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

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

Fischer, Anja; Lersch, Robert; de Andrade Krätzig, Niklas; Strong, Alexander; Friedrich, Mathias J; Weber, Julia; Engleitner, Thomas; Öllinger, Rupert; Yen, Hsi-Yu; Kohlhofer, Ursula; Gonzalez-Menendez, Irene; Sailer, David; Kogan, Liz; Lahnalampi, Mari; Laukkanen, Saara; Kaltenbacher, Thorsten; Klement, Christine; Rezaei, Majdaddin; Ammon, Tim; Montero, Juan J; Schneider, Günter; Mayerle, Julia; Heikenwälder, Mathias; Schmidt-Supprian, Marc; Quintanilla-Martinez, Leticia; Steiger, Katja; Liu, P...     »

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.      «

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...     »