 (G)	0. 206 (G)	0.425 (G)	0.313 (G)	<0.0001
A/A		343 (61.8%)	83 (61.0%)	39 (34.5%)	65 (44.2%)
A/G		190 (34.2%)	50 (36.8%)	52 (46.0%)	72 (49.0%)
G/G		22 (4%)	3 (2.2%)	22 (19.5%)	10 (6.8%)
Rs3769821	5′near gene
MAF		0.302 (G)	0.267 (G)	0.437 (G)	0.427 (A)	<0.0001
A/A		267 (48.2%)	24 (53.3%)	23 (36.5%)	10 (16.1%)
A/G		239 (43.1%)	18 (40.0%)	25 (39.7%)	33 (53.2%)
G/G		48 (8.7%)	3 (6.7%)	15 (23.8%)	19 (30.6%)
Rs3754935	intron
MAF		0.247 (C)	0.215 (C)	0.044 (C)	0.340 (C)	<0.0001
A/A		310 (56.0%)	84 (61.3%)	104 (92.0%)	65 (44.2%)
A/C		214 (38.6%)	47 (34.3%)	8 (7.1%)	64 (43.5%)
C/C		30 (5.4%)	6 (4.4%)	1 (0.9%)	18 (12.2%)
Rs12990906	intron
MAF		0.355 (G)	0.488 (G)	0.465 (A)	N/A	<0.0001
A/A		168 (30.3%)	9 (20.9%)	17 (26.2%)	N/A
A/G		274 (49.4%)	26 (60.5%)	27 (41.5%)	N/A
G/G		113 (20.3%)	8 (18.6%)	21 (32.3)	N/A
Rs3769825	intron
MAF		0.193 (G)	0.197 (G)	0.487 (G)	0.340 (G)	<0.0001
A/A		359 (64.8%)	85 (62.0%)	31 (27.4%)	60 (40.8%)
A/G		176 (31.8%)	50 (36.5%)	54 (47.8%)	74 (50.3%)
G/G		19 (3.4%)	2 (1.5%)	28 (24.8%)	13 (8.8%)
Rs7608692	intron
MAF		0.3 (A)	0.289 (A)	0.162 (A)	0.135 (A)	<0.0001
A/A		45 (8.1%)	2 (4.4%)	2 (3.1%)	3 (4.8%)
A/G		242 (43.7%)	22 (48.9%)	17 (26.2%)	11 (17.5%)
G/G		267 (48.2%)	21 (46.7%)	46 (70.8%)	49 (77.8%)

* p < 0.05. Abbreviations: UTR, untranslated region; MAF, Minor allele frequency; CHB, Han Chinese in Beijing, China;CEU, Utah residents with Northern and Western European ancestry from the CEPH collection; YRI, Yoruban in Ibadan, Nigeria

Table 3. Univariate Cox's regression analysis of 7 tagSNPs of CASP8 with OS in 555 advanced lung adenocarcinoma patients.

