TYMS/KRAS/BRAF molecular profiling predicts survival following adjuvant chemotherapy in colorectal cancer

doi:10.4251/wjgo.v11.i7.551

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World Journal of Gastrointestinal Oncology

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Retrospective Study

World J Gastrointest Oncol. Jul 15, 2019; 11(7): 551-566
Published online Jul 15, 2019. doi: 10.4251/wjgo.v11.i7.551

Table 1 TYMS polymorphisms’ groups according to risk group and level of expression respectively

Groups	Polymorphisms
3’UTR
A (low risk)	del/del
	del/LOH
	ins/del
	ins/ins
B (high risk)	ins/LOH
5’UTR
A (low expression)	2RG
	2RG/3RC
	3RC
B (medium expression)	2RG/3RG
	2RG/3RCLOH
	2RG/3RGLOH
	2RGLOH/3RC
C (high expression)	3RG
	3RG/3RC
	2RGLOH/3RG

UTR: Untranslated region; LOH: Loss of heterozygosity.

Table 2 Clinicopathologic data for colorectal cancer patients treated with adjuvant chemotherapy

Clinicopathologic data	Total (n = 130)
Median age (range)	67 (37-88)
Male	79 (60.8)
Primary site
Rectum	60 (46.2)
Positive lymph nodes	76 (58.5)
Stage according to AJCC
I	1 (0.8)
II	54 (41.5)
III	75 (57.7)
Histological grade
I + II	83 (63.8)
III + IV	47 (36.2)
KRAS mutation	48 (36.9)
BRAF V600E mutation	5 (3.8)
TYMS LOH	34 (26.2)
Overall survival
Deaths n (%)	45 (34.6)
Mean time month (95%CI)	110.0 (99.5-120.5)
Disease-free survival
Events n (%)	51 (39.2)
Mean time month (95%CI)	100.1 (88.3-112.0)
Median follow up in months (range)	71.2 (0.5-156.8)

AJCC: American Joint Committee on Cancer 7^th edition; TYMS: Thymidylate synthase gene; LOH: Loss of heterozygosity; CI: Confidence interval.

Table 3 Frequency of TYMS 5’UTR, 3’UTR genotypes

Genotype	Total n (%)
TYMS 5’UTR	130 (100)
2R	13 (10.0)
2R/3R	78 (60.0)
2R/3RG	34 (26.1)
2R/3RG	20 (15.4)
2R/3RGLOH	8 (6.2)
2RLOH/3RG	6 (4.6)
2R/3RC	44 (33.8)
2R/3RC	24 (18.5)
2R/3RCLOH	13 (10.0)
2RLOH/3RC	7 (5.4)
3R	39 (30.0)
3RG	10 (7.7)
3RG/3RC	20 (15.4)
3RC	9 (6.9)

TYMS 3’UTR	130 (100)
ins/ins	28 (21.5)
ins/LOH	27 (20.8)
ins/del	52 (40.0)
del/LOH	7 (5.4)
del/del	16 (12.3)

TYMS: Thymidylate synthase gene; UTR: Untranslated region; SNP: Single nucleotide polymorphism; LOH: Loss of heterozygosity.

Table 4 Associations between patient characteristics and TYMS polymorphisms

Patient characteristics	Polymorphisms	RR (95%CI)	P value
Birth after 1942	3RG/3RG	5.128 (1.131-23.26)	0.025
	3RC/3RC and 3RC/LOH	0.296 (0.088-0.988)	0.035
Male	3RG/3RG and 3RG/LOH	4.519 (1.072-19.06)	0.030
Grade III-IV	3RG/3RC	2.646 (1.167-6.024)	0.022
Stage III	3RG/3RG and 3RG/3RC and 3RG/LOH	2.198 (1.126-4.292)	0.020
	3RG/3RC	4.149 (1.280-13.51)	0.008
	Without any 3RG allele	0.733 (0.546-0.984)	0.050
	3RC/3RC and 3RC/LOH	0.333 (1.229-0.904)	0.030
	3RC/LOH	0.122 (0.015-0.986)	0.045
KRAS mutation	3RG/3RC	3.135 (1.344-7.299)	0.010
	3RC/3RC and 3RC/LOH	0.241 (0.057-1.015)	0.030

TYMS: Thymidylate synthase gene; RR: Relative risk; CI: Confidence interval; LOH: Loss of heterozygosity.

Table 5 Univariate Cox regression analysis for clinicopathological features and genotypes

