P21WAF1/CIP1 expression in colorectal carcinomas is related to Kras mutations and prognosis.
OBJECTIVE
P21WAF1/CIP1 is a cyclin-dependent kinase inhibitor activated by p53 to produce cell cycle arrest. A consensus has not been reached concerning the prognostic value of p21WAF1/CIP1 expression in colorectal cancers.


METHODS
P21WAF1/CIP1 expression was determined immunohistochemically in a series of 211 cases of colorectal carcinomas, together with its relation to p53, bcl-2, cell turnover (as assessed by Ki67 expression and apoptotic counts) and the Kras gene status. The expression of p21WAF1/CIP1 was also compared with reference to clinicopathological parameters and patient survival.


RESULTS
The median value for nuclear p21WAF1/CIP1 expression was 31% (interquartile range, 13-47%) and the fraction of cases considered to be high expressers (>20%) was 66%. Expression of p21WAF1/CIP1 was not associated with immunoreactivity for p53 or bcl-2, or cell turnover. P21WAF1/CIP1 high-expressing tumors were more often well differentiated (P<0.001), node-negative (P=0.037), Dukes' B (P=0.027) and Kras gene-mutated cases (P=0.04). On univariate analysis, low p21WAF1/CIP1 expressers (<or=20%) had lower cancer-related survival as compared with high expressers (5-year survival, 56 vs. 70%; P=0.042). Lymph node status, liver metastasis and tumor size were also significant predictors. Multivariate analysis revealed lymph node-positive (P<0.001), liver metastasis (P<0.001), and low p21WAF1/CIP1 expression (P=0.017) to be independent predictors of short survival.


CONCLUSIONS
The regulation of p21WAF1/CIP1, independent of p53 or bcl-2 expression, appears to be associated with Kras mutations. The immunohistochemical detection of p21WAF1/CIP11 might thus be used to predict more precise outcome in colorectal cancer patients.
Mitomi
Hiroyuki
H
Department of Clinical Research Laboratory (Pathology Division), National Hospital Organization Sagamihara Hospital, Sakura-dai, Sagamihara, Kanagawa, Japan. mitomi@sagamihara-hosp.gr.jp
Ohkura
Yasuo
Y
Fukui
Naoshi
N
Kanazawa
Hideki
H
Kishimoto
Ichiro
I
Nakamura
Takatoshi
T
Yokoyama
Kaoru
K
Sada
Miwa
M
Kobayashi
Kiyonori
K
Tanabe
Satoshi
S
Saigenji
Katsunori
K
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D000368:Aged; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics*
D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C117307:KRAS protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins