Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer.
OBJECTIVE
Colon tumors with defective DNA mismatch repair (dMMR) have a well-characterized phenotype and accounts for approximately 15% to 20% of sporadic colon cancer as well as those colon cancer patients with Lynch syndrome. Although the presence of dMMR seems to be a favorable prognostic marker, data suggest that these patients do not respond as well to adjuvant chemotherapy.


METHODS
In this study, we examined the prognostic significance of tumor MMR deficiency and the presence of a specific mutation in BRAF (V600E) in a group of patients (n = 533) who participated in a randomized prospective clinical trial through the North Central Cancer Treatment Group.


RESULTS
Tumors with dMMR were found to be associated with higher tumor grade (P = 0.001), proximal location (P < 0.0001), and improved overall and disease-free survival (P = 0.05 and 0.04, respectively). Among all cases examined, evaluation of the BRAF V600E mutation status revealed no statistically significant differences in either disease-free or overall survival. Patients were then grouped into four categories for further analysis: dMMR/BRAF(-), dMMR/BRAF(+), pMMR/BRAF(-), and pMMR/BRAF(+). The dMMR/BRAF(-) group had a significantly improved overall survival (5-year overall survival of 100% versus 73%, P = 0.002) compared with all others. The remaining three groups had very similar survival outcomes. An additional cohort of tumors previously classified as having dMMR were also tested for the BRAF V600E alteration. Results remained significant (P = 0.006) when the two groups were combined for analysis.


CONCLUSIONS
Overall, these data suggest that the underlying molecular etiology of those tumors having dMMR may influence the disease outcome in these patients.
Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street Southwest, 920 Hilton Building, Rochester, MN 55905, USA.
Amy J
AJ
French
Daniel J
DJ
Sargent
Lawrence J
LJ
Burgart
Nathan R
NR
Foster
Brian F
BF
Kabat
Richard
R
Goldberg
Lois
L
Shepherd
Harold E
HE
Windschitl
Stephen N
SN
Thibodeau
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D017326:Clinical Trials, Phase III as Topic; D003110:Colonic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D053843:DNA Mismatch Repair; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
D014408:Biomarkers, Tumor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf