BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair

Liang Wang, Julie M Cunningham, Jennifer L. Winters, Jennifer C. Guenther, Amy J. French, Lisa Allyn Boardman, Lawrence J. Burgart, Shannon K. McDonnell, Daniel J Schaid, Stephen N Thibodeau

Research output: Contribution to journalArticle

231 Citations (Scopus)

Abstract

Frequent BRAF mutations were reported recently in a variety of human malignancies, including colorectal cancer. In this study, we screened 293 colorectal cancers for mutations in exons 11 and 15, two regions containing hotspots for BRAF mutation. Of the 293 cancers, 170 had normal mismatch repair, and 123 had defective mismatch repair (originating from both somatic as well as germ-line mutations in several of the mismatch repair genes). A total of 63 exonic mutations (22%) were detected, 60 of which were V599E, and one each of D593G, G468E, and D586A. Of the tumors with defective mismatch repair, 34% (42 of 123) had a mutation in BRAF, whereas only 12% (21 of 170) of tumors with proficient mismatch repair demonstrated a mutation (P < 0.0001). Interestingly, BRAF mutations were found most often in cases with an hMHL1 abnormality (35 of 60) and rarely in cases with an hMSH2 abnormality (1 of 39; P < 0.0001). More interestingly, of the 31 hMLH1 cases with a BRAF mutation, 30 occurred in tumors known to have hypermethylation of hMLH1 promoter. Only 1 of the 15 cases with a germ-line mutation in hMLH1 had a mutation in BRAF. In this series, BRAF mutations occurred rarely in tumors with defective mismatch repair attributable to the presence of germ-line mutation in either hMLH1 or hMSH2. Furthermore, BRAF mutations were strongly associated with the epigenetic alteration of hMLH1. Overall, these data suggest that BRAF mutations are not a consequence of defective mismatch repair per se.

Original languageEnglish (US)
Pages (from-to)5209-5212
Number of pages4
JournalCancer Research
Volume63
Issue number17
StatePublished - Sep 1 2003

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DNA Mismatch Repair
Colonic Neoplasms
Mutation
Germ-Line Mutation
Neoplasms
Colorectal Neoplasms
Epigenomics
Exons

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair. / Wang, Liang; Cunningham, Julie M; Winters, Jennifer L.; Guenther, Jennifer C.; French, Amy J.; Boardman, Lisa Allyn; Burgart, Lawrence J.; McDonnell, Shannon K.; Schaid, Daniel J; Thibodeau, Stephen N.

In: Cancer Research, Vol. 63, No. 17, 01.09.2003, p. 5209-5212.

Research output: Contribution to journalArticle

Wang, L, Cunningham, JM, Winters, JL, Guenther, JC, French, AJ, Boardman, LA, Burgart, LJ, McDonnell, SK, Schaid, DJ & Thibodeau, SN 2003, 'BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair', Cancer Research, vol. 63, no. 17, pp. 5209-5212.
Wang, Liang ; Cunningham, Julie M ; Winters, Jennifer L. ; Guenther, Jennifer C. ; French, Amy J. ; Boardman, Lisa Allyn ; Burgart, Lawrence J. ; McDonnell, Shannon K. ; Schaid, Daniel J ; Thibodeau, Stephen N. / BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair. In: Cancer Research. 2003 ; Vol. 63, No. 17. pp. 5209-5212.
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abstract = "Frequent BRAF mutations were reported recently in a variety of human malignancies, including colorectal cancer. In this study, we screened 293 colorectal cancers for mutations in exons 11 and 15, two regions containing hotspots for BRAF mutation. Of the 293 cancers, 170 had normal mismatch repair, and 123 had defective mismatch repair (originating from both somatic as well as germ-line mutations in several of the mismatch repair genes). A total of 63 exonic mutations (22{\%}) were detected, 60 of which were V599E, and one each of D593G, G468E, and D586A. Of the tumors with defective mismatch repair, 34{\%} (42 of 123) had a mutation in BRAF, whereas only 12{\%} (21 of 170) of tumors with proficient mismatch repair demonstrated a mutation (P < 0.0001). Interestingly, BRAF mutations were found most often in cases with an hMHL1 abnormality (35 of 60) and rarely in cases with an hMSH2 abnormality (1 of 39; P < 0.0001). More interestingly, of the 31 hMLH1 cases with a BRAF mutation, 30 occurred in tumors known to have hypermethylation of hMLH1 promoter. Only 1 of the 15 cases with a germ-line mutation in hMLH1 had a mutation in BRAF. In this series, BRAF mutations occurred rarely in tumors with defective mismatch repair attributable to the presence of germ-line mutation in either hMLH1 or hMSH2. Furthermore, BRAF mutations were strongly associated with the epigenetic alteration of hMLH1. Overall, these data suggest that BRAF mutations are not a consequence of defective mismatch repair per se.",
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