Mireille Snel - Academia.edu (original) (raw)

Papers by Mireille Snel

European Journal of Cancer Supplements, 2009

Annals of Surgery, 2013

The aim of this study was to independently validate a genomic signature developed both to assess ... more The aim of this study was to independently validate a genomic signature developed both to assess recurrence risk in stage II patients and to assist in treatment decisions. Adjuvant therapy is recommended for high-risk patients with stage II colon cancer, but better tools to assess the patients' prognosis accurately are still required. Previously, an 18-gene signature had been developed and validated on an independent cohort, using full genome microarrays. In this study, the gene signature was translated and validated as a robust diagnostic test (ColoPrint), using customized 8-pack arrays. In addition, clinical validation of the diagnostic ColoPrint assay was performed on 135 patients who underwent curative resection (R0) for colon cancer stage II in Munich. Fresh-frozen tissue, microsatellite instability status, clinical parameters, and follow-up data for all patients were available. The diagnostic ColoPrint readout was determined blindly from the clinical data. ColoPrint identified most stage II patients (73.3%) as at low risk. The 5-year distant-metastasis free survival was 94.9% for low-risk patients and 80.6% for high-risk patients. In multivariable analysis, ColoPrint was the only significant parameter to predict the development of distant metastasis with a hazard ratio of 4.28 (95% confidence interval, 1.36-13.50; P = 0.013). Clinical risk parameters from the American Society of Clinical Oncology (ASCO) recommendation did not add power to the ColoPrint classification. Technical validation of ColoPrint confirmed stability and reproducibility of the diagnostic platform. ColoPrint is able to predict the development of distant metastasis of patients with stage II colon cancer and facilitates the identification of patients who may be safely managed without chemotherapy.

The Journal of Molecular Diagnostics, 2014

Colorectal cancer intrinsic subtypes predict chemotherapy

Current biology : CB, 2006

The phosphoinositide phosphatidylinositol 4, 5-bisphosphate (PtdIns(4,5)P(2)) is essential for ma... more The phosphoinositide phosphatidylinositol 4, 5-bisphosphate (PtdIns(4,5)P(2)) is essential for many cellular processes and is linked to the etiology of numerous human diseases . PtdIns(4,5)P(2) has been indirectly implicated as a negative regulator of apoptosis ; however, it is unclear if apoptotic stimuli negatively regulate PtdIns(4,5)P(2) levels in vivo. Here, we show that two apoptotic-stress stimuli, hydrogen peroxide (H(2)O(2)) and UV irradiation, cause PtdIns(4,5)P(2) depletion during programmed cell death independently of and prior to caspase activation. Depletion of PtdIns(4,5)P(2) is essential for apoptosis because maintenance of PtdIns(4,5)P(2) levels by overexpression of PIP5Kalpha rescues cells from H(2)O(2)-induced apoptosis. PIP5Kalpha expression promotes both basal and sustained ERK1/2 activation after H(2)O(2) treatment, and importantly, pharmacological inhibition of ERK1/2 signaling blocks PIP5Kalpha-mediated cell survival. H(2)O(2) induces tyrosine phosphorylation...

European Journal of Cancer

Annals of Oncology

Background Centralized MammaPrint (MP) and BluePrint (BP) microarray-based genomic tests on FFPE ... more Background Centralized MammaPrint (MP) and BluePrint (BP) microarray-based genomic tests on FFPE RNA were succesfully translated to a targeted RNA NGS kit that can be performed locally in decentralized sites. Since the launch of the CE-marked MP and BP NGS test, more data has been generated on this platform as well as on the established FDA-cleared microarray platform. Furthermore, decentralized sites worldwide have been onboarded and are certified to locally run the MP and BP NGS test. Methods Paired MP and BP results were generated from FFPE RNA samples using the standard microarray as well as the MP and BP NGS test. The results from both platforms were compared to assess the concordance. Since the launch of the MP and BP NGS kit several decentralized sites underwent the onboarding process. As part of the onboarding, these sites processed a set of RNA and FFPE tissue samples previously processed at Agendia using the MP and BP NGS test. A site could only be certified if NGS results...

The Journal of Molecular Diagnostics

Next-generation DNA sequencing is rapidly becoming an indispensable tool for genome-directed canc... more Next-generation DNA sequencing is rapidly becoming an indispensable tool for genome-directed cancer diagnostics, but next-generation RNA sequencing (RNA-seq) is currently not standardly used in clinical diagnostics for expression assessment. However, multigene RNA diagnostic assays are used increasingly in the routine diagnosis of early-stage breast cancer. Two of the most widely used tests are currently available only as a central laboratory service, which limits their clinical use. We evaluated the use of RNA-seq as a decentralized method to perform such tests. The MammaPrint and BluePrint RNA-seq tests were found to be equivalent to the clinically validated microarray tests. The RNA-seq tests were highly reproducible when performed in different locations and were stable over time. The MammaPrint RNA-seq test was clinically validated. Our data demonstrate that RNA-seq can be used as a decentralized platform, yielding results substantially equivalent to results derived from the predicate diagnostic device.

Background: The Rational Therapy for Breast Cancer (RATHER) Consortium aims to identify novel kin... more Background: The Rational Therapy for Breast Cancer (RATHER) Consortium aims to identify novel kinase targets for therapy in poor-prognosis subtypes of breast cancer for which there are currently no targeted therapies available. In this project, the focus is on invasive lobular carcinomas (ILC), which represent 10% of breast tumors. The main strength of the RATHER project is the unique combination of comprehensive molecular data together with detailed clinical information, which enables translation of state-of-the art genomics analyses to the clinic. Our main goal is to identify and validate novel kinase targets for breast cancer therapy in a comprehensive way using large-scale and complementary genomics data (DNA and RNA sequence, copy number variation, gene expression and protein expression). Integrated analysis of these molecular data is performed to define molecular subtypes of ILC with differential clinical outcome. Methods: One hundred and fifty ILC samples (fresh frozen) with >5 years follow-up were collected from two institutes (Cambridge, Netherlands Cancer Institute). All samples were processed following one standard operating protocol to isolate RNA, DNA and protein of high quality. We used a five-pronged approach to identify and validate novel kinase targets for therapy in ILC, namely i) direct re-sequencing of the kinome of 150 ILC breast tumors, ii) determination of abundance and activation status of kinases in these tumors by reverse phase protein lysate array (RPPA) technology, iii) determination of copy number variation (CNV) by genome-wide SNP arrays, iv) mRNA quantitation of both genome and kinome using DNA microarrays and v) RNAseq of a subset of ILC tumors. ILC are compared to triple negative, which allows us to highlight differences and/or similarities between these subtypes and provide clues for therapeutic targets. Results: Data from these independent genome-scale technologies were integrated, yielding a prioritized list of potential kinase targets for therapy in ILC breast cancer. Deep sequencing of the kinome has revealed somatic mutations characteristic of ILC, which are currently being validated via mass spectrometry-based genotyping technology and their possible effects confirmed with gene expression, protein expression and phosphorylation changes. In addition, on a subset of the ILC samples, RNA sequencing was performed to confirm expression of particular mutants. Known gene mutations in ILC such as loss of CDH1 were confirmed. Moreover, the PI3K pathway is found to be frequently altered (50% of the samples). Gene expression analysis, as well as integrative analysis of CNV and gene expression data revealed subsets of ILCs that significantly regulate alternate biological processes and show differential clinical outcome. Such biological subsets are currently being validated with clinical and follow-up data. Updated results will be presented at the meeting. Conclusion: The RATHER project aims to deliver proof-of-concept for novel therapeutic interventions, together with companion molecular diagnostic assays for patient stratification, for up to 10% of breast cancer patients, where current treatment options are unsatisfactory. Ongoing validation of a number of potential targets proves to be promising. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-04-02.

