Association of K-ras codon 12 transversions with short survival in non-small cell lung cancer

Vega, Francisco José Pérez; Iniesta, Pilar; Caldés, Trinidad; Sánchez, Aránzazu; Lopez, John; DeJuan, C.; Dı́az-Rubio, Eduardo; Torres, Antonio; Balibrea, J.L.; Benito, María

doi:10.3892/ijo.9.6.1307

Cited by 12 publications

(11 citation statements)

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“…In a German study of 135 patients with resectable PDAC, the G12D and G12V mutations were associated with poorer prognosis than the G12R subtype (18 ). However, our results are consistent with those of earlier studies on other cancer types, including colorectal and lung cancers, which reported that the KRAS mutant G12V subtype is associated with more aggressive biological behavior and shorter survival (25)(26)(27). In addition, in vitro studies showed that the basal GTPase activity of G12V is one-quarter that of G12D and one-tenth that of wild-type KRAS, keeping the mutant KRAS protein in the GTP-bound active state for a longer period of time (28,29 ).…”

Section: Discussionsupporting

confidence: 91%

Variant Profiling of Candidate Genes in Pancreatic Ductal Adenocarcinoma

Huang¹,

Löhr

Nilsson

et al. 2015

Clinical Chemistry

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Section: Discussionsupporting

confidence: 91%

Variant Profiling of Candidate Genes in Pancreatic Ductal Adenocarcinoma

Huang¹,

Löhr

Nilsson

et al. 2015

Clinical Chemistry

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“…17 Studies in ES-NSCLC report that KRAS mutations, especially at codon 12, are associated with worse PFS and OS. 18,19 Slebos et al were the first to show that differences in PFS and OS in patients with ES-NSCLC with and without KRAS mutations were significant ( P =0.038 and P =0.001). 20 The prognostic significance of KRAS in NSCLC was evaluated in a combined analysis of 8 studies with a total of 881 patients.…”

Section: Introductionmentioning

confidence: 99%

Biomarkers in Early-Stage Non–Small-Cell Lung Cancer: Current Concepts and Future Directions

Burotto

Thomas

Subramaniam

et al. 2014

Journal of Thoracic Oncology

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Advances in molecular biology and bioinformatics have resulted in the identification of a number of potential biomarkers that could be relevant in the management of patients with non-small cell lung cancer (NSCLC). Although there is an increasing amount of literature related to these biomarkers, major issues need to be resolved including validity and reproducibility of results. Additionally, in order to interpret the existing literature accurately a clear distinction must be made between the prognostic and predictive value of biomarkers. The practical applicability of biomarker discovery for patients with lung cancer includes the identification of patients with early-stage NSCLC who are most likely to benefit from adjuvant therapy. Information gleaned from biomarkers has the potential to help in evaluating the role of targeted therapies including immunotherapy in the neoadjuvant and adjuvant setting. The role of gene signatures and the use of newer platforms such as RNA, methylation and protein signatures is being explored in patients with early stage NSCLC. This review focuses on the applications of biomarker discovery in patients with early stage NSCLC

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“…5 Two studies of lung carcinoma have concluded that patients with Ras G12V have a poorer prognosis than those with Ras G12D. 6,7 Such studies require cautious interpretation, since tumour aggressiveness in vivo can be influenced by multiple genetic and epigenetic factors. Nevertheless, early in vitro studies showed consistent differences between Rat-1 cells harbouring different Ha-ras codon 12 mutants.…”

Section: Introductionmentioning

confidence: 99%

Structural differences between valine-12 and aspartate-12 Ras proteins may modify carcinoma aggression

et al. 1999

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Recent evidence associates the codon 12 valine‐for‐glycine (G12V) mutant Ki‐Ras protein with higher stage and increased lethality of colorectal carcinomas, while the codon 12 aspartate‐for‐glycine (G12D) Ras mutation shows no such association. Several observations may be relevant to this phenomenon. First, GTPase activity of G12V Ras is one‐quarter that of G12D Ras and one‐tenth that of wild‐type (WT) Ras. Second, binding of the GTP analogue GppNp to G12D Ras is 8‐fold weaker than its binding to G12V or WT Ras and crystal structures indicate that electrostatic repulsion between the carboxylate group of the G12D Asp‐12 side‐chain and the γ phosphate of the bound nucleotide may make GTP binding to G12D Ras weaker even than that of GppNp. It is proposed that this lowering of affinity for GTP allows G12D Ras an escape from the oncogenic GTP‐bound state, whereas GTP tightly bound to G12V mutant Ras generates a more persistent, potentially oncogenic, signal. Structural comparisons also suggest that differences between the Switch I (effector) region of G12D and G12V Ras could modify interactions with downstream signalling molecules such as Raf‐1, neurofibromin, and phosphatidylinositol 3‐hydroxy‐kinase. Other differences between the G12D and G12V mutant Ras proteins include a lower affinity of the GTPase activating protein GAP for G12V than for G12D or WT Ras; but, as both G12D and G12V Ras are refractory to GTPase activation by GAP binding, this may be less significant. These studies complement experimental data showing that such Ras mutations differ in their effects in vitro and in vivo and, with recent data indicating heterogeneity of ras mutation in colorectal carcinomas and other tumours, make it plausible that codon 12 Ras mutations differ in carcinogenic potential and prognostic significance. Copyright © 1999 John Wiley & Sons, Ltd.

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Association of K-ras codon 12 transversions with short survival in non-small cell lung cancer

Cited by 12 publications

References 0 publications

Variant Profiling of Candidate Genes in Pancreatic Ductal Adenocarcinoma

Variant Profiling of Candidate Genes in Pancreatic Ductal Adenocarcinoma

Biomarkers in Early-Stage Non–Small-Cell Lung Cancer: Current Concepts and Future Directions

Structural differences between valine-12 and aspartate-12 Ras proteins may modify carcinoma aggression

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