title: Paradoxical correlations of cyclin-dependent kinase inhibitors p21waf1/cip1 and p27kip1 in metastatic colorectal carcinoma.
abstract: The cyclin-dependent kinase inhibitors (CDIs) p27kip1 and p21waf1/cip1 are key cell cycle-negative regulatory enzymes. The objective of this study was to correlate expression of p27kip1 and p21waf1/cip1 with survival, chemotherapy responsiveness, and expression of the proliferation marker Ki-67 in patients with advanced colorectal cancer. Immunohistochemistry was performed with antibodies to p27kip1, p21waf1/cip1, and Ki-67 on samples from 66 patients with metastatic colorectal carcinoma. Interpretation was performed by visual inspection and automated image analysis. Patients who obtained a response to chemotherapy had greater p21waf1/cip1 tumor staining with a mean of 10.0 positive cells/high-powered field, compared with 4.5 positive cells/high-powered field for nonresponders (P = 0.03). A positive Spearman correlation was seen between Ki-67 and p27kip1 (r = 0.48; P = 0.0001), as well as between Ki-67 and p21waf1/cip1 (r = 0.48; P = 0.0001). A trend toward shorter survival was seen in patients with positive specimens (median survival of 10 months for patients with both p27kip1- and p21waf1/cip1-positive specimens, compared with 22 months for patients with neither p27kip1- nor p21waf1/cip1-positive specimens). In contrast to that previously reported in normal colonic mucosa or early-stage colorectal cancer, we observed positive correlations of Ki-67 with both p27kip1 and p21waf1/cip1, a trend toward greater CDI staining indicating worse prognosis, and greater p21waf1/cip1 staining in tumors that were chemosensitive. These findings suggest that in the metastatic setting, CDIs may show altered function, compared with their role in the normal cell cycle.
authors.affiliation: Division of Medical Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Cheng
authors.forename: B A
authors.initials: BA
authors.lastname: Werness
authors.forename: J S
authors.initials: JS
authors.lastname: Babb
authors.forename: N J
authors.initials: NJ
authors.lastname: Meropol
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry* / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000601:surgery; D002288:Adenocarcinoma, Mucinous / Q000737:chemistry / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D015179:Colorectal Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000601:surgery; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000032:analysis*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D019394:Ki-67 Antigen / Q000032:analysis; D015993:Life Tables; D008297:Male; D008869:Microtubule-Associated Proteins / Q000032:analysis*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000032:analysis*; D009367:Neoplasm Staging; D016019:Survival Analysis; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019394:Ki-67 Antigen; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27