Zeitschrift für Gastroenterologie, 2010

Cancer Research, 2013

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: The RATHE... more Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: The RATHER Consortium aims to identify novel kinase targets for therapy in poor-prognosis subtypes of breast cancer for which there are currently no targeted therapies available; namely invasive lobular carcinomas (ILC) which represent 10% of breast tumors. The RATHER approach differs in two fundamental ways from the ongoing cancer genome re-sequencing efforts. Firstly, the major cancer genome re-sequencing efforts focus on DNA sequence analysis of the whole genome. In RATHER, we identify and validate novel kinases as therapy targets in a more comprehensive way by analyzing the DNA sequence and by applying state-of-the-art proteomics, copy number analysis and gene expression profiling technologies to identify activated/altered kinases. Secondly, RATHER also differs by focusing on the lobular subtype of breast cancer. Methods: One hundred and fifty ILC samples (fresh frozen) with >5years follow-up were collected from two institutes (Cambridge, NKI). All samples were processed following one standard operating protocol to isolate RNA, DNA and protein of high quality. We used a five-pronged approach to identify and validate novel kinase targets for therapy in ILC breast cancer, namely i) direct re-sequencing of the kinome of 150 ILC breast tumors, ii) determination of abundance and activation status of kinases in these tumors by reverse phase protein lysate array (RPPA) technology, iii) determination of copy number aberration (CNA) in kinase genes by SNP arrays, iv) mRNA quantitation of both genome and kinome using DNA microarrays and v)RNAseq of a subset of ILC tumors. Results: Data from these independent genome-scale technologies were integrated, yielding a priority list of potential kinase targets for therapy in ILC breast cancer. Deep sequencing of the kinome has revealed somatic mutations characteristic of ILC, which are currently being validated via mass spectrometry-based genotyping technology and their possible effects confirmed with gene expression, protein expression and phosphorylation changes. In addition, a subset of the ILC samples was assessed via RNA sequencing approach to confirm expression of particular mutants. Known gene mutations in ILC such as loss of CDH1 were confirmed; furthermore, a high frequency of PI3K pathway alterations (50%) was observed. Gene expression analysis of such a large set of ILC can reveal subsets of these breast cancers that significantly regulate alternate biological processes. Such biological subsets are currently being validated with clinical and follow-up data. Conclusion: The RATHER project aims to deliver proof-of-concept for novel therapeutic interventions, together with companion molecular diagnostic assays for patient stratification, for up to 10% of breast cancer patients, where current treatment options are unsatisfactory. Citation Format: Justine K. Peeters, Ian Majewski, Leanne de Koning, Yue Fan, Finbarr Tarrant, Darran O'Connor, Jeroen Heijmans, Mireille Snel, Tesa Severson, Astrid Bosma, Magali Michaut, Lorenza Mittempergher, Suet-Feung Chin, Thierry Dubois, William Gallagher, Carlos Caldas, Rene Bernards, Iris Simon, RATHER Consortium. Development of comprehensive molecular portraits of lobular breast cancer within the RATHER (Rational Therapy for Breast Cancer) Consortium. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1218. doi:10.1158/1538-7445.AM2013-1218

International Journal of Cancer

To date, no systematic analyses are available assessing concordance of molecular classifications ... more To date, no systematic analyses are available assessing concordance of molecular classifications between primary tumors (PT) and matched liver metastases (LM) of metastatic colorectal cancer (mCRC). We investigated concordance between PT and

Experimental and Molecular Therapeutics

Journal of Clinical Oncology

High-throughput, Jan 6, 2017

Colorectal cancer patients with the (p.V600E) mutation have poor prognosis in metastatic setting.... more Colorectal cancer patients with the (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 -mutation-like subtype (accuracy 91.1%). Further experiments repurposed drug Vinorelbine as specifically lethal to this -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 -mutation-like subtype. 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 -mutation-like subtype group, 50% of tumours were known mutants, and 50% were wild-type. The stability of the ...

