Combined assessment of the TNM stage and BRAF mutational status at diagnosis in sporadic colorectal cancer patients
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José María Sayagués1,*, Sofía Del Carmen2,*, María Del Mar Abad2, Luís Antonio Corchete3, Oscar Bengoechea2, María Fernanda Anduaga4, María Jesús Baldeón5, Juan Jesús Cruz5, Jose Antonio Alcazar4, María Angoso4, Marcos González3, Jacinto García4,**, Luís Muñoz-Bellvis4,**, Alberto Orfao1,** and María Eugenia Sarasquete3,**
1Cytometry Service-NUCLEUS, Department of Medicine, Cancer Research Center (IBMCC-CSIC/USAL), CIBERONC and IBSAL (University Hospital of Salamanca), Salamanca, Spain
2Department of Pathology, University Hospital of Salamanca, Salamanca, Spain
3Cáncer Research Center and Service of Hematology (University Hospital of Salamanca), Salamanca, Spain
4Service of General and Gastrointestinal Surgery, University Hospital of Salamanca, Salamanca, Spain
5Department of Oncology (University Hospital of Salamanca) and IBSAL (University Hospital of Salamanca), Salamanca, Spain
*These authors have contributed equally to this work and they should be considered as first authors
**These authors have contributed equally to this work and they should both be considered as senior last authors and corresponding authors
Alberto Orfao, email: [email protected]
Keywords: colorectal cancer; anti-EGFR therapy; BRAF V600E mutation; prognosis
Received: June 14, 2017 Accepted: April 06, 2018 Published: May 08, 2018
The prognostic impact of KRAS mutations and other KRAS-related and non-related genes such as BRAF, NRAS and TP53, on sporadic colorectal cancer (sCRC) remain controversial and/or have not been fully established. Here we investigated the frequency of such mutations in primary sCRC tumors and their impact on patient progression-free survival (PFS) and overall survival (OS). Primary tumor tissues from 87 sCRC patients were analysed using a custom-built next generation sequencing (NGS) panel to assess the hotspot mutated regions of KRAS/NRAS (exons 2, 3 and 4), BRAF (exon 15) and TP53 (all exons). Overall, mutations in these genes were detected in 46/87 sCRC tumors analyzed (53%) with the following frequencies per gene: TP53, 33%; KRAS, 28%; BRAF, 7%; and NRAS, 1%. A significant association was found between KRAS mutations and right side colon tumor location (p=0.05), well-differentiated tumors (p=0.04) and absence of lymphovascular invasion (p=0.05). In turn, BRAF-mutated tumors frequently corresponded to poorly- or moderately-differentiated sCRC (p=0.02) and showed a higher frequency of peritoneal carcinomatosis (p=0.006) and microsatellite instability (p=0.007). From the prognostic point of view, the BRAF mutational status together with the TNM stage were the only variables that showed an independent adverse impact on patient outcome in the multivariate analyses for both PFS and OS. Based on these results a scoring system was built and patients were classified into three prognostic subgroups with different PFS rates at 2 years: 91% vs. 77% vs. 0%, respectively (p<0.0001). Additional prospective studies in larger series of sCRC patients where mutations in genes other than those investigated here are required to validate the utility of the proposed predictive model.
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