Background: Activation of oncogenes downstream the EGFR gene contributes to colorectal tumorigenesis and determines the sensitivity to anti-EGFR treatments. The aim of this study was to evaluate the prognostic value of KRAS, BRAF, NRAS and PIK3CA mutations in a large collection of CRC patients from genetically-homogeneous Sardinian population. Methods: A total of 1284 Sardinian patients with histologically-proven diagnosis of colorectal carcinoma (CRC) and presenting with metastatic disease were included into the study. Genomic DNA was isolated from formalin-fixed, paraffin-embedded primary tumour tissue samples of CRC patients and screened for mutations in RAS and BRAF genes, using pyrosequencing assays, and in PIK3CA gene, using automated DNA sequencing assays. Results: Overall, mutation rates were 35.6 % for KRAS, 4.1 % for NRAS, and 2.1 % for BRAF. Among available DNA samples, 114/796 (14.3 %) primary CRCs were found to carry a mutation in the PIK3CA gene. In this subset of patients analysed in all four genes, a pathogenetic mutation of at least one gene was discovered in about half (378/796; 47.5 %) of CRC cases. A mutated BRAF gene was found to steadily act as a negative prognostic factor for either time to progression as metastatic disease (from detection of primary CRC to diagnosis of first distant metastasis; p = 0.009) or partial survival (from diagnosis of advanced disease to the time of death or last control; p = 0.006) or overall survival (p < 0.001). No significant impact on prognosis was observed for mutated KRAS, NRAS, and PIK3CA genes or combined RAS mutations (all RAS). Conclusions: Our study defines both prevalence and prognostic role of main activated oncogenes in a population-based large collection of CRC patients.

Prognostic impact of KRAS, NRAS, BRAF, and PIK3CA mutations in primary colorectal carcinomas: a population-based study / Palomba, G.; Doneddu, V.; Cossu, A.; Paliogiannis, P.; Manca, A.; Casula, M.; Colombino, M.; Lanzillo, A.; Defraia, E.; Pazzola, A.; Sanna, G.; Putzu, C.; Ortu, S.; Scartozzi, M.; Ionta, M. T.; Baldino, G.; Sarobba, G.; Capelli, F.; Sedda, T.; Virdis, L.; Barca, M.; Gramignano, G.; Budroni, M.; Tanda, F.; Palmieri, G.. - In: JOURNAL OF TRANSLATIONAL MEDICINE. - ISSN 1479-5876. - 14:1(2016). [10.1186/s12967-016-1053-z]

Prognostic impact of KRAS, NRAS, BRAF, and PIK3CA mutations in primary colorectal carcinomas: a population-based study

Doneddu V.;Cossu A.;Paliogiannis P.;Pazzola A.;Putzu C.;Sedda T.;Tanda F.;Palmieri G.
2016-01-01

Abstract

Background: Activation of oncogenes downstream the EGFR gene contributes to colorectal tumorigenesis and determines the sensitivity to anti-EGFR treatments. The aim of this study was to evaluate the prognostic value of KRAS, BRAF, NRAS and PIK3CA mutations in a large collection of CRC patients from genetically-homogeneous Sardinian population. Methods: A total of 1284 Sardinian patients with histologically-proven diagnosis of colorectal carcinoma (CRC) and presenting with metastatic disease were included into the study. Genomic DNA was isolated from formalin-fixed, paraffin-embedded primary tumour tissue samples of CRC patients and screened for mutations in RAS and BRAF genes, using pyrosequencing assays, and in PIK3CA gene, using automated DNA sequencing assays. Results: Overall, mutation rates were 35.6 % for KRAS, 4.1 % for NRAS, and 2.1 % for BRAF. Among available DNA samples, 114/796 (14.3 %) primary CRCs were found to carry a mutation in the PIK3CA gene. In this subset of patients analysed in all four genes, a pathogenetic mutation of at least one gene was discovered in about half (378/796; 47.5 %) of CRC cases. A mutated BRAF gene was found to steadily act as a negative prognostic factor for either time to progression as metastatic disease (from detection of primary CRC to diagnosis of first distant metastasis; p = 0.009) or partial survival (from diagnosis of advanced disease to the time of death or last control; p = 0.006) or overall survival (p < 0.001). No significant impact on prognosis was observed for mutated KRAS, NRAS, and PIK3CA genes or combined RAS mutations (all RAS). Conclusions: Our study defines both prevalence and prognostic role of main activated oncogenes in a population-based large collection of CRC patients.
2016
Prognostic impact of KRAS, NRAS, BRAF, and PIK3CA mutations in primary colorectal carcinomas: a population-based study / Palomba, G.; Doneddu, V.; Cossu, A.; Paliogiannis, P.; Manca, A.; Casula, M.; Colombino, M.; Lanzillo, A.; Defraia, E.; Pazzola, A.; Sanna, G.; Putzu, C.; Ortu, S.; Scartozzi, M.; Ionta, M. T.; Baldino, G.; Sarobba, G.; Capelli, F.; Sedda, T.; Virdis, L.; Barca, M.; Gramignano, G.; Budroni, M.; Tanda, F.; Palmieri, G.. - In: JOURNAL OF TRANSLATIONAL MEDICINE. - ISSN 1479-5876. - 14:1(2016). [10.1186/s12967-016-1053-z]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11388/227674
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