6. Emerging clinically-relevant applications of ultra-sensitive mutation detection

Abstract

As the cost of next-generation sequencing decreases, ultra-deep targeted sequencing (UTS) provides an efficient approach for identifying low-frequency somatic mutations, allowing for earlier detection of the tumorigenic events responsible for cancer initiation and progression. We developed and experimentally validated a UTS-based pipeline to detect very-low-frequency mutations with in-silico error suppression. The potential utilities of ultra-sensitive mutation detection have been demonstrated in several recent clinically-relevant studies: 1) by comparing de novo mutations of individual-matched sun-exposed and non-sun-exposed normal skin areas, we identified a number of mutational features specifically associated with UV, including a 'mutation exempt' genomic region in TP53 that are almost never mutated during aging in non-sun-exposed skin but become highly mutable in sun-exposed skin [1]; 2) in a study of pelvic washing collected during radical-cystectomy of bladder cancers, we found the levels of residual tumor cells in pelvic washing are associated with tumor histology, and might be a potential biomarker for predicting cancer recurrence [2]; 3) to understand the mechanism of low-level tumor contamination in the histologically normal tissue adjacent to tumor, we designed and performed a special-collection procedure and found the tumor contamination in normal tissue was associated with inappropriate handling during pathology grossing and tissue procurement [3].