Variable	HR	DFS 95%CI	P value	HR	OS 95%CI	P value
Age < 65 yr	1.513	0.873-2.621	0.140	1.229	0.682-2.213	0.492
Rectal Ca	1.550	0.890-2.703	0.121	1.282	0.713-2.306	0.406
Stage III vs I%II	2.532	1.368-4.695	0.003	1.877	1.009-3.494	0.047
Grade III and IV vs I and II	1.984	1.143-3.436	0.015	2.097	1.166-3.770	0.013
KRAS mutation	1.330	0.761-2.326	0.321	1.283	0.702-2.346	0.418
BRAF V600E mutation	1.276	0.310-5.255	0.736	2.743	0.845-8.902	0.093
TYMS 5’UTR			0.397			0.766
2R	1			1
2R/3R	1.213	0.498-2.958	0.671	0.745	0.332-1.672	0.475
3R	1.690	0.678-4.213	0.260	0.846	0.355-2.020	0.707
TYMS 5’UTR			0.596			0.615
2RG/3RG	1			1
2RG/2RG	1.038	0.377-2.858	0.942	1.750	0.672-4.559	0.252
2RG/3RC	1.523	0.684-3.394	0.303	1.625	0.702-3.760	0.257
3RC/3RC	1.414	0.482-4.148	0.528	0.680	0.146-3.162	0.623
3RG/3RC	2.128	0.902-5.018	0.085	1.782	0.686-4.625	0.235
3RG/3RG	1.489	0.466-4.672	0.502	1.996	0.610-6.532	0.253
TYMS 5’UTR			0.204			0.589
2RG/3RG	1			1
2RG/2RG	1.702	0.343-8.441	0.515	3.322	0.787-14.03	0.102
2RG/3RC	2.935	0.778-11.08	0.112	3.034	0.803-11.46	0.102
2RG/3RCLOH	5.387	1.427-20.34	0.013	3.879	0.967-15.56	0.056
2RG/3RGLOH	2.138	0.431-10.60	0.352	2.026	0.408-10.06	0.388
2RGLOH/3RC	3.178	0.640-15.78	0.157	3.109	0.626-15.44	0.165
2RGLOH/3RG	7.402	1.648-33.24	0.009	6.127	1.358-27.64	0.018
3RC/3RC	4.326	1.031-18.15	0.045	1.733	0.288-10.42	0.548
3RG/3RC	4.865	1.336-17.72	0.016	3.438	0.888-13.32	0.074
3RG/3RG	3.413	0.761-15.30	0.109	3.994	0.887-17.99	0.071
TYMS 5’UTR groups			0.130			0.223
A¹	1.136	0.574-2.251	0.714	1.882	0.917-3.861	0.085
B²	1			1
C³	1.908	0.980-3.713	0.057	1.309	0.637-2.692	0.464
TYMS 3’UTR			0.791			0.846
del/del	1.170	0.496-2.760	0.721	1.145	0.456-2.873	0.773
ins/del	1.244	0.664-2.329	0.495	1.219	0.622-2.387	0.564
ins/ins	1			1
TYMS 3’UTR			0.299			0.391
del/del	0.624	0.244-1.595	0.324	0.634	0.228-1.761	0.382
del/LOH	0.374	0.086-1.630	0.190	0.408	0.093-1.797	0.236
ins/del	0.634	0.329-1.224	0.175	0.743	0.372-1.482	0.399
ins/LOH	1			1
ins/ins	0.417	0.172-1.016	0.054	0.391	0.140-1.087	0.072
ins/ins vs ELSE	0.593	0.267-1.318	0.200	0.511	0.201-1.297	0.158
ins/LOH vs ELSE	1.807	1.000-3.266	0.050	1.650	0.877-3.104	0.120
ins/del vs ELSE	0.976	0.556-1.713	0.933	1.131	0.626-2.044	0.684
del/del vs ELSE	0.964	0.411-2.262	0.934	0.907	0.358-2.299	0.837
del/LOH vs ELSE	0.565	0.137-2.327	0.430	0.570	0.138-2.359	0.438
LOH	1.480	0.833-2.629	0.181	1.350	0.732-2.487	0.336
SNP G->C	1.542	0.878-2.707	0.132	1.108	0.617-1.992	0.731

¹Low expression profile;

²Medium expression profile;

³High expression profile. DFS: Disease-free survival; OS: Overall survival; HR: Hazard ratios; CI: Confidence interval; Ca: Cancer; TYMS: Thymidylate synthase gene; UTR: Untranslated region; LOH: Loss of heterozygosity; 5FU: 5-fluorouracil; SNP: Single nucleotide polymorphism.

Table 6 Multivariate Cox regression analysis for clinicopathological features and selected genotypes

Variable	HR	DFS 95%CI	P value	HR	OS 95%CI	P value
Stage III vs I and II	2.432	1.279-4.625	0.007
Grade III and IV vs I and II	1.715	0.951-3.091	0.073	1.860	0.982-3.525	0.057
TYMS 5’UTR groups			0.031			0.052
A	3.122	1.193-8.169	0.020	2.715	1.093-6.739	0.031
B	1			1
C	2.919	1.258-6.772	0.013	2.540	1.098-5.876	0.029
TYMS 3’UTR groups
A (without ins/LOH)	1
B (ins/LOH)	4.124	1.744-9.753	0.001	3.335	1.474-7.548	0.004
BRAF V600E mutation				4.500	1.241-16.32	0.022

DFS: Disease-free survival; OS: Overall survival; HR: Hazard ratio; CI: Confidence interval; TYMS: Thymidylate synthase gene; UTR: Untranslated region; LOH: Loss of heterozygosity.

Citation: Ntavatzikos A, Spathis A, Patapis P, Machairas N, Vourli G, Peros G, Papadopoulos I, Panayiotides I, Koumarianou A. TYMS/KRAS/BRAF molecular profiling predicts survival following adjuvant chemotherapy in colorectal cancer. World J Gastrointest Oncol 2019; 11(7): 551-566
URL: https://www.wjgnet.com/1948-5204/full/v11/i7/551.htm
DOI: https://dx.doi.org/10.4251/wjgo.v11.i7.551