Identification of different mutational profiles in cancers arising in specific colon segments by next generation sequencing.

Duarte Mendes Oliveira,Flavia Biamonte,Chiara Mignogna,Donatella Malanga,Pietro Zoppoli,Rosario Sacco,Giuseppe Viglietto,Gianluca Santamaria,Laura Elia,Simona Migliozzi,Francesco Corcione,Antonia Rizzuto,Carmelo Laudanna,Katia Grillone

doi:10.18632/oncotarget.25251

Duarte Mendes Oliveira, Flavia Biamonte + Show 12 more

Open Access

https://doi.org/10.18632/oncotarget.25251

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Journal: Oncotarget	Publication Date: May 8, 2018
Citations: 13	License type: cc-by

Affiliation: Magna Graecia University

Abstract

The objective of this study was to investigate the mutational profiles of cancers arising in different colon segments. To this aim, we have analyzed 37 colon cancer samples by use of the Ion AmpliSeq™ Comprehensive Cancer Panel. Overall, we have found 307 mutated genes, most of which already implicated in the development of colon cancer. Among these, 15 genes were mutated in tumors originating in all six colon segments and were defined “common genes” (i.e. APC, PIK3CA, TP53) whereas 13 genes were preferentially mutated in tumors originating only in specific colon segments and were defined “site-associated genes” (i.e. BLNK, PTPRD).In addition, the presence of mutations in 10 of the 307 identified mutated genes (NBN, SMUG1, ERBB2, PTPRT, EPHB1, ALK, PTPRD, AURKB, KDR and GPR124) were found to be of clinical relevance. Among clinically relevant genes, NBN and SMUG1 were identified as independent prognostic factors that predicted poor survival in colon cancer patients.In conclusion, the findings reported here indicate that tumors arising in different colon segments present differences in the type and/or frequency of genetic variants, with two of them being independent prognostic factors that predict poor survival in colon cancer patients.

Highlights

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide [1]
In this study we have investigated the mutational profile of cancer that originated in six different segments of the colon that include ascending colon, descending colon, hepatic flexure, splenic flexure, transverse colon and cecum
The main results comprise: i) the identification of 1,385 potential protein-altering somatic variants in 307 different genes, with a median number of 24 mutated genes/tumor, ii) the identification of 15 genes that were mutated at least once in tumors originating in all colon segments; iii) the identification of 13 genes that were preferentially mutated in tumors originating in specific colon segments, iv) the identification of 10 genes (NBN, SMUG1, ERBB2, PTPRD, PTPRT, EPHB1, ALK, AURKB, KDR and GPR124) that were associated with node status, stage, tumor size and/or presence of metastasis and that predicted poor survival, v) the finding that mutations in two genes (NBN and SMUG1) were independent predictors of survival

Summary

Introduction

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide [1]. The lifetime risk of CRC in the United States is 6% and the average age at diagnosis is 66 years [2, 3]. CRC results from the accumulation of multiple somatic genetic and epigenetic aberrations that lead to the transformation of normal epithelial cells of the intestinal www.oncotarget.com mucosa [9]. According to the model proposed by Fearon and Vogelstein in 1990, CRC proceeds through a series of morphological steps leading from normal mucosa to adenoma and/or carcinoma cells. These morphological changes are caused by specific genetic and/or epigenetic alterations, the first of which is the aberrant activation of the APC/β-catenin pathway, followed by aberrant activation of the RAS/RAF/MAPK pathway due to mutations in genes such as RAS or BRAF and by the loss of p53 function at later stages [10]

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