SNP ID	genotype	N(%)	mOS(95%CI)	HR(95%CI)	P	P-adjusted
Rs1045494					0.125	0.438
	A/A	330 (61.8%)	20.6 (18.3–22.8)	R		—
	A/G	181 (33.9%)	17.7 (15.3–20.1)	1.22 (1.00–1.51)	0.054	—
	G/G	23 (4.3%)	27.7 (18.2–37.2)	0.92 (0.58–1.48)	0.738	—
Recessive (G)	AA +AG	511 (95.7%)	19.6 (17.8–21.4)
	GG	23 (4.3%)	27.7 (18.2–37.2)	0.86 (0.54–1.36)	0.916	0.916
Dominant (G)	AA	330 (61.8%)	20.6 (18.3–22.8)
	GG+AG	204 (38.2%)	18.1 (15.0–21.2)	1.18 (0.97–1.44)	0.103	0.361
additive	NA	NA	NA	1.09 (0.93–1.28)	0.282	0.611
Rs3769827					0.574	0.670
	A/A	343 (61.8%)	19.8 (17.1–22.5)	R		—
	A/G	190 (34.2%)	20.0 (17.9–22.1)	0.95 (0.7–1.17)	0.64	—
	G/G	22 (4%)	27.1 (9.9–44.3)	0.74 (0.41–1.36)	0.332	—
Recessive (G)	AA+AG	533 (96%)	19.9 (17.8–22.0)
	GG	22 (4%)	27.1 (9.9–44.3)	0.76 (0.42–1.38)	0.360	0.548
Dominant (G)	AA	343 (61.8%)	19.8 (17.1–22.5)
	GG+AG	212 (38.2%)	20.9 (18.3–23.4)	0.93 (0.76–1.14)	0.464	0.812
additive	NA	NA	NA	0.92 (0.77–1.10)	0.349	0.611
Rs3769821					0.019^*	0.133
	A/A	267 (48.2%)	24.4 (20.5–28.2)	R		—
	A/G	239 (43.1%)	17.7 (15.8–19.6)	1.31 (1.07–1.61)	0.009^*	—
	G/G	48 (8.7%)	23.8 (9.7–37.8)	0.96 (0.67–1.36)	0.807	—
Recessive (G)	AA+AG	506 (91.3%)	20.0 (18.0–22.0)
	GG	48 (8.7%)	23.8 (9.7–37.8)	0.84 (0.60–1.18)	0.323	0.548
Dominant (G)	AA	267 (48.2%)	24.4 (20.5–28.2)
	GG+AG	287 (51.8%)	17.7 (15.4–20.0)	1.24 (1.02–1.50)	0.033^*	0.231
additive	NA	NA	NA	1.09 (0.9–1.5)	0.252	0.611
Rs3754935					0.378	0.529
	A/A	310 (56.0%)	20.2 (17.6–22.8)	R		—
	A/C	214 (38.6%)	20.0 (16.7–23.3)	1.12 (0.92–1.37)	0.273	—
	C/C	30 (5.4%)	26.8 (19.6–34.0)	0.87 (0.57–1.34)	0.537	—
Recessive (C)	AA+AC	524 (94.6%)	20.04 (18.0–22.1)	0.83 (0.54–1.27)	0.392	0.548
	CC	30 (5.4%)	26.8 (19.6–34.0)
Dominant (C)	AA	310 (56.0%)	20.2 (17.6–22.8)
	CC+AC	244 (44.0%)	20.4 (17.0–23.7)	1.08 (0.89–1.31)	0.422	0.812
additive	NA	NA	NA	1.02 (0.88–1.20)	0.763	0.890
rs12990906					0.239	0.529
	A/G	274 (49.4%)	20.7 (18.1–23.3)	R		—
	A/A	168 (30.3%)	17.7 (13.9–21.6)	1.00 (0.80–1.24)	0.969	—
	G/G	113 (20.3%)	21.9 (15.1–28.7)	0.79 (0.60–1.05)	0.104	—
Recessive (G)	AA +AG	442 (79.7%)	19.9 (17.7–22.1)
	GG	113 (20.3%)	21.9 (15.1–28.7)	0.80 (0.61–1.04)	0.091	0.548
Dominant (G)	AA	168 (30.3%)	17.7 (13.9–21.6)
	GG+AG	387 (69.7%)	21.0 (18.4–23.7)	0.95 (0.77–1.17)	0.607	0.850
additive	NA	NA	NA	0.91 (0.80–1.04)	0.157	0.611
rs3769825					0.678	0.678
	A/A	359 (64.8%)	21.3 (18.3–24.3)	R		—
	A/G	176 (31.8%)	19.1 (15.8–22.4)	1.06 (0.86–1.30)	0.604	—
	G/G	19 (3.4%)	17.9 (7.2–28.6)	0.82 (0.45–1.50)	0.516	—
Recessive (G)	AA+AG	535 (96.6%)	20.4 (18.2–22.6)	0.80 (0.44–1.47)	0.477	0.557
	GG	19 (3.4%)	17.9 (7.2–28.6)
Dominant (G)	AA	359 (64.8%)	21.3 (18.3–24.3)
	GG+AG	195 (35.2%)	19.1 (15.8–22.4)	1.03 (0.84–1.27)	0.751	0.876
additive	NA	NA	NA	1.00 (0.84–1.20)	0.967	0.967
rs7608692					0.376	0.529
	G/G	267 (48.2%)	20.2 (16.6–23.8)	R		—
	A/G	242 (43.7%)	19.6 (16.8–22.5)	1.06 (0.86–1.29)	0.601	—
	A/A	45 (8.1%)	29.8 (16.9–42.7)	0.80 (0.54–1.18)	0.254	—
Dominant (A)	AA+AG	287 (51.8%)	20.6 (18.0–23.2)
	GG	267 (48.2%)	20.2 (16.6–23.8)	1.00 (0.82–1.20)	0.991	0.991
Recessive (A)	AA	45 (8.1%)	29.8 (16.9–42.7)
	GG+AG	509 (91.9%)	20.0 (18.0–22.0)	1.29 (0.88–1.89)	0.195	0.548
additive	NA	NA	NA	0.96 (0.83–1.12)	0.623	0.885

* p < 0.05. Abbreviations: mOS: median overall survival, HR: hazard ratio, CI: confidence interval, NA: Not available, R: Reference; p-adjusted was calculated with R language (FDR method) for CASP 8 tagSNPs genotype, domiant model, recessive and additive model respectively.

Table 4. Multivariate Cox's regression analysis of clinical factors and CASP8 tagSNPs for overall survival in the 555 advanced lung adenocarcinoma patients treated with platinum-based chemotherapy.

