Abstract
Mutational signatures provide a powerful alternative for understanding the pathophysiology of cancer. Currently, experimental efforts aimed at validating and understanding the etiologies of cancer-derived mutational signatures are underway. In this review, we highlight key aspects of mutational signature experimental design and describe the analytical framework. We suggest guidelines and quality control measures for handling whole-genome sequencing data for mutational signature analyses and discuss pitfalls in interpretation. We envision that improved next-generation sequencing technologies and molecular cell biology approaches will usher in the next generation of studies into the etiologies and mechanisms of mutational patterns uncovered in cancers.