KRAS mutation is associated with lung metastasis in patients with curatively resected colorectal cancer.
OBJECTIVE
Oncogene mutations contribute to colorectal cancer development. We searched for differences in oncogene mutation profiles between colorectal cancer metastases from different sites and evaluated these as markers for site of relapse.


METHODS
One hundred colorectal cancer metastases were screened for mutations in 19 oncogenes, and further 61 metastases and 87 matched primary cancers were analyzed for genes with identified mutations. Mutation prevalence was compared between (a) metastases from liver (n = 65), lung (n = 50), and brain (n = 46), (b) metastases and matched primary cancers, and (c) metastases and an independent cohort of primary cancers (n = 604). Mutations differing between metastasis sites were evaluated as markers for site of relapse in 859 patients from the VICTOR trial.


RESULTS
In colorectal cancer metastases, mutations were detected in 4 of 19 oncogenes: BRAF (3.1%), KRAS (48.4%), NRAS (6.2%), and PIK3CA (16.1%). KRAS mutation prevalence was significantly higher in lung (62.0%) and brain (56.5%) than in liver metastases (32.3%; P = 0.003). Mutation status was highly concordant between primary cancer and metastasis from the same individual. Compared with independent primary cancers, KRAS mutations were more common in lung and brain metastases (P < 0.005), but similar in liver metastases. Correspondingly, KRAS mutation was associated with lung relapse (HR = 2.1; 95% CI, 1.2 to 3.5, P = 0.007) but not liver relapse in patients from the VICTOR trial.


CONCLUSIONS
KRAS mutation seems to be associated with metastasis in specific sites, lung and brain, in colorectal cancer patients. Our data highlight the potential of somatic mutations for informing surveillance strategies.
Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research, Parkville, Melbourne, Australia.
Jeanne
J
Tie
Lara
L
Lipton
Jayesh
J
Desai
Peter
P
Gibbs
Robert N
RN
Jorissen
Michael
M
Christie
Katharine J
KJ
Drummond
Benjamin N J
BN
Thomson
Valery
V
Usatoff
Peter M
PM
Evans
Adrian W
AW
Pick
Simon
S
Knight
Peter W G
PW
Carne
Roger
R
Berry
Adrian
A
Polglase
Paul
P
McMurrick
Qi
Q
Zhao
Dana
D
Busam
Robert L
RL
Strausberg
Enric
E
Domingo
Ian P M
IP
Tomlinson
Rachel
R
Midgley
David
D
Kerr
Oliver M
OM
Sieber
D014408:Biomarkers, Tumor; D001932:Brain Neoplasms / Q000235:genetics / Q000556:secondary; D058534:Class I Phosphatidylinositol 3-Kinases; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D005260:Female; D020869:Gene Expression Profiling; D011905:Genes, ras; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary*; D008297:Male; D053842:Microsatellite Instability; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics*
D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins