Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status.
Genes of the RAF family encode kinases that are regulated by Ras and mediate cellular responses to growth signals. Activating mutations in one RAF gene, BRAF, have been found in a high proportion of melanomas and in a small fraction of other cancers. Here we show that BRAF mutations in colorectal cancers occur only in tumours that do not carry mutations in a RAS gene known as KRAS, and that BRAF mutation is linked to the proficiency of these tumours in repairing mismatched bases in DNA. Our results not only provide genetic support for the idea that mutations in BRAF and KRAS exert equivalent effects in tumorigenesis, but also emphasize the role of repair processes in establishing the mutation spectra that underpin human cancer.
Sidney Kimmel Comprehensive Cancer Centre, Howard Hughes Medical Institution and Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Harith
H
Rajagopalan
Alberto
A
Bardelli
Christoph
C
Lengauer
Kenneth W
KW
Kinzler
Bert
B
Vogelstein
Victor E
VE
Velculescu
D020137:Base Pair Mismatch / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D005787:Gene Frequency; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009857:Oncogenes / Q000235:genetics*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*
D019908:Proto-Oncogene Proteins c-raf