Identification of Drivers of Aneuploidy in Breast Tumors

Pfister, Katherine; Pipka, Justyna L.; Chiang, Colby; Liu, Yunxian; Clark, Royden A.; Keller, Ray; Skoglund, Paul; Guertin, Michael J.; Hall, Ira M.; Stukenberg, P. Todd

doi:10.1016/j.celrep.2018.04.102

Cited by 52 publications

(62 citation statements)

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“…Our results revealed a group of "accelerator" transcriptional factors, such as E2F7 and E2F8, can activate the genes associated with HRD as well as a series of genes involved in the cell cycle and proliferation. The overexpression E2F7 have been reported to result in an increase of aneuploidy in breast cancer cells (18). On the contrary, another group of "stabilizer" transcriptional factors, such as RFX2 and NFYA, can activate a number of CT genes to promise the timely repair of double-strand breaks in the late meiosis stages, but these CT genes were not co-activated with HRD related CT genes in cancer cells.…”

Section: Discussionmentioning

confidence: 98%

Meiosis related cancer-testis genes correlate with tumor aneuploidy and immune infiltration in 21 cancer types

Wang

Chang

et al. 2019

Preprint

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The meiosis stage of spermatogenesis and the aneuploidy generation in tumorigenesis are highly linked. Cancer-testis genes (CT genes) were specifically expressed in testis and cancers and may serve as the molecular basis of the shared features between spermatogenesis and tumorigenesis. In the present study, we integrated multi-omics data from bulk samples and cell lines, and single cell RNA-Seq data from testis and two tumors to systematically investigate the association between CT genes and aneuploidy. After ranking genes according to their association with aneuploidy level, we found that CT genes, especially CT genes specifically expressed in meiosis, showed a consistently positive correlation with aneuploidy and homologous recombination deficiency (HRD) level. Similar results were also found in the CT non-coding genes. Then, we constructed a regulatory network based on the single cell RNA-seq data and revealed that the gain of accelerator transcriptional factors (TFs) E2F7 and E2F8 and the loss of the stabilizer TFs RFX2 and NFYA aberrantly activated CT genes in the cancers and were associated with the increase of HRD level. Finally, we found that the association between CT genes and cytotoxic infiltrating lymphocytes can be influenced by the HRD level. In sum, our results revealed the evidence of pseudomeiotic functions of CT genes in the aneuploidy generation process in the cancer cells. The results may help illuminate the origin of aneuploidy in cancers and guide future immunotherapy targeting CT antigens.

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Section: Discussionmentioning

confidence: 98%

Meiosis related cancer-testis genes correlate with tumor aneuploidy and immune infiltration in 21 cancer types

Wang

Chang

et al. 2019

Preprint

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“…In recent studies, decreased levels of FOXM1 was shown to cause mitotic decline, genomic instability, and senescence during human aging (Macedo et al, 2018). Conversely, FOXM1 overexpression was found to promote mitotic defects and genomic instability (Pfister et al, 2018). Together, these data suggest that tight regulation of FOXM1 expression and function are important for maintaining proper mitotic function and genomic stability.…”

Section: Hgsc Tissues and Cells Show Robust Overexpression Of Both Fomentioning

confidence: 90%

Co-regulation and functional cooperativity of FOXM1 and RHNO1 bidirectional genes in ovarian cancer

