Tumor TP53 expression status, body mass index and prognosis in colorectal cancer.
Inactivation of the TP53 (p53) pathway by TP53 mutations is one of key steps in colorectal carcinogenesis. TP53 also plays an important role in cellular energy metabolism. We hypothesized that TP53-altered tumor cells might behave aggressively independent of energy balance, while progression of TP53-intact cells might depend on excess energy balance. Utilizing a database of 1,060 colon and rectal cancer patients in two prospective cohort studies, we evaluated TP53 expression by immunohistochemistry. Among 1,060 colorectal cancers, 457 (43%) tumors were positive for TP53. Cox proportional hazards model was used to compute mortality hazard ratio (HR), adjusting for clinical and tumoral features, including microsatellite instability, the CpG island methylator phenotype, LINE-1 methylation, KRAS, BRAF and PIK3CA. TP53 positivity was not significantly associated with cancer-specific survival in univariate analysis with HR of 1.16 [95% confidence interval (CI)=0.92-1.45], which became significant after stage adjustment (multivariate HR=1.30; 95% CI=1.02-1.65). Notably, we found a possible modifying effect of patient's body mass index (BMI) on tumor TP53. In non-obese patients (BMI<30 kg/m2), TP53 positivity was associated with shorter cancer-specific survival (multivariate HR=1.53; 95% CI=1.17-2.00), while TP53 positivity was not significantly associated with survival among obese patients (BMI≥30 kg/m2). Effect of TP53 positivity on cancer-specific survival significantly differed by BMI (pinteraction=0.0051). The adverse effect of obesity on patient mortality was limited to TP53-negative patients. These molecular pathological epidemiology data may support a dual role of TP53 alterations in cell-cycle deregulation and cell autonomy with respect to energy balance status.
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, and Department of Medicine Brigham and Women's Hospital, Boston, MA 02215, USA. tmorikawa-tky@umin.ac.jp
Teppei
T
Morikawa
Aya
A
Kuchiba
Xiaoyun
X
Liao
Yu
Y
Imamura
Mai
M
Yamauchi
Zhi Rong
ZR
Qian
Reiko
R
Nishihara
Kaori
K
Sato
Jeffrey A
JA
Meyerhardt
Charles S
CS
Fuchs
Shuji
S
Ogino
D000368:Aged; D001823:Body Composition; D015992:Body Mass Index; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality*; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D053842:Microsatellite Instability; D008910:Minnesota / Q000453:epidemiology; D009154:Mutation / Q000235:genetics; D009765:Obesity / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015996:Survival Rate; D018631:ras Proteins / Q000235:genetics
D004273:DNA, Neoplasm; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins