Characterization of the non-small cell lung cancer (NSCLC) genome has suggested that KRAS amplification is one of the commonest molecular abnormalities in NSCLC. However, the prevalence and clinicopathologic significance of KRAS amplification, and its relationship with KRAS activating mutations have not been well-defined. The purpose of this study was to establish the prevalence of KRAS amplification in two separate, large NSCLC cohorts, to define the clinicopathologic features of KRAS-amplified NSCLC in a single uniformly treated cohort, and to investigate the interplay between KRAS amplification and KRAS mutation.
Fluorescence in situ hybridization was utilized to detect KRAS amplification on tissue microarrays constructed from a Swiss cohort of 538 NSCLCs and a series of 402 patients with NSCLC treated in a single institution in New York. DNA sequencing to detect KRAS codon 12 activating mutations was performed on a subset of tumors. Amplification and mutation status were compared with patient baseline characteristics, tumor characteristics, and overall- and disease-free survival.
The prevalence of KRAS amplification was 13.7% in the Swiss cohort and 15.1% in the New York cohort. Among adenocarcinomas, KRAS amplification was associated with larger (mean size 2.8±1.8 cm vs. 2.1±1.3 cm, p=0.003), less well-differentiated tumors (18% vs. 42%, p=0.004) that were more likely to be invasive (95% vs. 77%, p=0.004) and to exhibit angiolymphatic invasion (24% vs. 12%, p=0.04). These differences were statistically significant within the subset of adenocarcinomas harboring activating KRAS mutations, suggesting a synergistic relationship between amplification and mutation. No significant association between KRAS amplification and nodal metastasis or survival was seen.
KRAS amplification is a common molecular alteration in NSCLC, characterizing ∼15% of tumors. This alteration is associated with indicators of local aggressiveness, and may act synergistically with KRAS mutations to promote tumor progression.
"In endometrial cancer trials of EGFR inhibitors have been limited, although some studies reported partial response (Oza et al, 2008; Dedes et al, 2011). Other measures for KRAS alterations, although less studied than mutations, have supported a relevance of KRAS status for clinical phenotype in cancer (Wagner et al, 2011). In lung cancer patients with KRAS amplification and KRAS mutations, the latter only associated with poor survival, but with no independent prediction of response to therapy (Sasaki et al, 2011). "
[Show abstract][Hide abstract] ABSTRACT: Background:
Three quarter of endometrial carcinomas are treated at early stage. Still, 15 to 20% of these patients experience recurrence, with little effect from systemic therapies. Homo sapiens v-Ki-ras2 Kirsten rat sarcoma viral oncogenes homologue (KRAS) mutations have been reported to have an important role in tumorigenesis for human cancers, but there is limited knowledge regarding clinical relevance of KRAS status in endometrial carcinomas.
We have performed a comprehensive and integrated characterisation of genome-wide expression related to KRAS mutations and copy-number alterations in primary- and metastatic endometrial carcinoma lesions in relation to clinical and histopathological data. A primary investigation set and clinical validation set was applied, consisting of 414 primary tumours and 61 metastatic lesions totally.
Amplification and gain of KRAS present in 3% of the primary lesions and 18% of metastatic lesions correlated significantly with poor outcome, high International Federation of Gynaecology and Obstetrics stage, non-endometrioid subtype, high grade, aneuploidy, receptor loss and high KRAS mRNA levels, also found to be associated with aggressive phenotype. In contrast, KRAS mutations were present in 14.7% of primary lesions with no increase in metastatic lesions, and did not influence outcome, but was significantly associated with endometrioid subtype, low grade and obesity.
These results support that KRAS amplification and KRAS mRNA expression, both increasing from primary to metastatic lesions, are relevant for endometrial carcinoma disease progression.
British Journal of Cancer 10/2012; 107(12). DOI:10.1038/bjc.2012.477 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This paper summarizes the current status of the activities related to the safety assessment and regulation conducted by the Eurocontrol GBAS (ground-based augmentation system) project under the aegis of the EATMP GNSS (global navigation satellite system) programme.
Digital Avionics Systems Conference, 2002. Proceedings. The 21st; 11/2002
[Show abstract][Hide abstract] ABSTRACT: In clinical cancer research, high throughput genomic technologies are increasingly used to identify copy number aberrations. However, the admixture of tumor and stromal cells and the inherent karyotypic heterogeneity of most of the solid tumor samples make this task highly challenging. Here, we propose a robust two-step strategy to detect copy number aberrations in such a context. A spatial mixture model is first used to fit the preprocessed data. Then, a calling algorithm is applied to classify the genomic segments in three biologically meaningful states (copy loss, copy gain and modal copy). The results of a simulation study show the good properties of the proposed procedure with complex patterns of genomic aberrations. The interest of the proposed procedure in clinical cancer research is then illustrated by the analysis of real lung adenocarcinoma samples.
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