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

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.

Triphasic Development of the Genetic Code

“…In a study of 44 solid tumors, evidence suggests that new driver mutations included CNVs, indels, and single nucleotide variations (SNVs), and evidence indicated that a small number of mutations sufficed to confer a neoplastic phenotype. These findings underlined the important role driver-gene mutations play in cancer mortality, yet treatment of driver gene mutants with monoclonal antibody was limited in efficacy . In cases where monoclonal antibodies were ineffective against such mutations, ncAAs may be employed to enhance the affinity of the paratope on the antibody toward the epitope on the antigen; incorporate an alkylating side chain into the paratope to construct a covalent paratope-epitope linkage; or reduce the bulky antibody structure to a stabilized loop containing the paratope in order to expedite tighter paratope-epitope interaction.…”

Comprehensive insights into AML relapse: genetic mutations, clonal evolution, and clinical outcomes

“…Historically, the prognosis for acute myeloid leukemia has been quite poor, and there have been extensive discussions regarding relapse and post-relapse treatment [ 13 ]. Research using NGS methods has focused on identifying driver mutations and understanding how clonal evolution progresses based on these drivers [ 14 ]. Recent studies have suggested the existence of linear evolution and branching evolution when specific AML clones survive during remission to later contribute to relapse [ 15 ].…”

Development, Implementation and Assessment of Molecular Diagnostics by Next Generation Sequencing in Personalized Treatment of Cancer: Experience of a Public Reference Healthcare Hospital

“…The knowledge of a tumor’s genetic profile is crucial to improve clinical-decision making in the patient management. Consequently, laboratories must integrate high-throughput sequencing technologies in routine molecular diagnostics [3]. These allow the simultaneous testing of multiple genetic alterations (point mutations, insertions, deletions, copy number variations and translocations) and quantify molecular subclones by procedures that provide accurate, reliable and cost-effective results.…”