Essential genes shape cancer genomes through linear limitation of homozygous deletions

Abstract

The landscape of somatic acquired deletions in cancer cells is shaped by positive and negative selection. Recurrent deletions typically target tumor suppressor, leading to positive selection. Simultaneously, loss of a nearby essential gene can lead to negative selection, and introduce latent vulnerabilities specific to cancer cells. Here we show that, under basic assumptions on positive and negative selection, deletion limitation gives rise to a statistical pattern where the frequency of homozygous deletions decreases approximately linearly between the deletion target gene and the nearest essential genes. Using DNA copy number data from 9,744 human cancer specimens, we demonstrate that linear deletion limitation exists and exposes deletion-limiting genes for seven known deletion targets ( CDKN2A , RB1, PTEN , MAP2K4 , NF1 , SMAD4 , and LINC00290 ). Downstream analysis of pooled CRISPR/Cas9 data provide further evidence of essentiality. Our results provide further insight into how the deletion landscape is shaped and identify potentially targetable vulnerabilities.

DEG 15, an update of the Database of Essential Genes that includes built-in analysis tools

“…An increasing number of essentiality screens are being performed in a context-specific manner. For instance, essential genes for cancer cells can reveal cancer-specific cellular processes, which are targets for cancer drugs ( 50 ). Determination of essential genes of A. baumannii revealed genes required for its infection and survival in the lung ( 24 ).…”

Weighted gene coexpression network analysis identifies critical genes in different subtypes of acute myeloid leukaemia

“…In accordance with these results, the involvement of SLC15A3 in AML progression is not surprising. In cancer, ADAP2 binds to b-tubulin and COPRS, which mediates the stability of microtubules and activates oncogenes [50]. However, there are no results regarding ADAP2 function in AML.…”

On the Relation of Gene Essentiality to Intron Structure: A Computational and Deep Learning Approach

“…Essential genes, those where a single-gene-knockout results in lethality or severe loss of fitness, have been well studied in many bacterial genomes to develop therapeutic targets for pathogens. Now, stemming from the discovery that the loss of an essential-nearby gene can introduce latent-vulnerabilities specific to cancer cells, the study of human-essential genes has come of practical importance 1 . This importance is magnified as essential genes for cancer-cell growth are found to be located close to target-deletion genes 1 .…”

“…Now, stemming from the discovery that the loss of an essential-nearby gene can introduce latent-vulnerabilities specific to cancer cells, the study of human-essential genes has come of practical importance 1 . This importance is magnified as essential genes for cancer-cell growth are found to be located close to target-deletion genes 1 . Therefore, identifying properties of essential genes can further therapeutic developments.…”

“…A positive association between singleton, highly-expressed, developmental genes and essentiality is observed, suggesting that essential genes resist duplication events 7,9 . Stemming from these results, copy-number-variants, which result from unequal-crossing-over, retroposition, or chromosomal duplication, were included in efforts to identify essential human genes 1,10 . Intron loss, occurring at an especially greater rate after gene duplication, is the most frequent copy-number-variant in humans, suggesting a likely link between introns and gene-essentiality 11,12 .…”