KRAS gene amplification and overexpression but not mutation associates with aggressive and metastatic endometrial cancer

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.Methods: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.Results: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.Conclusion:These results support that KRAS amplification and KRAS mRNA expression, both increasing from primary to metastatic lesions, are relevant for endometrial carcinoma disease progression.

High-Throughput Mutation Profiling of Primary and Metastatic Endometrial Cancers Identifies KRAS, FGFR2 and PIK3CA to Be Frequently Mutated

“…In total 264 patients were screened for point mutations in KRAS (exon 2) and PIK3CA (exon 9 and 20) as described [14]. Details regarding primers and conditions are available upon request.…”

Evidence of androgen action in endometrial and ovarian cancers

“…A recent integrated analysis of KRAS CNA and mutations found that increased KRAS copy number and mRNA expression but not KRAS mutations were associated with EC disease progression and poor disease-specific survival (Birkeland et al 2012). The authors report that mRNA expression levels and KRAS amplification were increased significantly in metastatic compared with primary lesions consistent with involvement of KRAS alterations in disease progression (Birkeland et al 2012). In a recent study, KRAS protein expression was reported to be decreased by AR signalling in ERK, PRK and ARC breast cancer cells (Lyu et al 2014), which may indicate a further target for androgen therapy in EC.…”

Lack of Estrogen Receptor-α Is Associated with Epithelial–Mesenchymal Transition and PI3K Alterations in Endometrial Carcinoma

“…SNP array and Sanger sequencing of PIK3CA (exon 9 and 20) was conducted for 230 and 215 cases, respectively, as previously described (19,29), overlapping with the primary investigation set and the prospective validation series.…”