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Assessing the clinical value of targeted massively parallel sequencing in a longitudinal, prospective population-based study of cancer patients.

Wong SQ, Fellowes A, Doig K, Ellul J, Bosma TJ, Irwin D, Vedururu R, Tan AY, Weiss J, Chan KS, Lucas M, Thomas DM, Dobrovic A, Parisot JP, Fox SB - Br. J. Cancer (2015)

Bottom Line: A subset of patients was validated for canonical mutations using the Agena Bioscience MassARRAY system with 100% concordance.Whereas the prevalence of mutations was consistent with other institutionally based series for some tumour streams (breast carcinoma and colorectal adenocarcinoma), others were different (lung adenocarcinoma and head and neck squamous cell carcinoma), which has significant implications for health economic modelling of particular targeted agents.Actionable mutations in tumours not usually thought to harbour such genetic changes were also identified.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Division of Cancer Research, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia.

ABSTRACT

Introduction: Recent discoveries in cancer research have revealed a plethora of clinically actionable mutations that provide therapeutic, prognostic and predictive benefit to patients. The feasibility of screening mutations as part of the routine clinical care of patients remains relatively unexplored as the demonstration of massively parallel sequencing (MPS) of tumours in the general population is required to assess its value towards the health-care system.

Methods: Cancer 2015 study is a large-scale, prospective, multisite cohort of newly diagnosed cancer patients from Victoria, Australia with 1094 patients recruited. MPS was performed using the Illumina TruSeq Amplicon Cancer Panel.

Results: Overall, 854 patients were successfully sequenced for 48 common cancer genes. Accurate determination of clinically relevant mutations was possible including in less characterised cancer types; however, technical limitations including formalin-induced sequencing artefacts were uncovered. Applying strict filtering criteria, clinically relevant mutations were identified in 63% of patients, with 26% of patients displaying a mutation with therapeutic implications. A subset of patients was validated for canonical mutations using the Agena Bioscience MassARRAY system with 100% concordance. Whereas the prevalence of mutations was consistent with other institutionally based series for some tumour streams (breast carcinoma and colorectal adenocarcinoma), others were different (lung adenocarcinoma and head and neck squamous cell carcinoma), which has significant implications for health economic modelling of particular targeted agents. Actionable mutations in tumours not usually thought to harbour such genetic changes were also identified.

Conclusions: Reliable delivery of a diagnostic assay able to screen for a range of actionable mutations in this cohort was achieved, opening unexpected avenues for investigation and treatment of cancer patients.

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Related in: MedlinePlus

Mutational landscape of actionable mutations and pathways in the Cancer 2015 cohort. (A) Landscape of actionable mutations from the Cancer 2015 cohort. Tracks are (from outside in): Gene name, Exon label with type of cancer gene (green: tumour-suppressor gene, orange: oncogene), exon size shown as a blue tile, amplicon covered by the TSACP platform (grey tiles) and variants occurring >10 times in the filtered data. Variants are colour-coded based on the type of actionable mutation: (I) sensitive or resistant to an, approved drug/treatment (IA) or experimental drug/treatment (IB). (II) Provides prognostic or diagnostic information based on significant functional or clinically characterisation, (III) Unknown significance due to lack of biological/functional evidence or (IV) benign. Recurrent mutations are also highlighted. (B) Tumour classification by the actionable pathway. Variants from patients were stratified based on known associated pathways, detailed in Supplementary Table 1. The overall percentage of variants in any particular pathway is shown in the x axis. In some cases, a gene was associated with multiple pathways, for example, NRAS for PI3K-Akt and Ras-Raf pathways. In some cases, multiple genes were mutated in the same pathway. Multiple variants in the same gene from the same patient were only counted once. Only tumour streams with more than five patients mutated in a pathway are shown, with other cases combined to the other subset.
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fig2: Mutational landscape of actionable mutations and pathways in the Cancer 2015 cohort. (A) Landscape of actionable mutations from the Cancer 2015 cohort. Tracks are (from outside in): Gene name, Exon label with type of cancer gene (green: tumour-suppressor gene, orange: oncogene), exon size shown as a blue tile, amplicon covered by the TSACP platform (grey tiles) and variants occurring >10 times in the filtered data. Variants are colour-coded based on the type of actionable mutation: (I) sensitive or resistant to an, approved drug/treatment (IA) or experimental drug/treatment (IB). (II) Provides prognostic or diagnostic information based on significant functional or clinically characterisation, (III) Unknown significance due to lack of biological/functional evidence or (IV) benign. Recurrent mutations are also highlighted. (B) Tumour classification by the actionable pathway. Variants from patients were stratified based on known associated pathways, detailed in Supplementary Table 1. The overall percentage of variants in any particular pathway is shown in the x axis. In some cases, a gene was associated with multiple pathways, for example, NRAS for PI3K-Akt and Ras-Raf pathways. In some cases, multiple genes were mutated in the same pathway. Multiple variants in the same gene from the same patient were only counted once. Only tumour streams with more than five patients mutated in a pathway are shown, with other cases combined to the other subset.

Mentions: Classification of curated mutations was resolved around a stratification approach adapted by Wagle et al (2012) using the frequency of mutations according to gene, type of mutation and the type of actionable mutation (Figure 2A). Approximately 63% (534 out of 854) of patients had at least one clinically relevant mutation (Classes I–III). Overall, 31% of patients had a variant of prognostic/diagnostic significance (Class II), with 26% having a variant that provides sensitivity or resistant information to an approved or preclinical drug available in principle (Class IA/IB). However, there were a substantial number of patients (34%) who had a variant of unknown clinical significance (Class III).


