RHAMM, p21 combined phenotype identifies microsatellite instability-high colorectal cancers with a highly adverse prognosis.
OBJECTIVE
The aim of this study was to identify prognostic subgroups of microsatellite instability-high (MSI-H) colorectal cancers by combined analysis of 10 well-established immunohistochemical tumor markers and 7 clinicopathologic features.


METHODS
Using a tissue microarray, immunohistochemistry was done on 223 cases of MSI-H cancers for the following protein markers: raf-1 kinase inhibitor protein, receptor for hyaluronic acid-mediated motility, apoptosis protease activating factor-1, mammalian sterile20-like kinase 1, p21, p27, p53, ephrin B2 receptor, Ki-67, and epidermal growth factor receptor. Seven clinicopathologic features and all tumor markers were evaluated in univariate and multivariable analyses.


RESULTS
RHAMM overexpression [P < 0.001; hazard ratio [HR; 95% confidence interval (95% CI)], 3.86 (2.19-6.81)], loss of p21 [P = 0.002; 0.33 (0.16-0.67)], and higher N stage [P < 0.001; 3.31 (1.9-5.8)] were independent adverse prognostic factors. RHAMM/p21 combinations were evaluated by N stage. Significant differences in survival were observed with various RHAMM/p21 combinations (P < 0.001). Both node-negative and node-positive patients with RHAMM- tumors survived more than 120 months. Node-positive RHAMM+ patients had a strikingly worse prognosis [16.0 (10.0-63.0) months] and could further be divided into p21- patients [14.0 (9.0-27.0) months] and p21+ patients surviving 47.0 months. RHAMM+/p21- node-negative patients had a significantly shorter survival time than RHAMM+/p21+ tumors (P = 0.021).


CONCLUSIONS
These results suggest that the combined phenotype of RHAMM and p21 expression is an invaluable independent prognostic immunohistochemical profile in MSI-H colorectal cancer. Based on the prognostic subgroups identified in our cohort, node-negative patients overexpressing RHAMM but with loss of p21 may derive a potential benefit from postoperative treatment, whereas adjuvant chemotherapy should be reconsidered for MSI-H node-positive RHAMM- tumors.
Zlobec
Inti
I
Institute of Pathology, University Hospital of Basel, Basel, Switzerland. izobec@uhbs.ch
Baker
Kristi
K
Terracciano
Luigi M
LM
Lugli
Alessandro
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D016019:Survival Analysis; D046888:Tissue Array Analysis
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; C098946:hyaluronan-mediated motility receptor