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. 2018 Mar 23;13(3):e0194790.
doi: 10.1371/journal.pone.0194790. eCollection 2018.

Novel putative drivers revealed by targeted exome sequencing of advanced solid tumors

Antonio Pannuti  1 , Aleksandra Filipovic  2 , Chindo Hicks  3   4 , Elliot Lefkowitz  5   6 , Travis Ptacek  5   6 , Justin Stebbing  2 , Lucio Miele  1   3
Affiliations

Novel putative drivers revealed by targeted exome sequencing of advanced solid tumors

Antonio Pannuti et al. PLoS One. .

Abstract

Next generation sequencing (NGS) is becoming increasingly integrated into oncological practice and clinical research. NGS methods have also provided evidence for clonal evolution of cancers during disease progression and treatment. The number of variants associated with response to specific therapeutic agents keeps increasing. However, the identification of novel driver mutations as opposed to passenger (phenotypically silent or clinically irrelevant) mutations remains a major challenge. We conducted targeted exome sequencing of advanced solid tumors from 44 pre-treated patients with solid tumors including breast, colorectal and lung carcinomas, neuroendocrine tumors, sarcomas and others. We catalogued established driver mutations and putative new drivers as predicted by two distinct algorithms. The established drivers we detected were consistent with published observations. However, we also detected a significant number of mutations with driver potential never described before in each tumor type we studied. These putative drivers belong to key cell fate regulatory networks, including potentially druggable pathways. Should our observations be confirmed, they would support the hypothesis that new driver mutations are selected by treatment in clinically aggressive tumors, and indicate a need for longitudinal genomic testing of solid tumors to inform second line cancer treatment.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Left Panel: variants obtained from exome sequencing of tumor samples from Triple Negative Breast Cancer (TNBC) patients.
Genes were grouped based on relevant biological activities/pathways. Right Panel: Variants identified as potential drivers (red: high-confidence drivers; gold: lower confidence drivers. Inset: Color coding scheme for types of mutations (mis-sense, termination, splice site, in-frame deletion), confidence of driver likelihood (high-confidence, lower confidence). Asterisks indicate mutations present in the COSMIC (Catalogue of Somatic Mutations in Cancer) database. The same coding scheme is used in Figs 2–5.
Fig 2
Fig 2
A) Left Panel: variants obtained from exome sequencing of tumor samples from Her2-enriched Breast Cancer (HER2+ BRC) patients. Right Panel: Variants identified as potential drivers. B) Left Panel: variants obtained from exome sequencing of tumor samples from ER positive Breast Cancer (ER+ BRC) patients. Right Panel: Variants identified as potential drivers. Color codes are as in Fig 1.
Fig 3
Fig 3. Left Panel: variants obtained from exome sequencing of tumor samples from Colorectal Cancer (CRC) patients.
Right Panel: Variants identified as potential drivers. Color codes are as in Fig 1.
Fig 4
Fig 4
A) Left Panel: variants obtained from exome sequencing of tumor samples from Lung Adenocarcinoma (LUAD) patients, Right Panel: Variants identified as potential drivers. B) Left Panel: variants obtained from exome sequencing of tumor samples from Squamous Cell Carcinoma (SCC) patients. Right Panel: Variants identified as potential drivers. C) Left Panel: variants obtained from exome sequencing of tumor samples from Soft Tissue Sarcoma (SRC) patients. Right Panel: Variants identified as potential drivers. Color codes are as in Fig 1.
Fig 5
Fig 5
A) Left Panel: variants obtained from exome sequencing of tumor samples from Neuroendocrine Tumors (NET) patients. Right Panel: Variants identified as potential drivers. B) Left Panel: variants obtained from exome sequencing of tumor samples from patients with Carcinomas of Unknown Primary Origin (CUPO). Right Panel: Variants identified as potential drivers. Color codes are as in Fig 1.
Fig 6
Fig 6. Absolute numbers of previously described and putative drivers identified in this study in different tumor types.
Inset: color coding reflecting tumor types. Abbreviations: TNBC (Triple Negative Breast Cancer), HER2+BC (Her2-enriched Breast Cancers), ER+BC (ER-positive Breast Cancer), CRC (Colorectal Cancer), LUAD (Lung Adenocarcinoma), LUSC (Lung Squamous Cell Carcinoma), SCC (Squamous Cell Carcinoma), SRC (Soft Tissue Sarcoma), NET (Neuroendocrine Tumor), TC (Thymic Carcinoma), GC (Gastric Cancer), SIGRCA/KRUK (Signet Ring Adenocarcinoma/Krukenberg Cell Tumor), CUPO (Carcinoma of Unknown Primary Origin).
Fig 7
Fig 7. Previously described and putative drivers identified in this study grouped by functional classes or biological pathways.
Pathway or functional class assignment was based on Gene Ontology supplemented by individual PathCards searches (http://pathcards.genecards.org/) for each gene. Inset: color coding reflecting tumor types. Abbreviations: TNBC (Triple Negative Breast Cancer), HER2+BC (Her2-enriched Breast Cancers), ER+BC (ER-positive Breast Cancer), CRC (Colorectal Cancer), LUAD (Lung Adenocarcinoma), LUSC (Lung Squamous Cell Carcinoma), SCC (Squamous Cell Carcinoma), SRC (Soft Tissue Sarcoma), NET (Neuroendocrine Tumor), TC (Thymic Carcinoma), GC (Gastric Cancer), SIGRCA/KRUK (Signet Ring Adenocarcinoma/Krukenberg Cell Tumor), CUPO (Carcinoma of Unknown Primary Origin).
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