Abstract
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. 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. 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. 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.
Highlights
20% of colorectal cancer patients present with distant metastasis, and about one third of patients undergoing curative-intent surgery for primary cancer will relapse at distant sites [1]
KRAS mutation was associated with lung relapse (HR 1⁄4 2.1; 95% CI, 1.2 to 3.5, P 1⁄4 0.007) but not liver relapse in patients from the VICTOR trial
KRAS mutation seems to be associated with metastasis in specific sites, lung and brain, in colorectal cancer patients
Summary
20% of colorectal cancer patients present with distant metastasis, and about one third of patients undergoing curative-intent surgery for primary cancer will relapse at distant sites [1]. Relapse often occurs within 3 years, with distant recurrence commonly found in the liver, lung, and peritoneum [2,3,4]. Given this pattern, surveillance of the abdomen and chest is recommended, though the optimal strategy remains uncertain [5, 6]. Activating mutations in oncogenes contribute to carcinogenesis, and more than 20 oncogenes have been identified in human solid malignancies [7]. Oncogenic mutations are commonly found in the mitogen-activated kinase (MAPK) pathway members BRAF 12, 13), and the phosphatidylinositol 3-kinase (PI3K) pathway member PIK3CA
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