Distinct KRAS Mutation Spectrum in Colorectal Carcinoma and Lung Adenocarcinoma Implicates Different Mutagenesis.
Xiaoping Zhou, Cheng Huang, Weiqiang Zhao, Wendy L Frankel. The Ohio State University, Columbus
Background: Mutations in KRAS oncogene result in constitutive activation of the MEK/ERK signaling pathway and are frequently present in human cancers, including colorectal carcinoma (CRC) and lung adenocarcinoma (LAC). The identification of KRAS mutations is useful for prediction of resistance to anti-EGFR therapies and prognosis. We analyzed and compared the prevalence and spectrum of KRAS mutations in CRC and LAC.
Design: The detection of KRAS mutations in exon 2 was performed on genomic DNA extracted from archived paraffin embedded tissue using target PCR followed by direct sequencing in a cohort of 173 CRC (99 primary and 74 metastatic) and 109 LAC (95 primary and 14 metastatic). Primary and metastatic tumors were not from the same patient in any case. The status of KRAS mutation was correlated with potential risk factors, including tobacco and alcohol use, diabetes mellitus, hypertension, hyperlipidemia, previous cancer history and family cancer history. The specific types of KRAS mutations in CRC and LAC were compared. Fisher's exact test was used.
Results: KRAS mutations were detected in 58 of 173 (33.5%) CRC and 52 of 109 (47.7%) LAC. KRAS mutations were associated with tobacco use in LAC (P < .0001), but not in CRC. No significant association was found between KRAS mutation and any of the other risk factors evaluated. All 8 frequent mutations previously described involving codons 12 and 13 were detected. A novel mutation, Val8Ile involving codon 8, was also identified in one metastatic CRC. Double mutations affecting codons 12 and 13 were detected in three cases. The specific types of KRAS mutations were different between CRC and LAC. In CRC, the G > A transitions (29/56, 51.8%) and the G > T and G > C transversions (27/56, 48.2%) occurred with a similar frequency. In contrast, in LAC, the G > T and G > C transversions (38/52, 73.1%) were more common than G > A transitions (14/52, 26.9%) (P = .0107).
|KRAS Mutation||LAC (n = 52)||CRC (n = 58)|
|Smoker||47 (90.4%)||25 (43.1%)|
|Non-Smoker||5 (9.6%)||33 (56.9%)|
|KRAS Mutation||LAC (n = 52)||CRC (n = 56)*|
|Transversion||38 (73.1%)||27 (48.2%)|
|Transition||14 (26.9%)||29 (51.8%)|