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Using high-throughput sequencing transcriptome data for INDEL detection: challenges for cancer drug discovery
Gabriel Wajnberg1, Fabio Passetti1
1a Laboratory of Functional Genomics and Bioinformatics, Oswaldo Cruz Institute , Fundação Oswaldo Cruz (FIOCRUZ) , Rio de Janeiro , RJ , Brazil.
Introduction:
A cancer cell is a mosaic of genomic and epigenomic alterations. Distinct cancer molecular signatures can be observed depending on tumor type or patient genetic background. One type of genomic alteration is the insertion and/or deletion (INDEL) of nucleotides in the DNA sequence, which may vary in length, and may change the encoded protein or modify protein domains. INDELs are associated to a large number of diseases and their detection is done based on low-throughput techniques. However, high-throughput sequencing has also started to be used for detection of novel disease-causing INDELs. This search may identify novel drug targets.
Areas Covered:
This review presents examples of using high-throughput sequencing (DNA-Seq and RNA-Seq) to investigate the incidence of INDELs in coding regions of human genes. Some of these examples successfully utilized RNA-Seq to identify INDELs associated to diseases. In addition, other studies have described small INDELs related to chemo-resistance or poor outcome of patients, while structural variants were associated with a better clinical outcome.
Expert Opinion:
On average, there is twice as much RNA-Seq data available at the most used repositories for such data compared to DNA-Seq. Therefore, using RNA-Seq data is a promising strategy for studying cancer samples with unknown mechanisms of drug resistance, aiming at the discovery of proteins with potential as novel drug targets.
Insights
High-throughput sequencing, particularly RNA-Seq, aids in identifying insertion/deletion (INDEL) mutations in cancer. This approach can uncover novel drug targets by analyzing cancer cell genomic alterations.
Area of Science:
- Genomics
- Cancer Biology
- Molecular Diagnostics
Background:
- Cancer cells exhibit diverse genomic and epigenomic alterations, forming distinct molecular signatures.
- Insertion/deletion (INDEL) mutations are a key type of genomic alteration, potentially altering protein function and linked to numerous diseases.
- Traditional low-throughput methods for INDEL detection are being complemented by high-throughput sequencing.
Purpose of the Study:
- To review the application of high-throughput sequencing (DNA-Seq and RNA-Seq) for investigating INDELs in human gene coding regions.
- To highlight the potential of RNA-Seq in identifying disease-associated INDELs and novel drug targets.
- To explore the relationship between INDELs and clinical outcomes in cancer patients.
Main Methods:
- Review of studies utilizing DNA-Seq and RNA-Seq for INDEL detection in coding regions.
- Analysis of RNA-Seq data for identifying disease-causing INDELs.
- Examination of associations between small INDELs, structural variants, and patient outcomes.
Main Results:
- RNA-Seq has been successfully employed to identify disease-associated INDELs.
- Small INDELs are linked to chemo-resistance and poor patient outcomes.
- Structural variants may be associated with better clinical outcomes.
Conclusions:
- RNA-Seq data is more abundant than DNA-Seq data in public repositories, making it a valuable resource.
- RNA-Seq is a promising strategy for investigating drug resistance mechanisms in cancer.
- This approach facilitates the discovery of potential novel drug targets through the identification of proteins affected by INDELs.
