Activating K-Ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumours – implications for personalised cancer medicine

• Published in: British journal of cancer Vol. 102; no. 4; pp. 693 - 703
• Main Authors: Smith, G, Bounds, R, Wolf, H, Steele, R J C, Carey, F A, Wolf, C R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-02-2010; Nature Publishing Group
• Subjects: 631/208/212/2166; 631/208/737; 692/699/67/1504/1885; Aged; Aged, 80 and over; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Codon - genetics; Colorectal cancer; Colorectal Neoplasms - genetics; Drug Resistance; Epidemiology; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene amplification; Gene Frequency; Genes, ras; Hospitals; Humans; Kinases; Male; Medical research; Medical sciences; Mice; Middle Aged; Models, Biological; Molecular Medicine; Mutation; Mutation - genetics; Mutation - physiology; NIH 3T3 Cells; Oncology; Pathology; Patient Selection; Patients; Plasmids; Polymorphism, Single Nucleotide - physiology; Precision Medicine - methods; Precision Medicine - trends; Proteins; Signal transduction; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Translational Therapeutics; Tumor Stem Cell Assay; Tumors; United Kingdom > UK; personalised medicine; mutation; K-Ras; gene amplification; colorectal tumour; Rectal disease; Sporadic; Hot spot; Colorectal cancer; Malignant tumor; Colonic disease; K ras Gene; Medicine; Gene amplification; Cancerology; Codon; C-Onc gene; Digestive diseases; Intestinal disease; Genetics; Mutation; Ras gene; Protooncogene; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605534

Background:
Response to
EGFR
-targeted therapies in colorectal cancer patients has been convincingly associated with Kirsten-Ras (
K-Ras
) mutation status. Current mandatory mutation testing for patient selection is limited to the
K-Ras
‘hotspot’ codons 12 and 13.
Methods:
Colorectal tumours (
n
=106) were screened for additional
K-Ras
mutations, phenotypes compared in transformation and Ras GTPase activating assays and gene and pathway changes induced by individual
K-Ras
mutants identified by microarray analysis. Taqman-based gene copy number and FISH analyses were used to investigate
K-Ras
gene amplification.
Results:
Four additional
K-Ras
mutations (Leu
19
Phe (1 out of 106 tumours), Lys
117
Asn (1 out of 106), Ala
146
Thr (7 out of 106) and Arg
164
Gln (1 out of 106)) were identified. Lys
117
Asn and Ala
146
Thr had phenotypes similar to the hotspot mutations, whereas Leu
19
Phe had an attenuated phenotype and the Arg
164
Gln mutation was phenotypically equivalent to wt
K-Ras
. We additionally identified a new
K-Ras
gene amplification event, present in approximately 2% of tumours.
Conclusions:
The identification of mutations outwith previously described hotspot codons increases the
K-Ras
mutation burden in colorectal tumours by one-third. Future mutation screening to facilitate optimal patient selection for treatment with
EGFR
-targeted therapies should therefore be extended to codon 146, and in addition should consider the unique molecular signatures associated with individual
K-Ras
mutations.