In vivo interrogation of regulatory genomes reveals extensive quasi-insufficiency in cancer evolution

Anja Fischer, Robert Lersch, Niklas de Andrade Krätzig, Alexander Strong, Mathias J. Friedrich, Julia Weber, Thomas Engleitner, Rupert Öllinger, Hsi Yu Yen, Ursula Kohlhofer, Irene Gonzalez-Menendez, David Sailer, Liz Kogan, Mari Lahnalampi, Saara Laukkanen, Thorsten Kaltenbacher, Christine Klement, Majdaddin Rezaei, Tim Ammon, Juan J. MonteroGünter Schneider, Julia Mayerle, Mathias Heikenwälder, Marc Schmidt-Supprian, Leticia Quintanilla-Martinez, Katja Steiger, Pentao Liu, Juan Cadiñanos, George S. Vassiliou, Dieter Saur, Olli Lohi, Merja Heinäniemi, Nathalie Conte, Allan Bradley, Lena Rad, Roland Rad

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In contrast to mono- or biallelic loss of tumor-suppressor function, effects of discrete gene dysregulations, as caused by non-coding (epi)genome alterations, are poorly understood. Here, by perturbing the regulatory genome in mice, we uncover pervasive roles of subtle gene expression variation in cancer evolution. Genome-wide screens characterizing 1,450 tumors revealed that such quasi-insufficiency is extensive across entities and displays diverse context dependencies, such as distinct cell-of-origin associations in T-ALL subtypes. We compile catalogs of non-coding regions linked to quasi-insufficiency, show their enrichment with human cancer risk variants, and provide functional insights by engineering regulatory alterations in mice. As such, kilo-/megabase deletions in a Bcl11b-linked non-coding region triggered aggressive malignancies, with allele-specific tumor spectra reflecting gradual gene dysregulations through modular and cell-type-specific enhancer activities. Our study constitutes a first survey toward a systems-level understanding of quasi-insufficiency in cancer and gives multifaceted insights into tumor evolution and the tissue-specific effects of non-coding mutations.

Original languageEnglish
Article number100276
Number of pages25
JournalCell Genomics
Issue number3
Publication statusPublished - 8 Mar 2023
Publication typeA1 Journal article-refereed


  • Bcl11b
  • cancer evolution
  • genetic screening
  • genomics
  • leukemia
  • lymphoma
  • mouse
  • non-coding genome
  • PiggyBac
  • quasi-insufficiency

Publication forum classification

  • Publication forum level 1

ASJC Scopus subject areas

  • Genetics
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)


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