European Journal of Cancer Supplements, 2009

Annals of Surgery, 2013

The aim of this study was to independently validate a genomic signature developed both to assess ... more The aim of this study was to independently validate a genomic signature developed both to assess recurrence risk in stage II patients and to assist in treatment decisions. Adjuvant therapy is recommended for high-risk patients with stage II colon cancer, but better tools to assess the patients' prognosis accurately are still required. Previously, an 18-gene signature had been developed and validated on an independent cohort, using full genome microarrays. In this study, the gene signature was translated and validated as a robust diagnostic test (ColoPrint), using customized 8-pack arrays. In addition, clinical validation of the diagnostic ColoPrint assay was performed on 135 patients who underwent curative resection (R0) for colon cancer stage II in Munich. Fresh-frozen tissue, microsatellite instability status, clinical parameters, and follow-up data for all patients were available. The diagnostic ColoPrint readout was determined blindly from the clinical data. ColoPrint identified most stage II patients (73.3%) as at low risk. The 5-year distant-metastasis free survival was 94.9% for low-risk patients and 80.6% for high-risk patients. In multivariable analysis, ColoPrint was the only significant parameter to predict the development of distant metastasis with a hazard ratio of 4.28 (95% confidence interval, 1.36-13.50; P = 0.013). Clinical risk parameters from the American Society of Clinical Oncology (ASCO) recommendation did not add power to the ColoPrint classification. Technical validation of ColoPrint confirmed stability and reproducibility of the diagnostic platform. ColoPrint is able to predict the development of distant metastasis of patients with stage II colon cancer and facilitates the identification of patients who may be safely managed without chemotherapy.

The Journal of Molecular Diagnostics, 2014

Colorectal cancer intrinsic subtypes predict chemotherapy

Current biology : CB, 2006

The phosphoinositide phosphatidylinositol 4, 5-bisphosphate (PtdIns(4,5)P(2)) is essential for ma... more The phosphoinositide phosphatidylinositol 4, 5-bisphosphate (PtdIns(4,5)P(2)) is essential for many cellular processes and is linked to the etiology of numerous human diseases . PtdIns(4,5)P(2) has been indirectly implicated as a negative regulator of apoptosis ; however, it is unclear if apoptotic stimuli negatively regulate PtdIns(4,5)P(2) levels in vivo. Here, we show that two apoptotic-stress stimuli, hydrogen peroxide (H(2)O(2)) and UV irradiation, cause PtdIns(4,5)P(2) depletion during programmed cell death independently of and prior to caspase activation. Depletion of PtdIns(4,5)P(2) is essential for apoptosis because maintenance of PtdIns(4,5)P(2) levels by overexpression of PIP5Kalpha rescues cells from H(2)O(2)-induced apoptosis. PIP5Kalpha expression promotes both basal and sustained ERK1/2 activation after H(2)O(2) treatment, and importantly, pharmacological inhibition of ERK1/2 signaling blocks PIP5Kalpha-mediated cell survival. H(2)O(2) induces tyrosine phosphorylation...

European Journal of Cancer

Annals of Oncology

Background Centralized MammaPrint (MP) and BluePrint (BP) microarray-based genomic tests on FFPE ... more Background Centralized MammaPrint (MP) and BluePrint (BP) microarray-based genomic tests on FFPE RNA were succesfully translated to a targeted RNA NGS kit that can be performed locally in decentralized sites. Since the launch of the CE-marked MP and BP NGS test, more data has been generated on this platform as well as on the established FDA-cleared microarray platform. Furthermore, decentralized sites worldwide have been onboarded and are certified to locally run the MP and BP NGS test. Methods Paired MP and BP results were generated from FFPE RNA samples using the standard microarray as well as the MP and BP NGS test. The results from both platforms were compared to assess the concordance. Since the launch of the MP and BP NGS kit several decentralized sites underwent the onboarding process. As part of the onboarding, these sites processed a set of RNA and FFPE tissue samples previously processed at Agendia using the MP and BP NGS test. A site could only be certified if NGS results...

