title: A cohort study of p27 localization in colon cancer, body mass index, and patient survival.
abstract: Energy balance and the AKT pathway are important in colorectal cancer development and regulate p27 (cyclin-dependent kinase inhibitor-1B/CDKN1B/KIP1), which plays a role in preventing cell cycle progression. However, little is known on the clinical outcome or prognostic significance of p27 alterations in relation to patient body mass index (BMI). Among 630 colon cancers (stage I-IV) in two prospective cohort studies, we detected p27 alterations (cytoplasmic p27 localization or p27 loss) in 500 tumors (79%) by immunohistochemistry. The remaining 130 (21%) tumors were "p27-nuclear+." Cox proportional hazard models computed hazard ratios (HR) of deaths, adjusted for patient and tumoral characteristics, including p53, p21, cyclin D1, KRAS, BRAF, PIK3CA, cyclooxygenase-2, fatty acid synthase (FASN), beta-catenin, microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and long interspersed nucleotide element-1 (LINE-1) hypomethylation. Compared with p27-nuclear+ patients, p27-altered patients experienced low colon cancer-specific [adjusted HR, 0.63; 95% confidence interval (95% CI), 0.42-0.94] and overall mortality (adjusted HR, 0.70; 95% CI, 0.51-0.95), independent of FASN, MSI, CIMP, LINE-1 methylation, and other potential confounders. The effect of p27 alteration on overall mortality significantly differed by BMI (P(interaction) = 0.013); adjusted HR (p27-altered versus p27-nuclear+ tumors) was 0.28 (95% CI, 0.13-0.59) for BMI >or=30 kg/m(2), 0.67 (95% CI, 0.40-1.14) for BMI 25 to 29 kg/m(2), and 0.91 (95% CI, 0.57-1.46) for BMI <25 kg/m(2). Obesity was associated with inferior overall survival among p27-nuclear+ cases (adjusted HR, 3.07; 95% CI, 1.49-6.32; versus nonobese cases), but not among p27-altered cases (adjusted HR, 1.08). In conclusion, p27 alterations in colon cancer are associated with superior prognosis. Adverse prognostic effect of obesity seems limited to patients with nuclear p27 expression, suggesting a host-tumor interaction.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Brigham and Women's Hospital, Boston, and Harvard Medical School 02115, USA. shuji_ogino@dfci.harvard.edu
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.forename: Kaori
authors.initials: K
authors.lastname: Shima
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.forename: Natsumi
authors.initials: N
authors.lastname: Irahara
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.forename: Brian M
authors.initials: BM
authors.lastname: Wolpin
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D015992:Body Mass Index; D015331:Cohort Studies; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D009367:Neoplasm Staging; D009765:Obesity / Q000150:complications; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D018809:Proliferating Cell Nuclear Antigen; C413374:p27 antigen