Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer

Amy J. French, Daniel J. Sargent, Lawrence J. Burgart, Nathan R. Foster, Brian F. Kabat, Richard Goldberg, Lois Shepherd, Harold E. Windschitl, Stephen N Thibodeau

Research output: Contribution to journalArticle

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Abstract

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 analysts: dMMR/BRAF(-), dMMH/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.

Original languageEnglish (US)
Pages (from-to)3408-3415
Number of pages8
JournalClinical Cancer Research
Volume14
Issue number11
DOIs
StatePublished - Jun 1 2008

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DNA Mismatch Repair
Colonic Neoplasms
Neoplasms
Survival
Hereditary Nonpolyposis Colorectal Neoplasms
Mutation
Adjuvant Chemotherapy
Disease-Free Survival
Colon
Research Design
Randomized Controlled Trials
Phenotype

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. / French, Amy J.; Sargent, Daniel J.; Burgart, Lawrence J.; Foster, Nathan R.; Kabat, Brian F.; Goldberg, Richard; Shepherd, Lois; Windschitl, Harold E.; Thibodeau, Stephen N.

In: Clinical Cancer Research, Vol. 14, No. 11, 01.06.2008, p. 3408-3415.

Research output: Contribution to journalArticle

French, AJ, Sargent, DJ, Burgart, LJ, Foster, NR, Kabat, BF, Goldberg, R, Shepherd, L, Windschitl, HE & Thibodeau, SN 2008, 'Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer', Clinical Cancer Research, vol. 14, no. 11, pp. 3408-3415. https://doi.org/10.1158/1078-0432.CCR-07-1489
French, Amy J. ; Sargent, Daniel J. ; Burgart, Lawrence J. ; Foster, Nathan R. ; Kabat, Brian F. ; Goldberg, Richard ; Shepherd, Lois ; Windschitl, Harold E. ; Thibodeau, Stephen N. / Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 11. pp. 3408-3415.
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T1 - Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer

AU - French, Amy J.

AU - Sargent, Daniel J.

AU - Burgart, Lawrence J.

AU - Foster, Nathan R.

AU - Kabat, Brian F.

AU - Goldberg, Richard

AU - Shepherd, Lois

AU - Windschitl, Harold E.

AU - Thibodeau, Stephen N

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N2 - 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 analysts: dMMR/BRAF(-), dMMH/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.

AB - 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 analysts: dMMR/BRAF(-), dMMH/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.

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