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Prognostic Significance of Defective Mismatch Repair and BRAF V600E in Patients with Colon Cancer

Authors' Affiliations: ¹ Laboratory Medicine and Pathology and ² Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota; ³ Department of Pathology, Abbott Northwestern Hospital/Virginia Piper Cancer Institute, Minneapolis, Minnesota; ⁴ Division of Hematology and Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; ⁵ National Cancer Institute of Canada Clinical Trials Group, Queen's University, Kingston, Ontario, Canada; and ⁶ CentraCare Clinic, St. Cloud, Minnesota

Requests for reprints: Stephen N. Thibodeau, Mayo Clinic College of Medicine, 200 First Street Southwest, 920 Hilton Building, Rochester, MN 55905. Phone: 507-284-9185; Fax: 507-284-0670; E-mail: sthibodeau{at}mayo.edu.

Purpose: Colon tumors with defective DNA mismatch repair (dMMR) have a well-characterized phenotype and accounts for 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.

Experimental Design: 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.