Ogino Shuji, Nosho Katsuhiko, Shima Kaori, Baba Yoshifumi, Irahara Natsumi, Kirkner Gregory J, Hazra Aditi, De Vivo Immaculata, Giovannucci Edward L, Meyerhardt Jeffrey A, Fuchs Charles S
Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Cancer Epidemiol Biomarkers Prev. 2009 Sep;18(9):2513-21. doi: 10.1158/1055-9965.EPI-09-0451. Epub 2009 Sep 1.
p21 (Cyclin-dependent kinase inhibitor-1A, CDKN1A or CIP1) plays a role in regulating cell cycle, and its expression is lost in most colorectal cancers. p21 Is related with energy balance status, cellular senescence, and stem cell aging. Thus, the influence of p21 loss on tumor behavior and clinical outcome may be modified by patient age and body mass index (BMI). Using 647 colon cancers in two independent prospective cohorts, p21 loss was observed in 509 (79%) tumors by immunohistochemistry. Cox proportional hazard models computed hazard ratio (HR) for death, adjusted for potential confounders, including p53, cyclin D1, KRAS, BRAF, PIK3CA, LINE-1 hypomethylation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI). p21 Loss was independently associated with low colon cancer-specific mortality [HR, 0.58; 95% confidence interval (95% CI), 0.38-0.89; adjusted for the covariates including MSI, CIMP, and LINE-1 methylation]. The prognostic effect of p21 loss differed significantly by age at diagnosis (P(interaction) < 0.0001) and BMI (P(interaction) = 0.002). The adjusted HR for cancer-specific mortality (p21 loss versus p21 expression) was 4.09 (95% CI, 1.13-14.9) among patients <60 year old and 0.37 (95% CI, 0.24-0.59) among patients >or=60 year old. The adverse prognostic effect of obesity was limited to p21-expressing cases (adjusted HR, 5.85; 95% CI, 2.28-15.0; BMI, >or=30 versus <30 kg/m(2)), but no such effect was observed among p21-lost cases. In conclusion, p21 loss in colon cancer is associated with longer survival among patients >or=60 year old, whereas it is associated with shorter survival among patients <60 year old. Patient BMI also differentially influences prognosis according to p21 CDKN1A status. Our data suggest host-tumor interactions influencing tumor aggressiveness.
p21（细胞周期蛋白依赖性激酶抑制剂-1A，CDKN1A或CIP1）在调节细胞周期中发挥作用，且其表达在大多数结直肠癌中缺失。p21与能量平衡状态、细胞衰老及干细胞老化相关。因此，p21缺失对肿瘤行为及临床结局的影响可能因患者年龄和体重指数（BMI）而改变。在两个独立的前瞻性队列中对647例结肠癌进行研究，通过免疫组化在509例（79%）肿瘤中观察到p21缺失。Cox比例风险模型计算死亡风险比（HR），并对包括p53、细胞周期蛋白D1、KRAS、BRAF、PIK3CA、LINE-1低甲基化、CpG岛甲基化表型（CIMP）及微卫星不稳定性（MSI）等潜在混杂因素进行校正。p21缺失与较低的结肠癌特异性死亡率独立相关[HR，0.58；95%置信区间（95%CI），0.38 - 0.89；校正包括MSI、CIMP及LINE-1甲基化等协变量]。p21缺失的预后效应在诊断时的年龄（P（交互作用）<0.0001）和BMI（P（交互作用） = 0.002）方面存在显著差异。在年龄<60岁的患者中，癌症特异性死亡率的校正HR（p21缺失与p21表达相比）为4.09（95%CI，1.13 - 14.9）；在年龄≥60岁的患者中为0.37（95%CI，0.24 - 0.59）。肥胖的不良预后效应仅限于p21表达的病例（校正HR，5.85；95%CI，2.28 - 15.0；BMI，≥30与<30 kg/m²相比），但在p21缺失的病例中未观察到此类效应。总之，结肠癌中p21缺失在年龄≥60岁的患者中与较长生存期相关，而在年龄<60岁的患者中与较短生存期相关。患者BMI也根据p21 CDKN1A状态对预后产生不同影响。我们的数据表明宿主-肿瘤相互作用影响肿瘤侵袭性。