The Journal of Molecular Diagnostics

Next-generation DNA sequencing is rapidly becoming an indispensable tool for genome-directed canc... more Next-generation DNA sequencing is rapidly becoming an indispensable tool for genome-directed cancer diagnostics, but next-generation RNA sequencing (RNA-seq) is currently not standardly used in clinical diagnostics for expression assessment. However, multigene RNA diagnostic assays are used increasingly in the routine diagnosis of early-stage breast cancer. Two of the most widely used tests are currently available only as a central laboratory service, which limits their clinical use. We evaluated the use of RNA-seq as a decentralized method to perform such tests. The MammaPrint and BluePrint RNA-seq tests were found to be equivalent to the clinically validated microarray tests. The RNA-seq tests were highly reproducible when performed in different locations and were stable over time. The MammaPrint RNA-seq test was clinically validated. Our data demonstrate that RNA-seq can be used as a decentralized platform, yielding results substantially equivalent to results derived from the predicate diagnostic device.

Background: The Rational Therapy for Breast Cancer (RATHER) Consortium aims to identify novel kin... more Background: The Rational Therapy for Breast Cancer (RATHER) Consortium aims to identify novel kinase targets for therapy in poor-prognosis subtypes of breast cancer for which there are currently no targeted therapies available. In this project, the focus is on invasive lobular carcinomas (ILC), which represent 10% of breast tumors. The main strength of the RATHER project is the unique combination of comprehensive molecular data together with detailed clinical information, which enables translation of state-of-the art genomics analyses to the clinic. Our main goal is to identify and validate novel kinase targets for breast cancer therapy in a comprehensive way using large-scale and complementary genomics data (DNA and RNA sequence, copy number variation, gene expression and protein expression). Integrated analysis of these molecular data is performed to define molecular subtypes of ILC with differential clinical outcome. Methods: One hundred and fifty ILC samples (fresh frozen) with >5 years follow-up were collected from two institutes (Cambridge, Netherlands Cancer Institute). All samples were processed following one standard operating protocol to isolate RNA, DNA and protein of high quality. We used a five-pronged approach to identify and validate novel kinase targets for therapy in ILC, namely i) direct re-sequencing of the kinome of 150 ILC breast tumors, ii) determination of abundance and activation status of kinases in these tumors by reverse phase protein lysate array (RPPA) technology, iii) determination of copy number variation (CNV) by genome-wide SNP arrays, iv) mRNA quantitation of both genome and kinome using DNA microarrays and v) RNAseq of a subset of ILC tumors. ILC are compared to triple negative, which allows us to highlight differences and/or similarities between these subtypes and provide clues for therapeutic targets. Results: Data from these independent genome-scale technologies were integrated, yielding a prioritized list of potential kinase targets for therapy in ILC breast cancer. Deep sequencing of the kinome has revealed somatic mutations characteristic of ILC, which are currently being validated via mass spectrometry-based genotyping technology and their possible effects confirmed with gene expression, protein expression and phosphorylation changes. In addition, on a subset of the ILC samples, RNA sequencing was performed to confirm expression of particular mutants. Known gene mutations in ILC such as loss of CDH1 were confirmed. Moreover, the PI3K pathway is found to be frequently altered (50% of the samples). Gene expression analysis, as well as integrative analysis of CNV and gene expression data revealed subsets of ILCs that significantly regulate alternate biological processes and show differential clinical outcome. Such biological subsets are currently being validated with clinical and follow-up data. Updated results will be presented at the meeting. Conclusion: The RATHER project aims to deliver proof-of-concept for novel therapeutic interventions, together with companion molecular diagnostic assays for patient stratification, for up to 10% of breast cancer patients, where current treatment options are unsatisfactory. Ongoing validation of a number of potential targets proves to be promising. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-04-02.

