KRAS mutation, KRAS–LCS6 polymorphism, and non-small cell lung cancer

Abstract

The let-7 family of microRNAs are important regulatory molecules in lung cancer. One downstream target of let-7 is the RAS gene family, including KRAS, an important oncogene in the etiology and clinical outcome of lung adenocarcinoma. Recently, a SNP in the let-7 binding region of the KRAS 3' UTR was identified (termed LCS6). This functional polymorphism alters let-7 binding, resulting in both increased KRAS expression and decreased let-7 exposure. Further, this SNP has been reported as a risk trait for lung cancer risk among low-moderate smokers. Given the functionality of LCS6, we tested the hypothesis that this SNP is associated with the occurrence of KRAS mutation as well as patient survival. Here, we report there is no association between the LCS6 KRAS polymorphism and KRAS mutation. Further, we find no association between the LCS6 polymorphism and lung cancer survival. These unexpected findings imply that this newly reported KRAS-LCS6 polymorphism will have limited clinical utility for NSCLC.

MicroRNAs, SNPs and Cancer

“…16 The second study, involving the same populations as the Chin et al paper uses a slightly different analysis of the data and the authors discuss that the use of a smaller subset of cases coupled with a very low association of LCS6 with lung tumors may play a role in the most current study negating the former study. 16 Other extremely important genes that require deeper investigation are those directly responsible for of miRNA processing. It cannot be ignored that any polymorphisms including SNPs within miRNA biosynthesis genes can have a direct effect on an individual's cancer susceptibility.…”

“…62 Shortly after LCS6 was shown to be tied to lung cancer involving low-dose smokers, a reexamination of the data cast doubt on the association. 16 Though involvement of KRAS as a lung cancer oncogene and lowered Let-7 expression is not in doubt, the LCS6 SNP is not found to be involved with greater risk of lung cancer. 16 The second study, involving the same populations as the Chin et al paper uses a slightly different analysis of the data and the authors discuss that the use of a smaller subset of cases coupled with a very low association of LCS6 with lung tumors may play a role in the most current study negating the former study.…”

“…16 Though involvement of KRAS as a lung cancer oncogene and lowered Let-7 expression is not in doubt, the LCS6 SNP is not found to be involved with greater risk of lung cancer. 16 The second study, involving the same populations as the Chin et al paper uses a slightly different analysis of the data and the authors discuss that the use of a smaller subset of cases coupled with a very low association of LCS6 with lung tumors may play a role in the most current study negating the former study. 16 Other extremely important genes that require deeper investigation are those directly responsible for of miRNA processing.…”

“…[13][14][15] SNPs are able in some cases to generate or abolish miRNA binding sites. 16,17 SNPs have also been credited as activating miRNAs to become oncogenes or tumor-suppressors. 18,19 These SNP base pair changes, whether within the target site of the miRNA or the miRNA itself have been associated with many cancers, both in vitro and in vivo.…”

MicroRNA reins in embryonic and cancer stem cells

“…101 The authors demonstrated that the SNP led to increased luciferase activity and decreased levels of let-7 family members, especially let-7b. 102 It was reported that reduced expression of the let-7 family of miRNAs is critical for maintaining the ''stemness'' of the ESCs where Lin28 acts as the inhibitor. 74 It is possible that the presence of the SNP within the miRNA binding region in KRAS switches on the oncogenicity and turns normal lung cells into CSCs.…”