Analysis of a gene panel for targeted sequencing of colorectal cancer samples

Klaus Højgaard Jensen, Jose M.G Izarzugaza, Agnieszka Sierakowska Juncker, Rasmus Borup Hansen, Torben Frøstrup Hansen, Pascal Timshel, Thorarinn Blondal, Thomas Skøt Jensen, Eske Rygaard-Hjalsted, Peter Mouritzen, Michael Thorsen, Rasmus Wernersson, Henrik Bjørn Nielsen, Anders Jakobsen, Søren Brunak*, Flemming Brandt Sørensen

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Colorectal cancer (CRC) is a leading cause of death worldwide. Surgical intervention is a successful treatment for stage I patients, whereas other more advanced cases may require adjuvant chemotherapy. The selection of effective adjuvant treatments remains, however, challenging. Accurate patient stratification is necessary for the identification of the subset of patients likely responding to treatment, while sparing others from pernicious treatment. Targeted sequencing approaches may help in this regard, enabling rapid genetic investigation, and at the same time easily applicable in routine diagnosis.

We propose a set of guidelines for the identification, including variant calling and filtering, of somatic mutations driving tumorigenesis in the absence of matched healthy tissue. We also discuss the inclusion criteria for the generation of our gene panel. Furthermore, we evaluate the prognostic impact of individual genes, using Cox regression models in the context of overall survival and disease-free survival. These analyses confirmed the role of commonly used biomarkers, and shed light on controversial genes such as CYP2C8.

Applying those guidelines, we created a novel gene panel to investigate the onset and progression of CRC in 273 patients. Our comprehensive biomarker set includes 266 genes that may play a role in the progression through the different stages of the disease. Tracing the developmental state of the tumour, and its resistances, is instrumental in patient stratification and reliable decision making in precision clinical practice.
Original languageEnglish
JournalOncoTarget
Volume9
Issue number10
Pages (from-to)9043-9060
Number of pages18
ISSN1949-2553
DOIs
Publication statusPublished - 2018

Bibliographical note

Jensen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Keywords

  • Colorectal cancer
  • Biomarker discovery
  • NGS
  • Precision medicine

Cite this

Jensen, K. H., Izarzugaza, J. M. G., Sierakowska Juncker, A., Borup Hansen, R., Frøstrup Hansen, T., Timshel, P., ... Brandt Sørensen, F. (2018). Analysis of a gene panel for targeted sequencing of colorectal cancer samples. OncoTarget, 9(10), 9043-9060. https://doi.org/10.18632/oncotarget.24138
Jensen, Klaus Højgaard ; Izarzugaza, Jose M.G ; Sierakowska Juncker, Agnieszka ; Borup Hansen, Rasmus ; Frøstrup Hansen, Torben ; Timshel, Pascal ; Blondal, Thorarinn ; Jensen, Thomas Skøt ; Rygaard-Hjalsted, Eske ; Mouritzen, Peter ; Thorsen, Michael ; Wernersson, Rasmus ; Nielsen, Henrik Bjørn ; Jakobsen, Anders ; Brunak, Søren ; Brandt Sørensen, Flemming. / Analysis of a gene panel for targeted sequencing of colorectal cancer samples. In: OncoTarget. 2018 ; Vol. 9, No. 10. pp. 9043-9060.
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title = "Analysis of a gene panel for targeted sequencing of colorectal cancer samples",
abstract = "Colorectal cancer (CRC) is a leading cause of death worldwide. Surgical intervention is a successful treatment for stage I patients, whereas other more advanced cases may require adjuvant chemotherapy. The selection of effective adjuvant treatments remains, however, challenging. Accurate patient stratification is necessary for the identification of the subset of patients likely responding to treatment, while sparing others from pernicious treatment. Targeted sequencing approaches may help in this regard, enabling rapid genetic investigation, and at the same time easily applicable in routine diagnosis.We propose a set of guidelines for the identification, including variant calling and filtering, of somatic mutations driving tumorigenesis in the absence of matched healthy tissue. We also discuss the inclusion criteria for the generation of our gene panel. Furthermore, we evaluate the prognostic impact of individual genes, using Cox regression models in the context of overall survival and disease-free survival. These analyses confirmed the role of commonly used biomarkers, and shed light on controversial genes such as CYP2C8.Applying those guidelines, we created a novel gene panel to investigate the onset and progression of CRC in 273 patients. Our comprehensive biomarker set includes 266 genes that may play a role in the progression through the different stages of the disease. Tracing the developmental state of the tumour, and its resistances, is instrumental in patient stratification and reliable decision making in precision clinical practice.",
keywords = "Colorectal cancer, Biomarker discovery, NGS, Precision medicine",
author = "Jensen, {Klaus H{\o}jgaard} and Izarzugaza, {Jose M.G} and {Sierakowska Juncker}, Agnieszka and {Borup Hansen}, Rasmus and {Fr{\o}strup Hansen}, Torben and Pascal Timshel and Thorarinn Blondal and Jensen, {Thomas Sk{\o}t} and Eske Rygaard-Hjalsted and Peter Mouritzen and Michael Thorsen and Rasmus Wernersson and Nielsen, {Henrik Bj{\o}rn} and Anders Jakobsen and S{\o}ren Brunak and {Brandt S{\o}rensen}, Flemming",
note = "Jensen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
year = "2018",
doi = "10.18632/oncotarget.24138",
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Jensen, KH, Izarzugaza, JMG, Sierakowska Juncker, A, Borup Hansen, R, Frøstrup Hansen, T, Timshel, P, Blondal, T, Jensen, TS, Rygaard-Hjalsted, E, Mouritzen, P, Thorsen, M, Wernersson, R, Nielsen, HB, Jakobsen, A, Brunak, S & Brandt Sørensen, F 2018, 'Analysis of a gene panel for targeted sequencing of colorectal cancer samples', OncoTarget, vol. 9, no. 10, pp. 9043-9060. https://doi.org/10.18632/oncotarget.24138