Assessing the clinical value of targeted massively parallel sequencing in a longitudinal, prospective population-based study of cancer patients.

Wong SQ, Fellowes A, Doig K, Ellul J, Bosma TJ, Irwin D, Vedururu R, Tan AY, Weiss J, Chan KS, Lucas M, Thomas DM, Dobrovic A, Parisot JP, Fox SB - Br. J. Cancer (2015)

Mutational landscape of actionable mutations and pathways in the Cancer 2015 cohort. (A) Landscape of actionable mutations from the Cancer 2015 cohort. Tracks are (from outside in): Gene name, Exon label with type of cancer gene (green: tumour-suppressor gene, orange: oncogene), exon size shown as a blue tile, amplicon covered by the TSACP platform (grey tiles) and variants occurring >10 times in the filtered data. Variants are colour-coded based on the type of actionable mutation: (I) sensitive or resistant to an, approved drug/treatment (IA) or experimental drug/treatment (IB). (II) Provides prognostic or diagnostic information based on significant functional or clinically characterisation, (III) Unknown significance due to lack of biological/functional evidence or (IV) benign. Recurrent mutations are also highlighted. (B) Tumour classification by the actionable pathway. Variants from patients were stratified based on known associated pathways, detailed in Supplementary Table 1. The overall percentage of variants in any particular pathway is shown in the x axis. In some cases, a gene was associated with multiple pathways, for example, NRAS for PI3K-Akt and Ras-Raf pathways. In some cases, multiple genes were mutated in the same pathway. Multiple variants in the same gene from the same patient were only counted once. Only tumour streams with more than five patients mutated in a pathway are shown, with other cases combined to the other subset.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4402458&req=5

fig2: Mutational landscape of actionable mutations and pathways in the Cancer 2015 cohort. (A) Landscape of actionable mutations from the Cancer 2015 cohort. Tracks are (from outside in): Gene name, Exon label with type of cancer gene (green: tumour-suppressor gene, orange: oncogene), exon size shown as a blue tile, amplicon covered by the TSACP platform (grey tiles) and variants occurring >10 times in the filtered data. Variants are colour-coded based on the type of actionable mutation: (I) sensitive or resistant to an, approved drug/treatment (IA) or experimental drug/treatment (IB). (II) Provides prognostic or diagnostic information based on significant functional or clinically characterisation, (III) Unknown significance due to lack of biological/functional evidence or (IV) benign. Recurrent mutations are also highlighted. (B) Tumour classification by the actionable pathway. Variants from patients were stratified based on known associated pathways, detailed in Supplementary Table 1. The overall percentage of variants in any particular pathway is shown in the x axis. In some cases, a gene was associated with multiple pathways, for example, NRAS for PI3K-Akt and Ras-Raf pathways. In some cases, multiple genes were mutated in the same pathway. Multiple variants in the same gene from the same patient were only counted once. Only tumour streams with more than five patients mutated in a pathway are shown, with other cases combined to the other subset.
Mentions: Classification of curated mutations was resolved around a stratification approach adapted by Wagle et al (2012) using the frequency of mutations according to gene, type of mutation and the type of actionable mutation (Figure 2A). Approximately 63% (534 out of 854) of patients had at least one clinically relevant mutation (Classes I–III). Overall, 31% of patients had a variant of prognostic/diagnostic significance (Class II), with 26% having a variant that provides sensitivity or resistant information to an approved or preclinical drug available in principle (Class IA/IB). However, there were a substantial number of patients (34%) who had a variant of unknown clinical significance (Class III).

Bottom Line: A subset of patients was validated for canonical mutations using the Agena Bioscience MassARRAY system with 100% concordance.Whereas the prevalence of mutations was consistent with other institutionally based series for some tumour streams (breast carcinoma and colorectal adenocarcinoma), others were different (lung adenocarcinoma and head and neck squamous cell carcinoma), which has significant implications for health economic modelling of particular targeted agents.Actionable mutations in tumours not usually thought to harbour such genetic changes were also identified.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Division of Cancer Research, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia.

ABSTRACT

Introduction: Recent discoveries in cancer research have revealed a plethora of clinically actionable mutations that provide therapeutic, prognostic and predictive benefit to patients. The feasibility of screening mutations as part of the routine clinical care of patients remains relatively unexplored as the demonstration of massively parallel sequencing (MPS) of tumours in the general population is required to assess its value towards the health-care system.

Methods: Cancer 2015 study is a large-scale, prospective, multisite cohort of newly diagnosed cancer patients from Victoria, Australia with 1094 patients recruited. MPS was performed using the Illumina TruSeq Amplicon Cancer Panel.

Results: Overall, 854 patients were successfully sequenced for 48 common cancer genes. Accurate determination of clinically relevant mutations was possible including in less characterised cancer types; however, technical limitations including formalin-induced sequencing artefacts were uncovered. Applying strict filtering criteria, clinically relevant mutations were identified in 63% of patients, with 26% of patients displaying a mutation with therapeutic implications. A subset of patients was validated for canonical mutations using the Agena Bioscience MassARRAY system with 100% concordance. Whereas the prevalence of mutations was consistent with other institutionally based series for some tumour streams (breast carcinoma and colorectal adenocarcinoma), others were different (lung adenocarcinoma and head and neck squamous cell carcinoma), which has significant implications for health economic modelling of particular targeted agents. Actionable mutations in tumours not usually thought to harbour such genetic changes were also identified.

Conclusions: Reliable delivery of a diagnostic assay able to screen for a range of actionable mutations in this cohort was achieved, opening unexpected avenues for investigation and treatment of cancer patients.

Show MeSH
Related in: MedlinePlus