High Prevalence and Clinical Relevance of Genes Affected by Chromosomal Breaks in Colorectal Cancer

E. van den Broek, M.J.J. Dijkstra, O. Krijgsman, D.L.S. Sie, J.C. Haan, J.J.H. Traets, M.A. van de Wiel, I.D. Nagtegaal, C.J.A. Punt, B. Carvalho, B. Ylstra, S. Abeln, G.A. Meijer, R.J.A. Fijneman

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Background: Cancer is caused by somatic DNA alterations such as gene point mutations, DNA copy number aberrations (CNA) and structural variants (SVs). Genome-wide analyses of SVs in large sample series with well-documented clinical information are still scarce. Consequently, the impact of SVs on carcinogenesis and patient outcome remains poorly understood. This study aimed to perform a systematic analysis of genes that are affected by CNA-associated chromosomal breaks in colorectal cancer (CRC) and to determine the clinical relevance of recurrent breakpoint genes. Methods: Primary CRC samples of patients with metastatic disease from CAIRO and CAIRO2 clinical trials were previously characterized by array-comparative genomic hybridization. These data were now used to determine the prevalence of CNA-associated chromosomal breaks within genes across 352 CRC samples. In addition, mutation status of the commonly affected APC, TP53, KRAS, PIK3CA, FBXW7, SMAD4, BRAF and NRAS genes was determined for 204 CRC samples by targeted massive parallel sequencing. Clinical relevance was assessed upon stratification of patients based on gene mutations and gene breakpoints that were observed in >3% of CRC cases. Results: In total, 748 genes were identified that were recurrently affected by chromosomal breaks (FDR >0.1). MACROD2 was affected in 41%of CRC samples and another 169 genes showed breakpoints in >3% of cases, indicating that prevalence of gene breakpoints is comparable to the prevalence of well-known gene point mutations. Patient stratification based on gene breakpoints and point mutations revealed one CRC subtype with very poor prognosis. Conclusions: We conclude that CNA-associated chromosomal breaks within genes represent a highly prevalent and clinically relevant subset of SVs in CRC.
Original languageEnglish
Article numbere0138141
JournalPLoS ONE
Volume10
Issue number9
DOIs
Publication statusPublished - 2015

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Chromosome Breakage
colorectal neoplasms
Colorectal Neoplasms
Genes
genes
Aberrations
Point Mutation
point mutation
sampling
comparative genomic hybridization
Mutation
mutation
Comparative Genomic Hybridization
Gene Dosage
DNA
carcinogenesis
prognosis
Carcinogenesis
clinical trials

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van den Broek, E., Dijkstra, M. J. J., Krijgsman, O., Sie, D. L. S., Haan, J. C., Traets, J. J. H., ... Fijneman, R. J. A. (2015). High Prevalence and Clinical Relevance of Genes Affected by Chromosomal Breaks in Colorectal Cancer. PLoS ONE, 10(9), [e0138141]. https://doi.org/10.1371/journal.pone.0138141
van den Broek, E. ; Dijkstra, M.J.J. ; Krijgsman, O. ; Sie, D.L.S. ; Haan, J.C. ; Traets, J.J.H. ; van de Wiel, M.A. ; Nagtegaal, I.D. ; Punt, C.J.A. ; Carvalho, B. ; Ylstra, B. ; Abeln, S. ; Meijer, G.A. ; Fijneman, R.J.A. / High Prevalence and Clinical Relevance of Genes Affected by Chromosomal Breaks in Colorectal Cancer. In: PLoS ONE. 2015 ; Vol. 10, No. 9.
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title = "High Prevalence and Clinical Relevance of Genes Affected by Chromosomal Breaks in Colorectal Cancer",
abstract = "Background: Cancer is caused by somatic DNA alterations such as gene point mutations, DNA copy number aberrations (CNA) and structural variants (SVs). Genome-wide analyses of SVs in large sample series with well-documented clinical information are still scarce. Consequently, the impact of SVs on carcinogenesis and patient outcome remains poorly understood. This study aimed to perform a systematic analysis of genes that are affected by CNA-associated chromosomal breaks in colorectal cancer (CRC) and to determine the clinical relevance of recurrent breakpoint genes. Methods: Primary CRC samples of patients with metastatic disease from CAIRO and CAIRO2 clinical trials were previously characterized by array-comparative genomic hybridization. These data were now used to determine the prevalence of CNA-associated chromosomal breaks within genes across 352 CRC samples. In addition, mutation status of the commonly affected APC, TP53, KRAS, PIK3CA, FBXW7, SMAD4, BRAF and NRAS genes was determined for 204 CRC samples by targeted massive parallel sequencing. Clinical relevance was assessed upon stratification of patients based on gene mutations and gene breakpoints that were observed in >3{\%} of CRC cases. Results: In total, 748 genes were identified that were recurrently affected by chromosomal breaks (FDR >0.1). MACROD2 was affected in 41{\%}of CRC samples and another 169 genes showed breakpoints in >3{\%} of cases, indicating that prevalence of gene breakpoints is comparable to the prevalence of well-known gene point mutations. Patient stratification based on gene breakpoints and point mutations revealed one CRC subtype with very poor prognosis. Conclusions: We conclude that CNA-associated chromosomal breaks within genes represent a highly prevalent and clinically relevant subset of SVs in CRC.",
author = "{van den Broek}, E. and M.J.J. Dijkstra and O. Krijgsman and D.L.S. Sie and J.C. Haan and J.J.H. Traets and {van de Wiel}, M.A. and I.D. Nagtegaal and C.J.A. Punt and B. Carvalho and B. Ylstra and S. Abeln and G.A. Meijer and R.J.A. Fijneman",
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van den Broek, E, Dijkstra, MJJ, Krijgsman, O, Sie, DLS, Haan, JC, Traets, JJH, van de Wiel, MA, Nagtegaal, ID, Punt, CJA, Carvalho, B, Ylstra, B, Abeln, S, Meijer, GA & Fijneman, RJA 2015, 'High Prevalence and Clinical Relevance of Genes Affected by Chromosomal Breaks in Colorectal Cancer' PLoS ONE, vol. 10, no. 9, e0138141. https://doi.org/10.1371/journal.pone.0138141

