Profound Tissue Specificity in Proliferation Control Underlies Cancer Drivers and Aneuploidy Patterns

Abstract

Genomics has provided a detailed structural description of the cancer genome. Identifying oncogenic drivers that work primarily through dosage changes is a current challenge. Unrestrained proliferation is a critical hallmark of cancer. We constructed modular, barcoded libraries of human open reading frames (ORFs) and performed screens for proliferation regulators in multiple cell types. Approximately 10% of genes regulate proliferation, with most performing in an unexpectedly highly tissue-specific manner. Proliferation drivers in a given cell type showed specific enrichment in somatic copy number changes (SCNAs) from cognate tumors and helped predict aneuploidy patterns in those tumors, implying that tissue-type-specific genetic network architectures underlie SCNA and driver selection in different cancers. In vivo screening confirmed these results. We report a substantial contribution to the catalog of SCNA-associated cancer drivers, identifying 147 amplified and 107 deleted genes as potential drivers, and derive insights about the genetic network architecture of aneuploidy in tumors.

Exploring genetic interaction manifolds constructed from rich phenotypes

“…We chose gain-of-function perturbations as they are an effective way of exploring cell states (5,(36)(37)(38), and with CRISPRa are now feasible to implement systematically for quantitative interaction studies. From a previous genome-wide CRISPRa screen, we selected 112 hit genes whose activation enhanced or retarded growth of K562 cells ( Fig.…”

Cancer-type specific aneuploidies hard-wire chromosome-wide gene expression patterns of their tissue of origin

“…Overall, our results indicate that differences of chromosome arm-wide gene expression levels in normal human tissues are enhanced by the acquisition of aneuploidies in the cognate tumors, suggesting a non-oncogenic, tissue-specific physiological basis for clonal expansion. 24 have demonstrated that the inclusion of tissue-specific growth promoting genes strengthens the correlation between chromosome arm loss/gain ratios and the proliferation-driving capability of each chromosome-arm in breast and pancreatic cancers. A general, yet not tissue-specific, role of copy number alterations and metabolic selection pressure was reported by Graham and colleagues 25 .…”

“…Indeed, Sack and colleagues (23) have demonstrated that the inclusion of tissue-specific growth promoting genes strengthens the correlation between chromosome arm loss/gain ratios and the proliferation-driving capability of each chromosome-arm in breast and pancreatic cancers, yet, other aspects of tumor biology, such as immune evasion, invasion and metastasis have to be considered. Graham and colleagues report a general, yet not tissue-specific, role of copy number alterations and metabolic selection pressure (24).…”

Distinct oncogenes drive different genome and epigenome alterations in human mammary epithelial cells

“…Noticeably, cancers of distinct anatomical origins exhibit quite different profiles of genomic and epigenetic anomalies . Recent work, based on human open reading frame library screening in three different cell types to identify proliferation drivers, elegantly showed the existence of a tissue‐specific selection for gains of function and loss of tumor suppressors …”

“…6 Recent work, based on human open reading frame library screening in three different cell types to identify proliferation drivers, elegantly showed the existence of a tissue-specific selection for gains of function and loss of tumor suppressors. 7 In breast cancer, molecular subtypes were defined on the basis of RNA expression, as well as of genomic anomalies and DNA methylation differences. [8][9][10][11] Although definitive proof remains missing, it is generally proposed that the genetic and epigenetic differences in different breast tumor subtypes are dictated by distinct cell types of origin.…”