Expression and mutation analysis of the discoidin domain receptors 1 and 2 in non-small cell lung carcinoma - PubMed (original) (raw)

Expression and mutation analysis of the discoidin domain receptors 1 and 2 in non-small cell lung carcinoma

C E Ford et al. Br J Cancer. 2007.

Abstract

The discoidin domain receptors, (DDR)1 and DDR2, have been linked to numerous human cancers. We sought to determine expression levels of DDRs in human lung cancer, investigate prognostic determinates, and determine the prevalence of recently reported mutations in these receptor tyrosine kinases. Tumour samples from 146 non-small cell lung carcinoma (NSCLC) patients were analysed for relative expression of DDR1 and DDR2 using quantitative real-time PCR (qRT-PCR). An additional 23 matched tumour and normal tissues were tested for differential expression of DDR1 and DDR2, and previously reported somatic mutations. Discoidin domain receptor 1 was found to be significantly upregulated by 2.15-fold (P=0.0005) and DDR2 significantly downregulated to an equivalent extent (P=0.0001) in tumour vs normal lung tissue. Discoidin domain receptor 2 expression was not predictive for patient survival; however, DDR1 expression was significantly associated with overall (hazard ratio (HR) 0.43, 95% CI=0.22-0.83, P=0.014) and disease-free survival (HR=0.56, 95% CI=0.33-0.94, P=0.029). Multivariate analysis revealed DDR1 is an independent favourable predictor for prognosis independent of tumour differentiation, stage, histology, and patient age. However, contrary to previous work, we did not observe DDR mutations. We conclude that whereas altered expression of DDRs may contribute to malignant progression of NSCLC, it is unlikely that this results from mutations in the DDR1 and DDR2 genes that we investigated.

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Figures

Figure 1

Figure 1

Kaplan–Meier analysis of (A) overall survival and (B) disease-free survival, according to DDR1 expression levels. Patients were dichotomised based on the median level of DDR1 expression.

Figure 2

Figure 2

Accumulated plot of DDR qRT-PCR data demonstrating relative expression of DDR1 and DDR2 in normal and cancerous tissues from lung cancer patients. Discoidin domain receptor 1 was found to be significantly upregulated by 2.15-fold (_P_=0.0005) and DDR2 significantly downregulated by an equivalent amount (_P_=0.0001) in tumour tissue compared with normal tissue from lung cancer patients. Expression values were calculated relative to that of four normaliser genes.

Figure 3

Figure 3

Results of sequence analyses. (A) Location of S495S synonymous change adjacent to A496S somatic mutation identified previously. (B) Overall prevalence of DDR1 mutations in clinical lung cohort and cell lines. Six patients had the S485S polymorphism in both their normal and tumour tissue.

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