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Essential genes shape cancer genomes through linear limitation of homozygous deletions

Pertesi, Maroulio LU ; Ekdahl, Ludvig LU ; Palm, Angelica LU ; Johnsson, Ellinor LU ; Järvstråt, Linnea LU ; Wihlborg, Anna Karin LU and Nilsson, Björn LU (2019) In Communications Biology 2(1).
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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Communications Biology
volume
2
issue
1
article number
262
publisher
Nature Research
external identifiers
  • pmid:31341961
  • scopus:85071177948
ISSN
2399-3642
DOI
10.1038/s42003-019-0517-0
language
English
LU publication?
yes
id
cefb391c-d4b8-4f66-aeaa-ed58ba8dc2bb
date added to LUP
2019-09-09 10:20:33
date last changed
2020-01-13 02:20:24
@article{cefb391c-d4b8-4f66-aeaa-ed58ba8dc2bb,
  abstract     = {<p>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.</p>},
  author       = {Pertesi, Maroulio and Ekdahl, Ludvig and Palm, Angelica and Johnsson, Ellinor and Järvstråt, Linnea and Wihlborg, Anna Karin and Nilsson, Björn},
  issn         = {2399-3642},
  language     = {eng},
  number       = {1},
  publisher    = {Nature Research},
  series       = {Communications Biology},
  title        = {Essential genes shape cancer genomes through linear limitation of homozygous deletions},
  url          = {http://dx.doi.org/10.1038/s42003-019-0517-0},
  doi          = {10.1038/s42003-019-0517-0},
  volume       = {2},
  year         = {2019},
}