Exploiting rare driver mutations for precision cancer medicine.

Catalyzed by the ability to develop precision therapies targeting the unique genetic changes that drive individual tumors, sequencing patients' tumor genomes is an increasingly common practice in oncology. In most cancer types, however, a limited number of common mutations are accompanied by a plethora of low-frequency variants whose functional consequences and clinical actionability are often unknown. We here illustrate that this 'long tail' of infrequent molecular alterations includes oncogenic drivers of biological significance that can be the genetic basis of extraordinary responses to systemic cancer therapies. Furthermore, we review current strategies to identify, prioritize, and experimentally validate novel long-tail driver mutations, efforts that will likely provide new insights into the clinically actionable genome and improve outcomes for patients.