Prognostic significance of numeric aberrations of genes for thymidylate synthase, thymidine phosphorylase and dihydrofolate reductase in colorectal cancer

Figures & data

Table I.  Distribution of thymidylate synthase (TYMS), thymidine phosphorylase (TP) and dihydrofolate reductase (DHFR) allele/nucleus according to clinical and pathological characteristics in 314 colorectal cancer patients.

	TYMS low; high% n = 303	P	TP (low; high)% n = 300	P	DHFR (low; high)% n = 216	P
Gender
Male	(24; 27)	0.4	(25; 26)	1.0	(26; 25)	0.8
Female	(26; 23)		(25; 24)		(24; 25)
Age
< 70	(42; 38)	0.09	(41; 39)	0.4	(39; 39)	0.9
≥ 70	(8; 12)		(9; 11)		(11; 11)
Tumor site
Colon	(38; 44)	0.01	(40; 42)	0.6	(40; 44)	0.2
Rectum	(12; 6)		(10; 8)		(10; 6)
Stage
II	(5; 6)	0.9	(5; 6)	0.1	(6; 6)
III	(41; 39)		(39; 40)		(40; 38)
IV	(4; 5)		(6; 4)		(4; 6)
Differentiation grade
Well	(15; 17)	0.8	(15; 15)	0.9	(13; 17)
Intermediary	(21; 18)		(20; 21)		(24; 19)
Poor	(14; 15)		(14; 15)		(13; 14)
Perineural invasion
+	(9; 10)	0.8	(8; 9)	0.9	(8; 10)	0.8
−	(27; 26)		(26; 28)		(26; 25)
not assessed	(14; 15)		(16; 13)		(16; 15)	0.2
Vascular tumor invasion
L0, V0	(27; 27)	0.6	(24; 29)	0.04	(26; 26)	0.7
L1, V1	(12; 10)		(13; 8)		(10; 12)
Lx, Vx	(11; 14)		(13; 13)		(14; 12)	0.8
Intestinal rupture at resection
+	(3; 5)	0.2	(3; 5)	0.3	(6; 4)	0.9
−	(47; 45)		(46; 45)		(44; 46)
Bowel obstruction before resection
+	(5; 8)	0.2	(6; 7)	0.8	(6; 8)	0.4
−	(45; 42)		(44; 43)		(44; 42)

Figure 1.  Distribution of thymidylate synthase expression score (0–3) assessed by immunohistochemistry according to number of TYMS allele/nucleus in colorectal cancer cells (n = 302).

Table II.  Univariate analyses of outcome according to TYMS, TP and DHFR allele/nucleus and disease stage in 314 colorectal cancer patients adjuvantly treated with 5-FU.

	Recurrence free survival					Overall survival
	No.	Events	Hazard ratio (95% CI)		P	Events	Hazard ratio (95% CI)		P
TYMS high/low*
II, III, IV	303	124	1.5	1.1–2.2	0.02	118	1.6	1.1–2.3	0.02
II	32	12	1.4	0.4–4.9	0.6	11	1.2	0.3–4.2	0.8
III	242	91	1.7	1.1–2.6	0.01	88	1.8	1.1–2.7	0.01
IV	29	21	0.8	0.3–2.0	0.7	19	0.8	0.3–1.9	0.5
TP high/low*
II, III, IV	300	121	0.9	0.6–1.3	0.6	115	1	0.7–1.4	0.9
II	33	13	0.6	0.2–1.8	0.3	12	0.7	0.2–2.5	0.6
III	238	87	1.1	0.7–1.7	0.7	84	1.2	0.7–1.8	0.5
IV	29	21	0.7	0.3–1.8	0.5	19	0.6	0.2–1.6	0.3
DHFR high/low*
II, III, IV	216	92	0.8	0.5–1.3	0.4	89	0.8	0.6–1.3	0.4
II	27	11	0.9	0.3–2.9	0.8	10	1.2	0.3–4.1	0.8
III	168	67	0.9	0.5–1.5	0.6	65	0.9	0.5–1.4	0.6
IV	21	14	0.4	0.1–1.3	0.1	14	0.5	0.2–1.4	0.2

*Hazard ratio of high relative to low allele/nucleus.

Figure 2.  Recurrence free survival following adjuvant chemotherapy of colorectal cancer stage II–IV by number of allele/nucleus for thymidylate synthase (A), thymidine phosphorylase (B) and dihydrofolate reductase (C) in tumor cells. Censored data are indicated (+).

Table III.  Multivariate analysis of outcome according to allele/nucleus of TYMS, TP, and DHFR adjusted for the independent prognostic variables stage, vascular tumor invasion and bowel obstruction.

	Recurrence free survival			Overall survival
	Hazard ratio	95% CI	P	Hazard ratio	95% CI	P
TYMS*	1.6	1.1–2.2	0.02	1.6	1.1–2.3	0.01
TP*	1.0	0.7–1.5	0.9	1.1	0.8–1.6	0.6
DHFR*	0.7	0.4–1.1	0.08	0.7	0.7–1.1	0.1

*high relative to low allele/nucleus.