Analysis of a gene panel for targeted sequencing of colorectal cancer samples. / Jensen, Klaus Højgaard; Izarzugaza, Jose M.G; Sierakowska Juncker, Agnieszka; Borup Hansen, Rasmus; Frøstrup Hansen, Torben; Timshel, Pascal; Blondal, Thorarinn; Jensen, Thomas Skøt; Rygaard-Hjalsted, Eske; Mouritzen, Peter; Thorsen, Michael; Wernersson, Rasmus; Nielsen, Henrik Bjørn; Jakobsen, Anders; Brunak, Søren; Brandt Sørensen, Flemming.

In: OncoTarget, Vol. 9, No. 10, 2018, p. 9043-9060.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Analysis of a gene panel for targeted sequencing of colorectal cancer samples

AU - Jensen, Klaus Højgaard

AU - Izarzugaza, Jose M.G

AU - Sierakowska Juncker, Agnieszka

AU - Borup Hansen, Rasmus

AU - Frøstrup Hansen, Torben

AU - Timshel, Pascal

AU - Blondal, Thorarinn

AU - Jensen, Thomas Skøt

AU - Rygaard-Hjalsted, Eske

AU - Mouritzen, Peter

AU - Thorsen, Michael

AU - Wernersson, Rasmus

AU - Nielsen, Henrik Bjørn

AU - Jakobsen, Anders

AU - Brunak, Søren

AU - Brandt Sørensen, Flemming

N1 - Jensen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2018

Y1 - 2018

N2 - Colorectal cancer (CRC) is a leading cause of death worldwide. Surgical intervention is a successful treatment for stage I patients, whereas other more advanced cases may require adjuvant chemotherapy. The selection of effective adjuvant treatments remains, however, challenging. Accurate patient stratification is necessary for the identification of the subset of patients likely responding to treatment, while sparing others from pernicious treatment. Targeted sequencing approaches may help in this regard, enabling rapid genetic investigation, and at the same time easily applicable in routine diagnosis.We propose a set of guidelines for the identification, including variant calling and filtering, of somatic mutations driving tumorigenesis in the absence of matched healthy tissue. We also discuss the inclusion criteria for the generation of our gene panel. Furthermore, we evaluate the prognostic impact of individual genes, using Cox regression models in the context of overall survival and disease-free survival. These analyses confirmed the role of commonly used biomarkers, and shed light on controversial genes such as CYP2C8.Applying those guidelines, we created a novel gene panel to investigate the onset and progression of CRC in 273 patients. Our comprehensive biomarker set includes 266 genes that may play a role in the progression through the different stages of the disease. Tracing the developmental state of the tumour, and its resistances, is instrumental in patient stratification and reliable decision making in precision clinical practice.

AB - Colorectal cancer (CRC) is a leading cause of death worldwide. Surgical intervention is a successful treatment for stage I patients, whereas other more advanced cases may require adjuvant chemotherapy. The selection of effective adjuvant treatments remains, however, challenging. Accurate patient stratification is necessary for the identification of the subset of patients likely responding to treatment, while sparing others from pernicious treatment. Targeted sequencing approaches may help in this regard, enabling rapid genetic investigation, and at the same time easily applicable in routine diagnosis.We propose a set of guidelines for the identification, including variant calling and filtering, of somatic mutations driving tumorigenesis in the absence of matched healthy tissue. We also discuss the inclusion criteria for the generation of our gene panel. Furthermore, we evaluate the prognostic impact of individual genes, using Cox regression models in the context of overall survival and disease-free survival. These analyses confirmed the role of commonly used biomarkers, and shed light on controversial genes such as CYP2C8.Applying those guidelines, we created a novel gene panel to investigate the onset and progression of CRC in 273 patients. Our comprehensive biomarker set includes 266 genes that may play a role in the progression through the different stages of the disease. Tracing the developmental state of the tumour, and its resistances, is instrumental in patient stratification and reliable decision making in precision clinical practice.

KW - Colorectal cancer

KW - Biomarker discovery

KW - NGS

KW - Precision medicine

U2 - 10.18632/oncotarget.24138

DO - 10.18632/oncotarget.24138

M3 - Journal article

C2 - 29507673

VL - 9

SP - 9043

EP - 9060

JO - OncoTarget

JF - OncoTarget

SN - 1949-2553

IS - 10

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Jensen KH, Izarzugaza JMG, Sierakowska Juncker A, Borup Hansen R, Frøstrup Hansen T, Timshel P et al. Analysis of a gene panel for targeted sequencing of colorectal cancer samples. OncoTarget. 2018;9(10):9043-9060. https://doi.org/10.18632/oncotarget.24138