Background: Little is known about the potential effect of genetic alterations in the NFkB and Notch pathways on NSCLC p. Musashi 2 activates HES-1 in the Notch pathway, and HES-1 can abrogate CYLD. A20, AEG-1, EZH2 and TRAF6 are also involved in NFkB activation. BRCA1 and RAP80 are modulators of cisplatin-based chemotherapy. Mutations in NFKBIA and DUSP22, which prevent NFkB activation, were described in the sequencing exome of a single NSCLC p, together with K-ras mutations. Methods: mRNA expression of Musashi 2, CYLD, HES-1, A20, EZH2, AEG-1, TRAF6, NFKBIA, RelA, BRCA1 and RAP80 was analyzed by quantitative RT-PCR in tumor samples from 60 advanced NSCLC p. Expression levels by terciles were correlated with clinical characteristics and outcome to chemotherapy. Mutations in NFKBIA and DUSP22 were sequenced in 28 and 21 patients, respectively, and in 12 cancer cell lines. Results: p characteristics: 36 male; 39 adenocarcinomas; 22 smokers; 23 bone metastases; 9 EGFR mutations; 10 K-ras mutations. No NFKBIA or DUSP22 mutations were observed in any of the p or cell lines. PFS was 12.3 months (m) for p in the lowest tercile of AEG-1 expression vs 9.3 m for p in the intermediate tercile and 4.8 for p in the highest tercile (P=0.002). The multivariate analysis showed that only AEG-1 expression was associated with shorter PFS (HR, 1.43; P=0.006). Expression levels of the other genes did not correlate with outcome. However, we had previously generated a two-gene risk model based on AEG-1 and BRCA1 expression: p with high levels of both genes are considered high-risk, p with low levels of both genes are low-risk, and p with high levels of one and low levels of the other gene are intermediate-risk. In the present study, PFS was 13 m in the low-risk group, while it was 7.6 m for the intermediate-risk group and 5.3 m for the high-risk group (P=0.02). Conclusions: NSCLCs have variegated gene expression. AEG-1 and BRCA1 mRNA expression is a genetic signature that can be used as a prognostic model for the management of NSCLC p.
The nuclear factor kB (NFkB) and Notch signaling pathways and BRCA1 mRNA expression in stage IV non-small cell lung cancer (NSCLC) patients (p).
SANTARPIA, Mariacarmela;ALTAVILLA, Giuseppe;
2011-01-01
Abstract
Background: Little is known about the potential effect of genetic alterations in the NFkB and Notch pathways on NSCLC p. Musashi 2 activates HES-1 in the Notch pathway, and HES-1 can abrogate CYLD. A20, AEG-1, EZH2 and TRAF6 are also involved in NFkB activation. BRCA1 and RAP80 are modulators of cisplatin-based chemotherapy. Mutations in NFKBIA and DUSP22, which prevent NFkB activation, were described in the sequencing exome of a single NSCLC p, together with K-ras mutations. Methods: mRNA expression of Musashi 2, CYLD, HES-1, A20, EZH2, AEG-1, TRAF6, NFKBIA, RelA, BRCA1 and RAP80 was analyzed by quantitative RT-PCR in tumor samples from 60 advanced NSCLC p. Expression levels by terciles were correlated with clinical characteristics and outcome to chemotherapy. Mutations in NFKBIA and DUSP22 were sequenced in 28 and 21 patients, respectively, and in 12 cancer cell lines. Results: p characteristics: 36 male; 39 adenocarcinomas; 22 smokers; 23 bone metastases; 9 EGFR mutations; 10 K-ras mutations. No NFKBIA or DUSP22 mutations were observed in any of the p or cell lines. PFS was 12.3 months (m) for p in the lowest tercile of AEG-1 expression vs 9.3 m for p in the intermediate tercile and 4.8 for p in the highest tercile (P=0.002). The multivariate analysis showed that only AEG-1 expression was associated with shorter PFS (HR, 1.43; P=0.006). Expression levels of the other genes did not correlate with outcome. However, we had previously generated a two-gene risk model based on AEG-1 and BRCA1 expression: p with high levels of both genes are considered high-risk, p with low levels of both genes are low-risk, and p with high levels of one and low levels of the other gene are intermediate-risk. In the present study, PFS was 13 m in the low-risk group, while it was 7.6 m for the intermediate-risk group and 5.3 m for the high-risk group (P=0.02). Conclusions: NSCLCs have variegated gene expression. AEG-1 and BRCA1 mRNA expression is a genetic signature that can be used as a prognostic model for the management of NSCLC p.Pubblicazioni consigliate
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