High Prevalence and Clinical Relevance of Genes Affected by Chromosomal Breaks in Colorectal Cancer. / van den Broek, E.; Dijkstra, M.J.J.; Krijgsman, O.; Sie, D.L.S.; Haan, J.C.; Traets, J.J.H.; van de Wiel, M.A.; Nagtegaal, I.D.; Punt, C.J.A.; Carvalho, B.; Ylstra, B.; Abeln, S.; Meijer, G.A.; Fijneman, R.J.A.

In: PLoS ONE, Vol. 10, No. 9, e0138141, 2015.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - High Prevalence and Clinical Relevance of Genes Affected by Chromosomal Breaks in Colorectal Cancer

AU - van den Broek, E.

AU - Dijkstra, M.J.J.

AU - Krijgsman, O.

AU - Sie, D.L.S.

AU - Haan, J.C.

AU - Traets, J.J.H.

AU - van de Wiel, M.A.

AU - Nagtegaal, I.D.

AU - Punt, C.J.A.

AU - Carvalho, B.

AU - Ylstra, B.

AU - Abeln, S.

AU - Meijer, G.A.

AU - Fijneman, R.J.A.

PY - 2015

Y1 - 2015

N2 - Background: Cancer is caused by somatic DNA alterations such as gene point mutations, DNA copy number aberrations (CNA) and structural variants (SVs). Genome-wide analyses of SVs in large sample series with well-documented clinical information are still scarce. Consequently, the impact of SVs on carcinogenesis and patient outcome remains poorly understood. This study aimed to perform a systematic analysis of genes that are affected by CNA-associated chromosomal breaks in colorectal cancer (CRC) and to determine the clinical relevance of recurrent breakpoint genes. Methods: Primary CRC samples of patients with metastatic disease from CAIRO and CAIRO2 clinical trials were previously characterized by array-comparative genomic hybridization. These data were now used to determine the prevalence of CNA-associated chromosomal breaks within genes across 352 CRC samples. In addition, mutation status of the commonly affected APC, TP53, KRAS, PIK3CA, FBXW7, SMAD4, BRAF and NRAS genes was determined for 204 CRC samples by targeted massive parallel sequencing. Clinical relevance was assessed upon stratification of patients based on gene mutations and gene breakpoints that were observed in >3% of CRC cases. Results: In total, 748 genes were identified that were recurrently affected by chromosomal breaks (FDR >0.1). MACROD2 was affected in 41%of CRC samples and another 169 genes showed breakpoints in >3% of cases, indicating that prevalence of gene breakpoints is comparable to the prevalence of well-known gene point mutations. Patient stratification based on gene breakpoints and point mutations revealed one CRC subtype with very poor prognosis. Conclusions: We conclude that CNA-associated chromosomal breaks within genes represent a highly prevalent and clinically relevant subset of SVs in CRC.

AB - Background: Cancer is caused by somatic DNA alterations such as gene point mutations, DNA copy number aberrations (CNA) and structural variants (SVs). Genome-wide analyses of SVs in large sample series with well-documented clinical information are still scarce. Consequently, the impact of SVs on carcinogenesis and patient outcome remains poorly understood. This study aimed to perform a systematic analysis of genes that are affected by CNA-associated chromosomal breaks in colorectal cancer (CRC) and to determine the clinical relevance of recurrent breakpoint genes. Methods: Primary CRC samples of patients with metastatic disease from CAIRO and CAIRO2 clinical trials were previously characterized by array-comparative genomic hybridization. These data were now used to determine the prevalence of CNA-associated chromosomal breaks within genes across 352 CRC samples. In addition, mutation status of the commonly affected APC, TP53, KRAS, PIK3CA, FBXW7, SMAD4, BRAF and NRAS genes was determined for 204 CRC samples by targeted massive parallel sequencing. Clinical relevance was assessed upon stratification of patients based on gene mutations and gene breakpoints that were observed in >3% of CRC cases. Results: In total, 748 genes were identified that were recurrently affected by chromosomal breaks (FDR >0.1). MACROD2 was affected in 41%of CRC samples and another 169 genes showed breakpoints in >3% of cases, indicating that prevalence of gene breakpoints is comparable to the prevalence of well-known gene point mutations. Patient stratification based on gene breakpoints and point mutations revealed one CRC subtype with very poor prognosis. Conclusions: We conclude that CNA-associated chromosomal breaks within genes represent a highly prevalent and clinically relevant subset of SVs in CRC.

U2 - 10.1371/journal.pone.0138141

DO - 10.1371/journal.pone.0138141

M3 - Article

VL - 10

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 9

M1 - e0138141

ER -