Prognostic implications of hMLH1 and p53 immunohistochemical status in right-sided colon cancer.
OBJECTIVE
Extensive research into the molecular biology of colorectal cancer has identified a plethora of molecular markers reputed to provide independent prognostic information. p53 mutational status has been associated with both improved and reduced survival; however, tumors expressing a particular phenotype associated with defective mismatch repair consistently do better. This study was designed to examine site-specific survival implications of p53 and mismatch repair status.


METHODS
Mismatch repair (hMLH1 and hMSH2) and p53 status was investigated immunohistochemically in 111 proximal colon cancers along with tumor TNM stage, grade, and extramural vascular invasion. Fisher's exact test was used to assess categoric data; univariate and multivariate models compared survival between the respective tumor phenotypes.


RESULTS
Thirty-two percent of tumors showed loss of expression of hMLH1 and in a multivariate analysis were associated with a significant survival advantage after adjustment for tumor stage, p53 status, and extramural vascular invasion (hazard ratio, 0.29; 95 percent confidence interval, 0.1-0.87; P = 0.027). Only two tumors showed loss of expression of hMSH2, which was not related further to survival. Aberrant p53 expression was detected in 39 percent of tumors. Such expression was found to be associated with a significantly reduced survival in univariate analysis (P = 0.037, log-rank test) but not in a multivariate model. Subgroup analysis showed no association between survival and p53 expression in mismatch repair proficient tumors.


CONCLUSIONS
Loss of hMLH1 expression is an independent predicator of improved survival in this series and perhaps the underlying cause of the observed survival difference associated with p53 expression.
Smyth
Edward F
EF
Postgraduate Medical Institute, University of Hull in Association with the Hull York Medical School, Hull, United Kingdom.
Sharma
Abhiram
A
Sivarajasingham
Nala
N
Hartley
John
J
Monson
John R T
JR
Cawkwell
Lynn
L
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D020137:Base Pair Mismatch / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002352:Carrier Proteins; D016009:Chi-Square Distribution; D003110:Colonic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics; D003644:Death Certificates; D004739:England / Q000453:epidemiology; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods* / Q000592:standards; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D009687:Nuclear Proteins; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016037:Single-Blind Method; D016019:Survival Analysis
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein