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How cells control gene expression is a fundamental question. The relative contribution of protein-level and RNA-level regulation to this process remains unclear. Here, we perform a proteogenomic analysis of tumors and untransformed cells containing somatic copy number alterations (SCNAs). By revealing how cells regulate RNA and protein abundances of genes with SCNAs, we provide insights into the rules of gene regulation. Protein complex genes have a strong protein-level regulation while non-complex genes have a strong RNA-level regulation. Notable exceptions are plasma membrane protein complex genes, which show a weak protein-level regulation and a stronger RNA-level regulation. Strikingly, we find a strong negative association between the degree of RNA-level and protein-level regulation across genes and cellular pathways. Moreover, genes participating in the same pathway show a similar degree of RNA- and protein-level regulation. Pathways including translation, splicing, RNA processing, and mitochondrial function show a stronger protein-level regulation while cell adhesion and migration pathways show a stronger RNA-level regulation. These results suggest that the evolution of gene regulation is shaped by functional constraints and that many cellular pathways tend to evolve one predominant mechanism of gene regulation at the protein level or at the RNA level.

An aneuploid-immune paradox encompasses somatic copy-number alterations (SCNAs), unleashing a cytotoxic response in experimental precancer systems, while conversely being associated with immune suppression and cytotoxic-cell depletion in human tumors, especially head and neck cancer (HNSC). We present evidence from patient samples and cell lines that alterations in chromosome dosage contribute to an immune hot-to-cold switch during human papillomavirus-negative (HPV(−)) head and neck tumorigenesis. Overall SCNA (aneuploidy) level was associated with increased CD3(+) and CD8(+) T cell microenvironments in precancer (mostly CD3(+), linked to trisomy and aneuploidy), but with T cell-deficient tumors. Early lesions with 9p21.3 loss were associated with depletion of cytotoxic T cell infiltration in TP53 mutant tumors; and with aneuploidy were associated with increased NK-cell infiltration. The strongest driver of cytotoxic T cell and Immune Score depletion in oral cancer was 9p-arm level loss, promoting profound decreases of pivotal IFN-γ-related chemokines (e.g., CXCL9) and pathway genes. Chromosome 9p21.3 deletion contributed mainly to cell-intrinsic senescence suppression, but deletion of the entire arm was necessary to diminish levels of cytokine, JAK-STAT, and Hallmark NF-κB pathways. Finally, 9p arm-level loss and JAK2-PD-L1 codeletion (at 9p24) were predictive markers of poor survival in recurrent HPV(−) HNSC after anti–PD-1 therapy; likely amplified by independent aneuploidy-induced immune-cold microenvironments observed here. We hypothesize that 9p21.3 arm-loss expansion and epistatic interactions allow oral precancer cells to acquire properties to overcome a proimmunogenic aneuploid checkpoint, transform and invade. These findings enable distinct HNSC interception and precision-therapeutic approaches, concepts that may apply to other CN-driven neoplastic, immune or aneuploid diseases, and immunotherapies.

Aneuploidy, the state of having gained or lost chromosomes, is a hallmark of cancer. Approximately 90% of tumors have gained or lost at least one chromosome. In spite of aneuploidy occurring as frequently as, if not more often than, disruption of the p53 pathway, whether and how aneuploidy influences tumorigenesis is still poorly understood. Here, we take advantage of large-scale tumor sequencing efforts to assess karyotypic alterations across many cancer types and review recent sequencing studies that show how karyotypes change in space and time. We further summarize findings that describe the effects of aneuploidy on untransformed cells, the mechanisms by which aneuploidy could drive tumorigenesis, and the potential to target aneuploidy for cancer therapy.

Tumors arise through waves of genetic alterations and clonal expansion that allow tumor cells to acquire cancer hallmarks, such as genome instability and immune evasion. Recent genomic analyses showed that the vast majority of cancer driver genes are mutated in a tissue-dependent manner, that is, are altered in some cancers but not others. Often the tumor type also affects the likelihood of therapy response. What is the origin of tissue specificity in cancer? Recent studies suggest that both cell-intrinsic and cell-extrinsic factors play a role. On one hand, cell type-specific wiring of the cell signaling network determines the outcome of cancer driver gene mutations. On the other hand, the tumor cells' exposure to tissue-specific microenvironments (e.g. immune cells) also contributes to shape the tissue specificity of driver genes and of therapy response. In the future, a more complete understanding of tissue specificity in cancer may inform methods to better predict and improve therapeutic outcomes.

Background: Alterations in pathways including BRAF , CDKN2A, and TERT contribute to the development of melanoma, but the sequence in which the genetic alterations occur and their prognostic significance remains unclear. To clarify the role of these pathways, we analyzed a primary melanoma and its metastasis. Methods: Immunohistochemistry for BRAF-V600E, Sanger sequencing of BRAF and the TERT promoter, fluorescence in-situ hybridization, and telomere analyses were performed on a primary melanoma and its asynchronous cerebellar metastasis. Using the log-rank test and Cox-proportional model, the cancer genome atlas (TCGA) cohort of melanomas was analyzed for the effect of BRAF mutation and CDKN2A loss on survival. Results: The primary melanoma expressed mutant BRAF -V600E and possessed a homozygous deletion of CDKN2A. In addition to these early defects, the metastatic lesion also possessed evidence of aneuploidy and an activating mutation of the TERT promoter. In the TCGA melanoma cohort, there was a non-significant trend toward poor prognosis in early stage cutaneous melanoma patients with concomitant BRAF mutation and CDKN2A loss. Conclusion: BRAF mutation and CDKN2A loss occurred early and TERT promoter mutation later in a case of lethal metastatic melanoma. The effects of these pathways on survival warrant further investigation in early stage cutaneous melanoma patients.

SummaryAneuploidy has been recognized as a hallmark of cancer for more than 100 years, yet no general theory to explain the recurring patterns of aneuploidy in cancer has emerged. Here, we develop Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method that analyzes the patterns of mutational signatures in tumors and predicts the likelihood that any individual gene functions as a tumor suppressor (TSG) or oncogene (OG). By analyzing >8,200 tumor-normal pairs, we provide statistical evidence suggesting that many more genes possess cancer driver properties than anticipated, forming a continuum of oncogenic potential. Integrating our driver predictions with information on somatic copy number alterations, we find that the distribution and potency of TSGs (STOP genes), OGs, and essential genes (GO genes) on chromosomes can predict the complex patterns of aneuploidy and copy number variation characteristic of cancer genomes. We propose that the cancer genome is shaped through a process of cumulative haploinsufficiency and triplosensitivity.

Although nearly all mammalian species are diploid, whole-genome duplications occur in select mammalian tissues as part of normal development. Such programmed polyploidization involves changes in the regulatory pathways that normally maintain the diploid state of the mammalian genome. Unscheduled whole-genome duplications, which lead primarily to tetraploid cells, also take place in a substantial fraction of human tumors and have been proposed to constitute an important step in the development of cancer aneuploidy. The origins of these polyploidization events and their consequences for tumor progression are explored in this review.

Since Boveri’s postulates in 1914, aneuploidy has been recognized as a hallmark of human cancer; however, no comprehensive theory exists to explain its patterns and its role in tumor evolution. We have developed Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method for the prediction of tumor suppressor genes (TSG) and oncogenes (OG) through the analysis of the pattern of somatic mutations in cancer. By integrating our prediction of TSGs and OGs with information of copy number alterations, we found that the distribution on chromosomes and the potency of TSGs and OGs can predict the frequency of arm-level and chromosome-level deletions and amplification (Davoli et al., 2013). We propose that it is the decrease or increase in the gene dosage of TSG and OG genes in deletion and amplification to determine the recurrent patterns of aneuploidy selected during tumor evolution. More recently, we have performed gene expression analysis on tumor samples, comparing tumors with different levels of aneuploidy (Davoli et al., 2017). We have found that tumors with high levels of aneuploidy show increased markers of proliferation as well as a strong decrease in infiltrating immune cells, especially CD8+ T cells. Notably, we show that aneuploidy predicts patients’ survival in two clinical trails of immunotherapy in cancer patients. Compared to neoantigen load, aneuploidy represents an independent and stronger predictor of survival. A combined score including aneuploidy and neoantigen load allows superior prediction of survival after immunotherapy. We are now investigating the mechanism by which aneuploidy affects cancer immune evasion. I will present novel data suggesting that aneuploidy may play a role in inhibiting and dysregulating antigen processing and presentation in tumor cells. Overall, our data indicate that aneuploidy is a driver event in human tumorigenesis. Citation Format: Teresa Davo4li. The role of aneuploidy during tumorigenesis [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA02.

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.

SummaryTetraploidization has been proposed as an intermediate step toward aneuploidy in human cancer but a general mechanism for the induction of tetraploidy during tumorigenesis is lacking. We report that tetraploidization occurs in p53-deficient cells experiencing a prolonged DNA damage signal due to persistent telomere dysfunction. Live-cell imaging revealed that these cells have an extended G2 due to ATM/ATR- and Chk1/Chk2-mediated inhibition of Cdk1/CyclinB and eventually bypass mitosis. Despite their lack of mitosis, the cells showed APC/Cdh1-dependent degradation of the replication inhibitor geminin, followed by accumulation of Cdt1, which is required for origin licensing. Cells then entered a second S phase resulting in whole-genome reduplication and tetraploidy. Upon restoration of telomere protection, these tetraploid cells resumed cell division cycles and proliferated. These observations suggest a general mechanism for the induction of tetraploidization in the early stages of tumorigenesis when telomere dysfunction can result from excessive telomere shortening.PaperFlick

Aneuploidy has been recognized as a hallmark of cancer for over 100 years, yet no general theory to explain the recurring patterns of aneuploidy in cancer has emerged. We developed Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method that analyzes the patterns of mutational signatures in tumors and predicts the likelihood that any individual gene functions as a tumor suppressor (TSG) or oncogene (OG). By analyzing >8200 tumor-normal pairs we provide statistical evidence suggesting many more genes possess cancer driver properties than anticipated, forming a continuum of oncogenic potential. These genes represent the vast majority of cancer drivers and the genetic networks they drive are a focus of future cancer system biological approaches to cancer research. Integrating our driver predictions with information on somatic copy number alterations, we find that the distribution and the potency of TSGs (STOP genes), OGs and essential genes (GO genes) on chromosomes can predict the complex patterns of aneuploidy and copy number variation characteristic of cancer genomes. We propose that the cancer genome is shaped through a process of cumulative haploinsufficiency and triplosensitivity. We are now assessing how aneuploidy drives cancer and the potency with which it does so. We have found that aneuploidy predicts survival better than mutational drivers and as well as existing clinical parameters in many cases. We have also discovered that different classes of aneuploidy drive transcriptional programs for two hallmarks of cancer and will present data supporting these observations and their implications. Citation Format: Teresa Davoli, Hajima Uno, Andrew Xu, Kristen Mengwasser, Laura Sack, Peter J. Park, Stephen J. Elledge. How aneuploidy drives cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY10-01.

Aneuploidy has been recognized as a hallmark of cancer for over 100 years, yet no general theory to explain the recurring patterns of aneuploidy in cancer has emerged. Here we describe the development of Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method that analyzes the patterns of mutational signatures in tumors and predicts the likelihood that any individual gene functions as a tumor suppressor (TSG) or oncogene (OG). By analyzing >8200 tumor-normal pairs we provide statistical evidence suggesting many more genes possess cancer driver properties than anticipated, forming a continuum of oncogenic potential. Integrating our driver predictions with information on somatic copy number alterations, we find that the distribution and the potency of TSGs (STOP genes), OGs and essential genes (GO genes) on chromosomes can predict the complex patterns of aneuploidy and copy number variation characteristic of cancer genomes. We propose that the cancer genome is shaped through a process of cumulative haploinsufficiency and triplosensitivity. Citation Format: Teresa Davoli, Wei Xu, Peter Park, Stephen J. Elledge. How aneuploidy drives tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY36-03. doi:10.1158/1538-7445.AM2014-SY36-03

Since Boveri's postulates in 1914, aneuploidy has been recognized as a hallmark of human cancer. However, no comprehensive theory exists to explain the patterns of aneuploidy and its role in tumor evolution. Recurrent gains or losses of specific chromosomes have been observed in cancer, but it is not clear whether a recurrent pattern of aneuploidy exists among cancer karyotypes and whether the recurrent patterns just happen to occur more frequently or are specifically selected during tumor evolution. We have developed the Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method for the prediction of tumor suppressor genes (TSGs) and oncogenes (OGs) through the analysis of the pattern of somatic mutations in cancer (Davoli et al., Cell, 2013). By analyzing >8200 tumor-normal pairs from more than 20 tumor types we provide statistical evidence suggesting that many more genes possess cancer driver properties than anticipated, forming a continuum of oncogenic potential. The TUSON Explorer analysis on the entire dataset has identified new potential TSGs such as RASA1, TP53BP1, USP28 and OGs such as PPP2R1A and PPP6C. The TUSON Explorer was also applied to individual tumor types, leading to the identification of new potential tissue-specific drivers. In addition, we have integrated our prediction of TSGs and OGs with information of copy number alterations. We found that the distribution on chromosome and the potency of TSGs and OGs can predict the frequency of arm-level and chromosome-level deletions and amplification. For example, the density and potency of TSGs strongly positively and negatively correlated with the frequency of arm and chromosome deletion and amplification, respectively (r value=∼0.6, p Citation Format: Teresa Davoli, Andrew Wei Xu, Kristen E. Mengwasser, Laura M. Sack, John C. Yoon, Peter J. Park, Stephen J. Elledge. Cumulative dosage effect of TSGs and OGs drives aneuploidy patterns in cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2404. doi:10.1158/1538-7445.AM2014-2404