TP53 and long-term prognosis in colorectal cancer: mutations in the L3 zinc-binding domain predict poor survival.
In a consecutive series of 222 colorectal carcinomas from patients with a median follow-up time of 56.8 months (range, 0.5-92.2) treated with surgery, the TP53 gene was screened for mutations. Exons 5-8 were analyzed using constant denaturant gel electrophoresis followed by sequencing, and mutations were found in 102 cases (45.9%). Mutations were found more frequently in rectal tumors versus other locations (P = 0.029) and in aneuploid compared to diploid tumors (P < 0.001). Presence of a TP53 mutation was also significantly associated with absence of microsatellite instability (P = 0.028), as well as with loss of heterozygosity at 17p13 (P < 0.001). The TP53 mutations in the left-sided and rectal tumors were more often transversions than transitions, indicating a different etiology in the development of these tumors. The tendency for shorter cancer-related survival among patients with mutations in their tumors was only statistically significant for patients with left-sided tumors (P = 0.003). All patients with mutations affecting the L3 domain of the protein involved in zinc binding had a significantly shorter cancer-related survival (P = 0.036), indicating that mutations affecting this domain have biological relevance in terms of colorectal cancer disease course. These results suggest that knowledge of a patient's TP53 status, with respect to both the presence and the localization of the mutation, may be important in prognosis evaluation, particularly when selecting patients for more aggressive postoperative therapeutic intervention.
Børresen-Dale
A L
AL
Department of Genetics, Norwegian Radium Hospital, Oslo, Norway. alb@radium.uio.no
Lothe
R A
RA
Meling
G I
GI
Hainaut
P
P
Rognum
T O
TO
Skovlund
E
E
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001665:Binding Sites; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality; D005260:Female; D016158:Genes, p53; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D015996:Survival Rate; D015032:Zinc / Q000378:metabolism*
D015032:Zinc