We have shown that MuTect is much more sensitive at a given specificity than competing methods, allowing us to more comprehensively characterize the landscape of somatic mutations, particularly those present in a small fraction of cancer cells. Moreover, this can be done with standard sequencing depths enabling analysis of the large datasets that are being generated worldwide. Analysis of subclonal mutations and changes in the fractions of cancer cells which harbor them is a powerful way to study the evolution of subclones as they progress during treatment, metastasis and relapse11,12,44,45. In particular, we demonstrated that the presence of subclonal mutations in genes involved in driving chronic lymphocytic leukemia (CLL) is an independent prognostic factor beyond the currently used clinical parameters13. In fact, using standard exome sequencing data, we were able to detect mutations present in as low as 10% of cancer cells, representing an expected allele fraction of 0.05 (assuming a heterozygous mutations in a diploid region) even before accounting for stromal contamination, which appear to have an effect on time to therapy13.
