Significance and limitations of the use of next-generation sequencing technologies for detecting mutational signatures.

Next generation sequencing technologies (NGS) have been critical in characterizing the genomic landscape and untangling the genetic heterogeneity of human cancer. Since its advent, NGS has played a pivotal role in identifying the patterns of somatic mutations imprinted on cancer genomes and in deciphering the signatures of the mutational processes that have generated these patterns. Mutational signatures serve as phenotypic molecular footprints of exposures to environmental factors as well as deficiency and infidelity of DNA replication and repair pathways. Since the first roadmap of mutational signatures in human cancer was generated from whole-genome and whole-exome sequencing data, there has been a growing interest to extract mutational signatures from other NGS technologies such as targeted panel sequencing, RNA sequencing, single-cell sequencing, duplex sequencing, reduced representation sequencing, and long-read sequencing. Many of these technologies have their inherent sequencing biases and produce technical artifacts that can confound the extraction of reliable and interpretable mutational signatures. In this review, we highlight the relevance, limitations, and prospects of using different NGS technologies for examining mutational patterns and for deciphering mutational signatures.
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