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

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 enrich-ment 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 malig-nancies, 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 under-standing of quasi-insufficiency in cancer and gives multifaceted insights into tumor evolution and the tissue-specific effects of non-coding mutations.

Automated summary

Compared to the loss of tumor-suppressor function, the effects of discrete gene dysregulations caused by non-coding genome alterations are poorly understood. In this study, by perturbing the regulatory genome in mice, the researchers reveal the pervasive roles of subtle gene expression variation in cancer evolution. They identified extensive quasi-insufficiency across different tumors and discovered diverse context dependencies. The study provides important insights into tumor evolution and the tissue-specific effects of non-coding mutations.