High MACC1 expression in combination with mutated KRAS G13 indicates poor survival of colorectal cancer patients.
BACKGROUND
The metastasis-associated in colon cancer 1 (MACC1) gene has been identified as prognostic biomarker for colorectal cancer (CRC). Here, we aimed at the refinement of risk assessment by separate and combined survival analyses of MACC1 expression with any of the markers KRAS mutated in codon 12 (KRAS G12) or codon 13 (KRAS G13), BRAF V600 mutation and MSI status in a retrospective study of 99 CRC patients with tumors UICC staged I, II and III.


RESULTS
We showed that only high MACC1 expression (HR: 6.09, 95% CI: 2.50-14.85, P < 0.001) and KRAS G13 mutation (HR: 5.19, 95% CI: 1.06-25.45, P = 0.042) were independent prognostic markers for shorter metastasis-free survival (MFS). Accordingly, Cox regression analysis revealed that patients with high MACC1 expression and KRAS G13 mutation exhibited the worst prognosis (HR: 14.48, 95% CI: 3.37-62.18, P < 0.001). Patients were classified based on their molecular characteristics into four clusters with significant differences in MFS (P = 0.003) by using the SPSS 2-step cluster function and Kaplan-Meier survival analysis.


CONCLUSIONS
According to our results, patients with high MACC1 expression and mutated KRAS G13 exhibited the highest risk for metachronous metastases formation. Moreover, we demonstrated that the "Traditional pathway" with an intermediate risk for metastasis formation can be further subdivided by assessing MACC1 expression into a low and high risk group with regard to MFS prognosis. This is the first report showing that identification of CRC patients at high risk for metastasis is possible by assessing MACC1 expression in combination with KRAS G13 mutation.
Experimental and Clinical Research Center, Charité University Medicine Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str.10, 13125, Berlin, Germany. Katharina.Ilm@mdc-berlin.de.
Katharina
K
Ilm
Experimental and Clinical Research Center, Charité University Medicine Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str.10, 13125, Berlin, Germany. Wolfgang.Kemmner@charite.de.
Wolfgang
W
Kemmner
Experimental and Clinical Research Center, Charité University Medicine Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str.10, 13125, Berlin, Germany. marc.osterland@fu-berlin.de.
Marc
M
Osterland
Charité Comprehensive Cancer Center, Berlin, Germany. susen.burock@charite.de.
Susen
S
Burock
Experimental and Clinical Research Center, Charité University Medicine Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str.10, 13125, Berlin, Germany. gudrun.koch@charite.de.
Gudrun
G
Koch
Experimental and Clinical Research Center, Charité University Medicine Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str.10, 13125, Berlin, Germany. pia.herrmann@charite.de.
Pia
P
Herrmann
Charité Comprehensive Cancer Center, Berlin, Germany. Peter-Michael.Schlag@charite.de.
Peter M
PM
Schlag
Experimental and Clinical Research Center, Charité University Medicine Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str.10, 13125, Berlin, Germany. ustein@mdc-berlin.de.|German Cancer Consortium, Heidelberg, Germany. ustein@mdc-berlin.de.
Ulrike
U
Stein
D000328:Adult; D000368:Aged; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics*
C117307:KRAS protein, human; C544162:MACC1 protein, human; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins