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Next Generation Sequencing and Cancer Treatment




  •                   Next Generation Sequencing and Cancer Treatment

    Mahnoor Jamil1, Sonia Zulfiqar1, Shakra Jamil2, Rahil Shahzad2, Dr. Muhammad Zaffar Iqbal2

    1. Centre of Agricultural Biochemistry and Biotechnology, University of Agriculture, Faisalabad
    2. Agricultural Biotechnology Research Institute, AARI, Faisalabad

    Cancer is a group of diseases which involves abnormal cell growth with the potential to spread to other parts of the body. It is a complex disease caused by various genetic and environmental factors and accounts for one in eight deaths worldwide. This significant global burden of cancer has emphasized on making efforts to determine prevention strategies, early detection, and successful management of patients diagnosed with cancer. Early detection and successful treatment of cancer are considered important factors in reducing mortality rate. Moreover, accurate and early diagnosis of cancer is necessary so that an appropriate treatment can be given to the individual patient. In this regard, new DNA sequencing technologies will have a significant impact on the detection, management and treatment of disease.

    1.    Next-Generation Sequencing

    Next-generation sequencing (NGS) is one of the most significant technological advances in the biological sciences of the last 30 years. NGS broadly describes those technologies that have the ability to massively parallel sequence millions of DNA templates.  From a clinical point of view, there is great potential for NGS in the management and treatment of human health.  Medical research has embraced this technology and the cancer field is major focus. The sensitivity, speed and reduced cost per sample make NGS a highly attractive platform for various purposes as compared to other sequencing technologies. Moreover, as more genetic determinants of cancer are being identified, there is a greater need to adopt multi-gene assays that can quickly and reliably sequence complete genes from individual patient samples.

    1.1 NGS Approaches

    NGS approaches are concerned with either DNA analysis or RNA analysis. DNA sequencing includes whole-genome sequencing (WGS), whole-exome sequencing (WES) and targeted sequencing. WGS is linked to sequencing of the entire genome while WES focuses on the coding regions (exons) of a genome. The advantages of WES over WGS reduced cost and time. RNA sequencing on the other hand facilitates the detection of transcripts, post-transcriptional modifications, gene fusion, mutations/single-nucleotide polymorphisms (SNPs) and changes in gene expression. In case of RNA sequencing, the extracted RNA is first enriched, reverse-transcribed into complementary DNA and then finally this cDNA is processed.

    1.2 Advantages

    NGS holds many advantages, such as the ability to fully sequence all types of mutations for a large number of genes (hundreds to thousands), high sensitivity, high speed and relatively low cost as compared to the other sequencing technologies. The sensitivity of NGS is much higher than Sanger sequencing i.e. detection of 2% –10% versus 15% –25% allele frequency, respectively and allows quantitative evaluation of the mutated allele. It has played a major role in understanding various diseases at molecular level. Briefly, we can say that next generation sequencing has overcome the limitations caused by conventional DNA sequencing.

    2.    Next generation sequencing and oncology

    There are three general ways in which NGS can aid a clinician. The first is with diagnosis; tumor subtypes that only a few years ago were defined by morphological criteria are now defined by genetic mutations. Now, we can diagnose the cancer by detecting these mutations. The second is finding an appropriate “targeted therapy” for individual patient, as an increasing number of therapies have indications based on DNA sequencing results. The third point at which clinicians stand to be benefited from NGS is when a patient stops responding to a targeted therapy with known resistance mutations.