Variables	HR (95% CI)	p	P-adjusted
Age (< 60 vs.> = 60)	1.33 (1.09–1.63)	0.005^*	—
Sex (male vs. female)	0.75 (0.61–0.93)	0.008^*	—
TNM (III vs.IV)	1.19 (1.00–1.42)	0.055	—
Double regimen	0.94 (0.77–1.15)	0.548	—
Rs3769821 dominant (G)	1.52 (1.20–1.94)	0.001^*	0.007^*
Rs1045494 dominant (G)	1.45 (1.15–1.82)	0.002^*	0.014^*
Rs3769825 dominant (G)	1.31 (1.03–1.66)	0.027^*	0.063
Rs7608692 recessive (G)	0.80 (0.64–1.00)	0.047^*	0.329
Rs1045494 recessive (G)	0.78 (0.48–1.28)	0.327	0.913
Rs7608692 dominant (G)	1.21 (0.79–1.85)	0.385	0.602
Rs3754935 recessive (C)	1.21 (0.53–2.76)	0.656	0.913
Rs12990906 dominant (G)	1.10 (0.79–1.51)	0.601	0.602
Rs12990906 recessive (G)	1.12 (0.71–1.77)	0.616	0.913
Rs3769827 domiant (G)	0.92 (0.67–1.26)	0.598	0.602
Rs3769827 recessive (G)	0.85 (0.45–1.61)	0.617	0.913
Rs3754935 dominant (C)	1.38 (0.57–3.38)	0.476	0.602
Rs3769825 recessive (G)	0.94 (0.49–1.79)	0.844	0.913
Rs3769821 recessive (G)	1.13 (0.13–9.5)	0.913	0.913

* p < 0.05. Abbreviations: HR: hazard ratio, CI: confidence interval; p-adjusted was calculated with R language (FDR method) for CASP 8 tagSNPs domiant model and recessive model respectively.

Figure 1. Kaplan-Meier curve of overall survival (OS) according to rs3769821 of CASP8 The patients with AA genotype of rs3769821 had longer survival than patients with AG or GG genotype of rs3769821.

Figure 2. Kaplan-Meier curve of overall survival according to the haplotypes of CASP8. (A) The patients with zero copy number of haplotype 1 had longer OS than patients with copy number one or 2 of haplotype 1. (B) The Kaplan-Meier curve between haplotype 2 and OS, no significantly difference was observed. (C) The Kaplan-Meier curve between haplotype 3 and OS, no significantly difference was observed. (D) The Kaplan-Meier curve between haplotype 4 and OS, no significantly difference was observed.

Table 5. Association between CASP8 haplotypes with OS in patients with adenocarcinoma lung cancer.

Haplotype	N (%)	mOS (95% CI), mo	HR (95% CI)	P-value
AGGAAAGA
Copy number 0	288 (51.9%)	23.9 (20.5–27.2)	R	0.016^*
Copy number 1–2	267 (48.1%)	17.7 (15.8–19.6)	1.27 (1.05–1.54)
AGAACAG
Copy number 0	396 (71.4%)	19.8 (17.6–22.0)	R	0.286
Copy number 1–2	159 (28.6%)	22.7 (16.8–28.6)	1.02 (0.83–1.26)
AAAGAAA
Copy number 0	357 (64.3%)	19.1 (16.7–21.5)	R	0.311
Copy number 1–2	198 (35.7%)	22.7 (18.4–27.0)	0.90 (0.73–1.10)
GGGGAAA
Copy number 0	411 (74.1%)	19.9 (17.5–22.3)	R
Copy number 1–2	144 (25.9%)	20.9 (16.3–25.4)	0.96 (0.77–1.20)	0.719

* p < 0.05. Abbreviations: mOS: median overall survival, mo: months, HR: hazard ratio, CI: confidence interval

Table 6. Association between CASP8 tagSNPs or haplotypes and toxicity in the 555 patients with adenocarcinoma lung cancer.

Toxicities	SNP/haplotype	grade3/4 (%)	OR (95%CI)	p
	Rs7608692
	GG	41/251 (16.3%)	1	0.031^*
	AG	22/230 (9.6%)	0.51 (0.28–0.92)	0.024^*
	AA	3/41 (7.3%)	0.29 (0.07–1.26)	0.098
Neutropenia	Additive model		0.52 (0.32–0.85)	0.009^*
	Haplotype AGAACAG
	Copy number 0	38/368 (10.3%)
	Copy number 1–2	28/155 (18.1%)	1.92 (1.13–3.25)	0.016^*
	Haplotype GGGGAAA
Thrombocytopenia	Copy number 0	22/394 (5.6%)
	Copy number 1–2	1/137 (0.7%)	0.12 (0.02–0.93)	0.042^*

* p < 0.05. Abbreviations: OR: odds ratio, CI: confidence interval

Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin 2016; 66:115-32; PMID:26808342; https://doi.org/10.3322/caac.21338

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