A computational workflow translates a 58-gene signature to a formalin-fixed, paraffin-embedded sample-based companion diagnostic for personalized treatment of the BRAF-mutation-like subtype of colorectal cancers

Sjors G.J.G. In’t Veld, Kim N. Duong, Mireille Snel, Anke Witteveen, Inès J. Beumer, Leonie J.M.J. Delahaye, Diederik Wehkamp, René Bernards, Annuska M. Glas, Sun Tian

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Colorectal cancer patients with the BRAF(p.V600E) mutation have poor prognosis in metastatic setting. Personalized treatment options and companion diagnostics are needed to better treat these patients. Previously, we developed a 58-gene signature to characterize the distinct gene expression pattern of BRAF-mutation-like subtype (accuracy 91.1%). Further experiments repurposed drug Vinorelbine as specifically lethal to this BRAF-mutation-like subtype. The aim of this study is to translate this 58-gene signature from a research setting to a robust companion diagnostic that can use formalin-fixed, paraffin-embedded (FFPE) samples to select patients with the BRAF-mutation-like subtype. BRAF mutation and gene expression data of 302 FFPE samples were measured (mutants = 57, wild-type = 245). The performance of the 58-gene signature in FFPE samples showed a high sensitivity of 89.5%. In the identified BRAF-mutation-like subtype group, 50% of tumours were known BRAF mutants, and 50% were BRAF wild-type. The stability of the 58-gene signature in FFPE samples was evaluated by two control samples over 40 independent experiments. The standard deviations (SD) were within the predefined criteria (control 1: SD = 0.091, SD/Range = 3.0%; control 2: SD = 0.169, SD/Range = 5.5%). The fresh frozen version and translated FFPE version of this 58-gene signature were compared using 170 paired fresh frozen and FFPE samples and the result showed high consistency (agreement = 99.3%). In conclusion, we translated this 58-gene signature to a robust companion diagnostic that can use FFPE samples.

Original languageEnglish
Article number16
JournalHigh-Throughput
Volume6
Issue number4
DOIs
Publication statusPublished - 1 Dec 2017
Externally publishedYes

Cite this

In’t Veld, Sjors G.J.G. ; Duong, Kim N. ; Snel, Mireille ; Witteveen, Anke ; Beumer, Inès J. ; Delahaye, Leonie J.M.J. ; Wehkamp, Diederik ; Bernards, René ; Glas, Annuska M. ; Tian, Sun. / A computational workflow translates a 58-gene signature to a formalin-fixed, paraffin-embedded sample-based companion diagnostic for personalized treatment of the BRAF-mutation-like subtype of colorectal cancers. In: High-Throughput. 2017 ; Vol. 6, No. 4.
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title = "A computational workflow translates a 58-gene signature to a formalin-fixed, paraffin-embedded sample-based companion diagnostic for personalized treatment of the BRAF-mutation-like subtype of colorectal cancers",
abstract = "Colorectal cancer patients with the BRAF(p.V600E) mutation have poor prognosis in metastatic setting. Personalized treatment options and companion diagnostics are needed to better treat these patients. Previously, we developed a 58-gene signature to characterize the distinct gene expression pattern of BRAF-mutation-like subtype (accuracy 91.1{\%}). Further experiments repurposed drug Vinorelbine as specifically lethal to this BRAF-mutation-like subtype. The aim of this study is to translate this 58-gene signature from a research setting to a robust companion diagnostic that can use formalin-fixed, paraffin-embedded (FFPE) samples to select patients with the BRAF-mutation-like subtype. BRAF mutation and gene expression data of 302 FFPE samples were measured (mutants = 57, wild-type = 245). The performance of the 58-gene signature in FFPE samples showed a high sensitivity of 89.5{\%}. In the identified BRAF-mutation-like subtype group, 50{\%} of tumours were known BRAF mutants, and 50{\%} were BRAF wild-type. The stability of the 58-gene signature in FFPE samples was evaluated by two control samples over 40 independent experiments. The standard deviations (SD) were within the predefined criteria (control 1: SD = 0.091, SD/Range = 3.0{\%}; control 2: SD = 0.169, SD/Range = 5.5{\%}). The fresh frozen version and translated FFPE version of this 58-gene signature were compared using 170 paired fresh frozen and FFPE samples and the result showed high consistency (agreement = 99.3{\%}). In conclusion, we translated this 58-gene signature to a robust companion diagnostic that can use FFPE samples.",
keywords = "Bioinformatics workflow, BRAF-mutation-like subtype, Colorectal cancer, Companion diagnostic, Drug repurposing, Personalized medicine",
author = "{In’t Veld}, {Sjors G.J.G.} and Duong, {Kim N.} and Mireille Snel and Anke Witteveen and Beumer, {In{\`e}s J.} and Delahaye, {Leonie J.M.J.} and Diederik Wehkamp and Ren{\'e} Bernards and Glas, {Annuska M.} and Sun Tian",
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A computational workflow translates a 58-gene signature to a formalin-fixed, paraffin-embedded sample-based companion diagnostic for personalized treatment of the BRAF-mutation-like subtype of colorectal cancers. / In’t Veld, Sjors G.J.G.; Duong, Kim N.; Snel, Mireille; Witteveen, Anke; Beumer, Inès J.; Delahaye, Leonie J.M.J.; Wehkamp, Diederik; Bernards, René; Glas, Annuska M.; Tian, Sun.