Barger

Branick

Chee

et al. 2019

Preprint

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We report that the oncogenic transcription factor FOXM1 is arranged in a head-to-head configuration with RHNO1, a gene involved in the ATR/CHK1-dependent DNA replication stress (DRS) response. FOXM1 and RHNO1 are both amplified and upregulated in high-grade serous ovarian cancer (HGSC). FOXM1 and RHNO1 expression are closely associated in normal and cancer tissues, including single cells, and a bidirectional promoter (F/R-BDP) mediates balanced expression. Targeting of FOXM1 and RHNO1 in HGSC cells using shRNA, CRISPR mutagenesis, or CRISPR interference directed to the F/R-BDP reduced DNA homologous recombination repair (HR) capacity, increased DNA damage, reduced clonogenic survival, and sensitized HGSC cells to the poly-ADP ribosylase inhibitor (PARPi) olaparib. Thus, there is functional cooperativity between FOXM1 and RHNO1 in cancer cells, and combinatorial targeting of this bidirectional gene pair may be a novel cancer therapeutic strategy. More broadly, our data provide evidence that bidirectional gene units function in human cancer.Here, we show that FOXM1 and RHNO1 are co-amplified and co-expressed in HGSC, and that their expression in controlled by a bidirectional promoter (named the F/R-BDP). We additionally show that FOXM1 and RHNO1 they cooperatively promote HR, cell survival, and PARPi resistance. Co-regulation and functional cooperativity between FOXM1 and RHNO1 suggests that this bidirectional gene unit is a potential therapeutic target in HGSC and/or other cancers. More generally, our data provide evidence that cooperative bidirectional gene units functionally contribute to cancer. ResultsThe 12p13.33 amplicon contains FOXM1 and RHNO1, co-expressed bidirectional genes FOXM1 is located at 12p13.33, a region with frequent copy number gains in HGSC and several other cancers (Barger et al., 2019;Barger et al., 2015). 12p13.33 amplification was associated with reduced overall survival in HGSC but, unexpectedly, FOXM1 mRNA expression did not (Barger et al., 2015). The 12p13.33 amplicon includes 33 genes (Figure S1). To identify genes at 12p13.33 that might functionally cooperate with FOXM1, we performed expression correlation analyses. FOXM1 expression showed the strongest correlation with RHNO1 expression in HGSC (Figure 1A), pan-cancer (data not shown), and normal human tissues ( Figure S2). In addition, RHNO1 mRNA expression correlated with reduced HGSC survival (data not shown). Genomic analyses of FOXM1 and RHNO1 revealed a head-to-head arrangement with an intervening putative bidirectional promoter (BDP) ( Figure S3). Approximately 10% of human genes are arranged in this manner, and the gene pairs are frequently co-regulated and can function in similar biochemical pathways (Trinklein et al., 2004;Wakano et al., 2012;. The FOXM1/RHNO1 BDP (F/R-BDP) region contains a CpG island (CGI), a common feature of BDPs ( Figure S3) (Antequera, 2003;Takai and Jones, 2004;Wakano et al., 2012).BDPs are often enriched with specific histone modifications H3K4me3, H3K9ac, H3K27ac, and H3K4me2 (Bornelov et al., 20...

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“…A recent analysis of highly aneuploidy breast cancers in TCGA found overexpression of three transcriptional regulators, E2F1, MYBL2, and FOXM1 [13]. Overexpression of these genes in nontransformed Xenopus embryos was sufficient to significantly increase the rate of chromosomal missegregation and initiate aneuploidy.…”

Section: Differentially Expressed Genes In Cin-mentioning

confidence: 99%

Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential

Miller

You

Cadaneanu

et al. 2020

Preprint

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Background: Metastatic prostate cancer (PC) is highly lethal. The ability to identify primary tumors capable of dissemination is an unmet need in the quest to understand lethal biology and improve patient outcomes. Previous studies have linked chromosomal instability (CIN), which generates aneuploidy following chromosomal missegregation during mitosis, to PC progression. Evidence of CIN includes broad copy number alterations (CNAs) spanning >300 base pairs of DNA, which may also be measured via RNA expression signatures associated with CNA frequency. Signatures of CIN in metastatic PC, however, have not been interrogated or well defined. We examined a published 70-gene CIN signature (CIN70) in untreated and castration-resistant prostate cancer (CRPC) cohorts from The Cancer Genome Atlas (TCGA) and previously published reports. We also performed transcriptome and CNA analysis in a unique cohort of untreated primary tumors collected from diagnostic prostate needle biopsies (PNBX) of localized (M0) and metastatic (M1) cases to determine if CIN was linked to clinical stage and outcome. Methods: PNBX were collected from 99 patients treated in the VA Greater Los Angeles (GLA-VA) