The Importance of Variant Calling in Cancer Studies

Farhad Hariri Akbari

Biotechnical Faculty, Department of Biology, University of Ljubljana, Ljubljana, Slovenia

Cancer is a complex disease driven by genetic mutations that alter normal cellular functions, leading to uncontrolled cell growth, invasion, and metastasis. Understanding the genetic alterations behind cancer is crucial for developing targeted therapies, improving diagnosis, and personalizing treatment approaches. Variant calling, the process of identifying genetic variants such as mutations, insertions, deletions, and structural changes in a genome, plays a pivotal role in cancer studies. It enables researchers to pinpoint the genetic drivers of cancer and offers insights into tumor evolution, resistance mechanisms, and therapeutic strategies.

1. Identification of Somatic Mutations

In cancer, somatic mutations accumulate in tumor cells, contributing to cancer initiation and progression. Variant calling helps to identify these somatic mutations by comparing the DNA sequence of cancerous cells to normal tissue from the same patient. This comparison reveals the mutations that are specific to the tumor, known as somatic variants, which include point mutations, small insertions or deletions (indels), and larger structural changes.

Identifying these somatic mutations is vital for several reasons:

• Understanding Cancer Drivers: Some mutations, known as driver mutations, play a direct role in cancer development. Variant calling allows researchers to identify these mutations and distinguish them from passenger mutations that do not contribute to cancer progression .
• Therapeutic Targets: Many therapies in oncology, particularly targeted therapies, are designed to inhibit proteins produced by genes that harbor cancer-driving mutations. Identifying specific variants allows clinicians to select the most effective treatment for individual patients .

2. Personalized Medicine

Variant calling plays a critical role in personalized medicine, which tailors treatment to the genetic profile of a patient’s tumor. By identifying the specific genetic alterations in a patient's cancer, clinicians can select therapies that target those alterations, improving the efficacy of treatment.

• Precision Oncology: Cancer therapies are increasingly shifting towards precision oncology, where treatments are chosen based on the molecular characteristics of a tumor . For example, if variant calling reveals a mutation in the EGFR gene in a lung cancer patient, targeted therapies that inhibit the mutated EGFR protein can be used, leading to better treatment outcomes .
• Predicting Drug Resistance: Variant calling also helps predict resistance mechanisms that may arise during cancer treatment. Tumors evolve over time, and some may acquire additional mutations that render them resistant to specific drugs. Identifying these mutations early can help in modifying treatment plans before resistance fully develops .

3. Tumor Heterogeneity and Clonal Evolution

Tumor heterogeneity refers to the presence of genetically diverse subpopulations of cells within a tumor. This diversity contributes to therapy resistance and tumor relapse. Variant calling allows researchers to track clonal evolution by identifying the genetic variants that exist within different regions of the tumor or that evolve over time .

• Clonal Architecture: By analyzing variant data, researchers can reconstruct the clonal architecture of a tumor, revealing how different subclones contribute to tumor progression and resistance . This understanding is essential for developing combination therapies that target multiple clones simultaneously.
• Tracking Metastasis: Variant calling can be used to trace the origin of metastatic tumors by identifying common mutations between the primary and metastatic tumors, providing insight into the mechanisms of tumor spread .

4. Biomarker Discovery

Genetic variants identified through variant calling can serve as biomarkers for early detection, prognosis, and response to treatment. Biomarkers are essential in guiding clinical decisions, and variant calling helps discover these genetic markers .

• Prognostic Biomarkers: Some genetic variants are associated with disease progression or patient survival. By identifying these variants, clinicians can better predict the course of the disease and tailor the monitoring and treatment of patients accordingly .
• Predictive Biomarkers: Predictive biomarkers help determine which patients are likely to respond to certain treatments. For instance, identifying mutations in the BRCA1 or BRCA2 genes in breast cancer patients can predict the response to PARP inhibitors, a class of targeted therapies .

5. Whole-Genome and Exome Sequencing in Variant Calling

Advances in high-throughput sequencing technologies, such as whole-genome sequencing (WGS) and whole-exome sequencing (WES), have revolutionized variant calling in cancer research. These technologies allow for the comprehensive analysis of the entire genome or the protein-coding regions (exome), enabling the discovery of novel variants that may not have been previously associated with cancer .

• WGS: Whole-genome sequencing provides a complete picture of all genetic changes in the tumor genome, including non-coding regions that may play a role in gene regulation and tumorigenesis .
• WES: Whole-exome sequencing focuses on coding regions, where most of the known disease-causing mutations occur. It is more cost-effective than WGS while still capturing most clinically relevant variants .

6. Challenges and Future Directions

While variant calling has significantly advanced cancer research, there are challenges in interpreting the vast amount of data generated by sequencing technologies. Some variants are of unknown significance, meaning their impact on cancer is not fully understood. Moreover, distinguishing between driver and passenger mutations can be difficult, especially in highly mutated cancers .

• Bioinformatics Tools: Ongoing advancements in bioinformatics tools for variant calling and analysis are improving the accuracy and speed of detecting clinically relevant variants .
• Integration with Multi-Omics: The integration of variant calling with other omics data, such as transcriptomics (gene expression) and proteomics (protein expression), is helping to build a more comprehensive understanding of cancer biology and treatment response .

Conclusion

Variant calling is an indispensable tool in cancer studies, enabling researchers and clinicians to uncover the genetic alterations driving cancer, personalize treatment strategies, and track tumor evolution. With continued advancements in sequencing technologies and bioinformatics, variant calling will further enhance our understanding of cancer and contribute to the development of more effective and precise therapeutic interventions. By leveraging this powerful approach, we can move closer to a future where cancer is a manageable and even curable disease.

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