Discovering subclones and their driver genes in tumors sequenced at standard depths

Understanding intratumor heterogeneity and their driver genes is critical to

designing personalized treatments and improving clinical outcomes of cancers. Such

investigations require accurate delineation of the subclonal composition of a tumor, which

to date can only be reliably inferred from deep-sequencing data (>300x depth). The

resulting algorithm from the work presented here, incorporates an adaptive error model

into statistical decomposition of mixed populations, which corrects the mean-variance

dependency of sequencing data at the subclonal level and enables accurate subclonal

discovery in tumors sequenced at standard depths (30-50x). Tested on extensive computer

simulations and real-world data, this new method, named model-based adaptive grouping

of subclones (MAGOS), consistently outperforms existing methods on minimum

sequencing depth, decomposition accuracy and computation efficiency. MAGOS supports

subclone analysis using single nucleotide variants and copy number variants from one or

more samples of an individual tumor. GUST algorithm, on the other hand is a novel method

in detecting the cancer type specific driver genes. Combination of MAGOS and GUST

results can provide insights into cancer progression. Applications of MAGOS and GUST

to whole-exome sequencing data of 33 different cancer types’ samples discovered a

significant association between subclonal diversity and their drivers and patient overall

survival.