    2.1 Early detection

    Early detection of cancer is important for reducing the mortality rate and NGS has played a major role in this respect. Molecular characterization of tumors prior to therapy selection has greatly improved the personalized treatment of individual patients. NGS is a key player in cancer diagnostics. Application of NGS for cancer diagnosis has greatly improved the level of understanding of this disease. NGS can help in detecting the genetic mutations which are associated with tumor formation and its progression. The higher sensitivity of NGS has made this strategy conducive for the analysis of mutations in starting samples which contain highly fragmented and lower levels of DNA. NGS can simultaneously detect deletions, insertions, copy number alterations and translocations in all known cancer-related genes. Rare somatic mutations can also be better identified and distinguished from germline mutations. The somatic alterations of cancer genomes identified by NGS constitute the “genetic fingerprint” of the cancer and determine how each cancer occurs and behaves. Some genomic alterations causing cancer are present at very low levels in clinical samples isolated from patients. Thus here NGS employs high base coverage and results in a higher sensitivity mutations appearing in tumor cells. The technology may represent a revolution in cancer biology and medicine by providing information for the design of specific targeted drugs and a better prediction of clinical results.

    2.2 Cancer management

    There are many advantages of using NGS in the management of cancer. Data generated from the complete molecular profiling of the cancer patient genome can be used for the accurate molecular diagnosis, classification of cancer types, to predict individual prognosis and likely patient’s treatment response. Thus, it is believed that NGS provides a faster, less invasive but more clinically useful tool for diagnostics and treatment monitoring.

    2.3 Evaluation of treatment efficiency

    The efficiency of cancer treatment can be evaluated by MRD. MRD is defined as the small number of cancer cells that persist in a patient during or after treatment, even though clinical and microscopic examinations confirm complete absence and even the patient shows no signs or symptoms of disease. MRD detection and quantification are used for the evaluation of treatment efficiency, patient-risk stratification and long-term outcome predictions. NGS has played its role here too. NGS approaches allow for searching not only for known mutations but also for all clonal gene mutations and rearrangements present in diagnostic samples to understand the possible evolution of MRD better. In addition, the NGS approaches enable the analysis of genetic diversity which may contribute to our current knowledge of disease biology.

     

                     

    Summary of workflow for NGS in oncology

    3.    Future prospect

    It is believed that soon every patient will have their cancer genomes sequenced multiple times so that their disease progression can be monitored easily and timely, thus enabling an accurate molecular subtyping of disease and the rational use of molecularly guided therapies. As technology advances, NGS has the potential to make the future of genome sequencing an integral aspect of personalized medicine.

    4.    Conclusion

    At present, the clinical utility of comprehensive genomic profiling with the NGS is under evaluation, so that this technology can be introduced in clinical guidelines for cancer management. NGS might improve patient care, guiding them toward specific screening programs and targeted therapies with more accuracy and specificity than traditional sequencing methods, even if other many studies are needed. Broadly, clinicians and researchers will need to make efforts to advance the integration of genomic information and clinical phenotypes and enable precision cancer medicine through NGS approaches.

    5.    References

    • Guan YF, Li GR, Wang RJ & Peng Y. (2012). Application of next-generation sequencing in clinical oncology to advance personalized treatment of cancer. Chinese journal of cancer, 31(10), 463-470.
    • Cronin M, Ross JS. (2011) .Comprehensive next-generation cancer genome sequencing in the era of targeted therapy and personalized oncology. Biomarkers in medicine. 5(3), 293-305.
    • Ross JS, Cronin M. (2011). Whole cancer genome sequencing by next-generation methods. American journal of clinical pathology 136(4), 527-539.
    • Simona Serratì ,Simona De Summa, Brunella Pilato, Daniela Petriella, Rosanna Lacalamita, Stefania Tommasi and Rosamaria Pinto. (2016). Next-generation sequencing: advances and applications in cancer diagnosis. Onco-targets and therapy, 9, 7355-7365.
    • Jeffrey Gagan and Eliezer M. Van Allen. (2015). Next-generation sequencing to guide cancer therapy. Genomic medicine ,7(1),80

     

     

     

    About Rahil Shahzad

    I belong to District Sialkot. I am MSc (Hons) in Plant Breeding and Genetics, worked as Agriculture Officer Daska, Assistant Research Officer (Maize and Millet's Research Officer and Agricultural Biotechnology Research Institute, AARI, Faisalabad).

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