MUTATIONAL SIGNATURES IN CANCER GENOMES π️
𧬠Cancer arises from the accumulation of somatic mutations, each carrying clues about the biological and environmental forces that shaped the tumor’s evolution. With the advent of high-throughput sequencing and large-scale projects like TCGA and ICGC, we have uncovered distinct mutational signatures; recurring patterns of DNA alterations that reflect specific mutagenic processes.
πΉ What are mutational signatures?
They are characteristic patterns of nucleotide substitutions, insertions, or deletions, shaped by mechanisms such as aging, tobacco exposure, UV light, or defective DNA repair. For example, Signature 1 correlates with age-related deamination, while Signature 4 reflects tobacco-induced DNA damage.
πΉ Why do they matter?
Mutational signatures help decode a tumor’s etiology and guide therapy. The presence of Signature 3, linked to homologous recombination deficiency (HRD), predicts sensitivity to PARP inhibitors; drugs used in BRCA-mutated breast and ovarian cancers. They also offer a means to assess carcinogenic exposures at the population level, informing public health prevention strategies.
πΉ What’s next?
Challenges remain in linking signatures to precise biological causes and accounting for tumor heterogeneity. Advances in AI and machine learning are now improving signature extraction, helping us integrate genomic data with clinical outcomes for personalized treatment.
➡️ Future directions include standardizing signature databases and exploring how the tumor microenvironment shapes mutation patterns.
⚠️ In an Oystershell, mutational signatures serve as the genomic “fingerprints” of cancer’s history. They not only deepen our understanding of tumor origins but also unlock pathways toward precision oncology and cancer prevention.
Abubakar Abubakar ✍π»
• Alexandrov LB et al. (2013). Signatures of mutational processes in human cancer. Nature, 500:415-421.
• Nik-Zainal S et al. (2016). Mutational processes molding the genomes of 21 breast cancers. Cell, 149:979-993.
• Alexandrov LB et al. (2020). The repertoire of mutational signatures in human cancer. Nature, 578:94-101.
• Degasperi A et al. (2020). A practical framework and online tool for mutational signature analyses. Genome Medicine, 12:108.
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