Analytical Approaches and Applications of Whole Exome Sequencing (WES) in Oncology
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from the Health category at
25 Jul 2023 02:18:17 am.
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Genomics has revolutionized cancer research, transforming the way we diagnose, treat, and monitor cancer. Among the powerful genetic analysis methods, Whole Exome Sequencing (WES) stands out as a cutting-edge technique that employs sequence capture technology to enrich DNA from the whole exome regions, enabling high-throughput sequencing. WES offers a simpler, more cost-effective, and efficient alternative to whole genome sequencing, with higher target region coverage, facilitating accurate variant detection.
Enhancing Cancer Genomic Research with WES
Mutations occurring within the whole exome regions of the cancer genome play a pivotal role in tumor development. WES's precise detection of Single Nucleotide Variants (SNVs) and Insertions/Deletions (InDels) efficiently elucidates cancer susceptibility and pathogenicity genes, making it a reliable method for cancer genomic research. Consequently, WES has become the preferred approach for comparing tumor-normal samples.
Tumor Mutational Burden (TMB) Analysis using WES
Tumor Mutational Burden (TMB) quantifies the number of somatic mutations per megabase (MB) of the longest transcript sequence. Although TMB shows potential as a biomarker for immunotherapy in solid tumors, consensus on the optimal TMB threshold for specific tumor types remains elusive. Refining the TMB threshold could significantly enhance therapeutic approaches for certain refractory tumors. Researchers have conducted WES-based analyses to explore the relationship between WES and TMB across 32 cancer types. They found that certain cancers, such as uterine, bladder, and colon cancers, exhibit greater variability in TMB values compared to lung and head cancers.
Homologous Recombination Defect (HRD) Analysis using WES
Homologous recombination (HR) is a crucial process involved in DNA repair, replication, meiotic chromosome segregation, and telomere maintenance. HRD can result from various factors, including germline or somatic mutations in HR-related genes and epigenetic inactivation. Notably, somatic mutations in BRCA1 and BRCA2, encoding homologous recombination proteins, have been extensively studied in HRD due to their association with hereditary breast and ovarian cancers. WES facilitates the detection of HRD status in cancer cells, enabling its use as a biomarker for individualized tumor treatment. Identifying HRD becomes crucial in guiding drug therapy and monitoring patient prognosis. In one study, WES analysis of 9321 patients with colorectal cancer (CRC) revealed that 13.6% of cases were HRD positive, demonstrating higher incidence in MSI tumors compared to MSS tumors. The study also found that overall survival was longer in patients with MSS and HRD tumors than in those with MSS and HRP (HRP=homologous recombination proficient) tumors, highlighting HRD as a specific marker of MSS CRC tumors with distinct molecular and prognostic features.
Microsatellite Instability Analysis (MSI) using WES
Microsatellites (MS) are short tandem repeats (STR) or simple sequence repeats (SSR) consisting of 1-6 base pair repeating units distributed throughout eukaryotic genomes, including coding and non-coding regions. Numerous studies have shown that MSI is closely associated with tumorigenesis and serves as a crucial molecular marker for prognostication and development of adjuvant treatment plans in solid tumors, such as colorectal cancer. WES enables MSI analysis at the somatic cell level, providing insights into the microsatellite status of tumor samples. In a study of 96 constitutional mismatch repair deficiency (CMMRD) cancers and 8 normal tissues, researchers found that 17 of the 96 CMMRD tumors exhibited high MSI status (MSI-H), independent of the specific mismatch repair gene mutation. Interestingly, different tumors within the same patient displayed varying MSI classifications, correlating with tissue specificity. For instance, gastrointestinal cancers exhibited the highest percentage of MSI-H compared to brain tumors.
Conclusion
Whole Exome Sequencing has emerged as a powerful tool in cancer research, providing valuable insights into diagnosis, treatment, and monitoring through the identification of tumor biomarkers. The method's cost-effectiveness and efficiency make it highly applicable in tumor mechanism studies, and its future holds great promise in advancing molecular biology and personalized cancer treatment. As genomics continues to evolve, WES will undoubtedly play a pivotal role in unraveling the complexities of cancer and contributing to improved patient outcomes.
Tags: WES
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