In: High-Throughput, Vol. 6, No. 4, 16, 01.12.2017.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - A computational workflow translates a 58-gene signature to a formalin-fixed, paraffin-embedded sample-based companion diagnostic for personalized treatment of the BRAF-mutation-like subtype of colorectal cancers

AU - In’t Veld, Sjors G.J.G.

AU - Duong, Kim N.

AU - Snel, Mireille

AU - Witteveen, Anke

AU - Beumer, Inès J.

AU - Delahaye, Leonie J.M.J.

AU - Wehkamp, Diederik

AU - Bernards, René

AU - Glas, Annuska M.

AU - Tian, Sun

PY - 2017/12/1

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N2 - Colorectal cancer patients with the BRAF(p.V600E) mutation have poor prognosis in metastatic setting. Personalized treatment options and companion diagnostics are needed to better treat these patients. Previously, we developed a 58-gene signature to characterize the distinct gene expression pattern of BRAF-mutation-like subtype (accuracy 91.1%). Further experiments repurposed drug Vinorelbine as specifically lethal to this BRAF-mutation-like subtype. The aim of this study is to translate this 58-gene signature from a research setting to a robust companion diagnostic that can use formalin-fixed, paraffin-embedded (FFPE) samples to select patients with the BRAF-mutation-like subtype. BRAF mutation and gene expression data of 302 FFPE samples were measured (mutants = 57, wild-type = 245). The performance of the 58-gene signature in FFPE samples showed a high sensitivity of 89.5%. In the identified BRAF-mutation-like subtype group, 50% of tumours were known BRAF mutants, and 50% were BRAF wild-type. The stability of the 58-gene signature in FFPE samples was evaluated by two control samples over 40 independent experiments. The standard deviations (SD) were within the predefined criteria (control 1: SD = 0.091, SD/Range = 3.0%; control 2: SD = 0.169, SD/Range = 5.5%). The fresh frozen version and translated FFPE version of this 58-gene signature were compared using 170 paired fresh frozen and FFPE samples and the result showed high consistency (agreement = 99.3%). In conclusion, we translated this 58-gene signature to a robust companion diagnostic that can use FFPE samples.

AB - Colorectal cancer patients with the BRAF(p.V600E) mutation have poor prognosis in metastatic setting. Personalized treatment options and companion diagnostics are needed to better treat these patients. Previously, we developed a 58-gene signature to characterize the distinct gene expression pattern of BRAF-mutation-like subtype (accuracy 91.1%). Further experiments repurposed drug Vinorelbine as specifically lethal to this BRAF-mutation-like subtype. The aim of this study is to translate this 58-gene signature from a research setting to a robust companion diagnostic that can use formalin-fixed, paraffin-embedded (FFPE) samples to select patients with the BRAF-mutation-like subtype. BRAF mutation and gene expression data of 302 FFPE samples were measured (mutants = 57, wild-type = 245). The performance of the 58-gene signature in FFPE samples showed a high sensitivity of 89.5%. In the identified BRAF-mutation-like subtype group, 50% of tumours were known BRAF mutants, and 50% were BRAF wild-type. The stability of the 58-gene signature in FFPE samples was evaluated by two control samples over 40 independent experiments. The standard deviations (SD) were within the predefined criteria (control 1: SD = 0.091, SD/Range = 3.0%; control 2: SD = 0.169, SD/Range = 5.5%). The fresh frozen version and translated FFPE version of this 58-gene signature were compared using 170 paired fresh frozen and FFPE samples and the result showed high consistency (agreement = 99.3%). In conclusion, we translated this 58-gene signature to a robust companion diagnostic that can use FFPE samples.

KW - Bioinformatics workflow

KW - BRAF-mutation-like subtype

KW - Colorectal cancer

KW - Companion diagnostic

KW - Drug repurposing

KW - Personalized medicine

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U2 - 10.3390/ht6040016

DO - 10.3390/ht6040016

M3 - Article

VL - 6

JO - High-Throughput

JF - High-Throughput

SN - 2571-5135

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