Abstract
The incidence of colorectal cancer (CRC) increases with age and early onset indicates an increased likelihood for genetic predisposition for this disease. The somatic genetics of tumor development in relation to patient age remains mostly unknown. We have examined the mutation status of five known cancer critical genes in relation to age at diagnosis, and compared the genomic complexity of tumors from young patients without known CRC syndromes with those from elderly patients. Among 181 CRC patients, stratified by microsatellite instability status, DNA sequence changes were identified in KRAS (32%), BRAF (16%), PIK3CA (4%), PTEN (14%) and TP53 (51%). In patients younger than 50 years (n = 45), PIK3CA mutations were not observed and TP53 mutations were more frequent than in the older age groups. The total gene mutation index was lowest in tumors from the youngest patients. In contrast, the genome complexity, assessed as copy number aberrations, was highest in tumors from the youngest patients. A comparable number of tumors from young (<50 years) and old patients (>70 years) was quadruple negative for the four predictive gene markers (KRAS-BRAF-PIK3CA-PTEN); however, 16% of young versus only 1% of the old patients had tumor mutations in PTEN/PIK3CA exclusively. This implies that mutation testing for prediction of EGFR treatment response may be restricted to KRAS and BRAF in elderly (>70 years) patients. Distinct genetic differences found in tumors from young and elderly patients, whom are comparable for known clinical and pathological variables, indicate that young patients have a different genetic risk profile for CRC development than older patients.
Highlights
The incidence of colorectal cancer (CRC, MIM#114500) has increased in the western world including Norway during the last 50 years [1]
The oncogenes KRAS (HGNC:6407), BRAF (HGNC:1097), and PIK3CA (HGNC:8975) and the tumor suppressor gene PTEN (HGNC:9588) are all affected in response to cytokines, growth factors and hormones signaling through Receptor tyrosine kinase (RTK)
MSI was significantly associated with localized disease, Table S1
Summary
The incidence of colorectal cancer (CRC, MIM#114500) has increased in the western world including Norway during the last 50 years [1]. CRC is typically found in elderly people with a median age at onset of 70 years, and only about five percent of all cases are diagnosed in patients younger than 50 years of age. Hereditary syndromes such as familial adenomatous polyposis (FAP, MIM#175100) and Lynch syndrome (HNPCC, MIM#120435) are found in less than five percent of all CRCs [2]. Receptor tyrosine kinase (RTK) signaling is essential for maintaining the metabolism, proliferation, survival and motility of a cell [7]. Errors in components regulated by receptor tyrosine kinases (RTKs) are commonly observed in human cancers [8,9]. The oncogenes KRAS (HGNC:6407), BRAF (HGNC:1097), and PIK3CA (HGNC:8975) and the tumor suppressor gene PTEN (HGNC:9588) are all affected in response to cytokines, growth factors and hormones signaling through RTK
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