Zeitschrift für Gastroenterologie, 2010

Cancer Research, 2013

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: The RATHE... more Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: The RATHER Consortium aims to identify novel kinase targets for therapy in poor-prognosis subtypes of breast cancer for which there are currently no targeted therapies available; namely invasive lobular carcinomas (ILC) which represent 10% of breast tumors. The RATHER approach differs in two fundamental ways from the ongoing cancer genome re-sequencing efforts. Firstly, the major cancer genome re-sequencing efforts focus on DNA sequence analysis of the whole genome. In RATHER, we identify and validate novel kinases as therapy targets in a more comprehensive way by analyzing the DNA sequence and by applying state-of-the-art proteomics, copy number analysis and gene expression profiling technologies to identify activated/altered kinases. Secondly, RATHER also differs by focusing on the lobular subtype of breast cancer. Methods: One hundred and fifty ILC samples (fresh frozen) with >5years follow-up were collected from two institutes (Cambridge, NKI). All samples were processed following one standard operating protocol to isolate RNA, DNA and protein of high quality. We used a five-pronged approach to identify and validate novel kinase targets for therapy in ILC breast cancer, namely i) direct re-sequencing of the kinome of 150 ILC breast tumors, ii) determination of abundance and activation status of kinases in these tumors by reverse phase protein lysate array (RPPA) technology, iii) determination of copy number aberration (CNA) in kinase genes by SNP arrays, iv) mRNA quantitation of both genome and kinome using DNA microarrays and v)RNAseq of a subset of ILC tumors. Results: Data from these independent genome-scale technologies were integrated, yielding a priority list of potential kinase targets for therapy in ILC breast cancer. Deep sequencing of the kinome has revealed somatic mutations characteristic of ILC, which are currently being validated via mass spectrometry-based genotyping technology and their possible effects confirmed with gene expression, protein expression and phosphorylation changes. In addition, a subset of the ILC samples was assessed via RNA sequencing approach to confirm expression of particular mutants. Known gene mutations in ILC such as loss of CDH1 were confirmed; furthermore, a high frequency of PI3K pathway alterations (50%) was observed. Gene expression analysis of such a large set of ILC can reveal subsets of these breast cancers that significantly regulate alternate biological processes. Such biological subsets are currently being validated with clinical and follow-up data. Conclusion: The RATHER project aims to deliver proof-of-concept for novel therapeutic interventions, together with companion molecular diagnostic assays for patient stratification, for up to 10% of breast cancer patients, where current treatment options are unsatisfactory. Citation Format: Justine K. Peeters, Ian Majewski, Leanne de Koning, Yue Fan, Finbarr Tarrant, Darran O'Connor, Jeroen Heijmans, Mireille Snel, Tesa Severson, Astrid Bosma, Magali Michaut, Lorenza Mittempergher, Suet-Feung Chin, Thierry Dubois, William Gallagher, Carlos Caldas, Rene Bernards, Iris Simon, RATHER Consortium. Development of comprehensive molecular portraits of lobular breast cancer within the RATHER (Rational Therapy for Breast Cancer) Consortium. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1218. doi:10.1158/1538-7445.AM2013-1218

International Journal of Cancer

To date, no systematic analyses are available assessing concordance of molecular classifications ... more To date, no systematic analyses are available assessing concordance of molecular classifications between primary tumors (PT) and matched liver metastases (LM) of metastatic colorectal cancer (mCRC). We investigated concordance between PT and

Experimental and Molecular Therapeutics

Journal of Clinical Oncology

High-throughput, Jan 6, 2017

Colorectal cancer patients with the (p.V600E) mutation have poor prognosis in metastatic setting.... more Colorectal cancer patients with the (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 -mutation-like subtype (accuracy 91.1%). Further experiments repurposed drug Vinorelbine as specifically lethal to this -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 -mutation-like subtype. 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 -mutation-like subtype group, 50% of tumours were known mutants, and 50% were wild-type. The stability of the ...