Benjamin, D. | Search bioRxiv

bioRxiv2019

Somatic Truth Data from Cell Lineage

Existing somatic benchmark datasets for human sequencing data use germline variants, synthetic methods, or expensive validations, none of which are satisfactory for providing a large collection of true somatic variation across a whole genome. Here we propose a dataset of short somatic mutations, that are validated using a known cell lineage. The dataset contains 56,974 (2,687 unique) Single Nucleotide Variations (SNV), 6,370 (316 unique) small Insertions and Deletions (Indels), and 144 (8 unique) Copy Number Variants (CNV) across 98 in silico mixed truth sets with a high confidence region covering 2.7 gigabases per mixture. The data is publicly available for use as a benchmarking dataset for somatic short mutation discovery pipelines.

bioinformatics↗

bioRxiv2019

mTOR dependent transformed human cells have a distinct set of essential genes from bcr-abl transformed cells

Constitutively active intracellular signaling drives and sustains cancer growth. The mTOR kinase integrates multiple inputs sensing nutrient, energy and growth factor levels to promote protein synthesis and anabolic metabolism, and is hyperactivated in a broad range of cancers. The bcr-abl kinase is a fusion protein generated by chromosomal translocation and gives rise to chronic myeloid leukemia and a small sub-set of leukemias. Using an in vitro transformed murine cell model, we performed shRNA knockdown of 25 genes previously shown to be essential for mTOR dependent oncogenic growth and survival. None of the genes were essential in the bcr-abl transformed line. Interrogation of this gene set in human cancer cell lines revealed that many of these genes were essential in cells dependent on mTOR signaling (defined by sensitivity to pharmacological mTOR inhibition). However, none of the genes were essential in bcr-abl transformed K562 cells that are insensitive to mTOR inhibition. Thus there is a clear divide between cells transformed via bcr-abl directed oncogenesis and other modes of transformation where mTOR, due to its central role in regulating cell growth and metabolism, is recruited as part of an oncogenic program. These validated hits represent a set of genes essential for executing critical functions downstream of mTOR and may be novel therapeutic targets for cancer.

cell biology↗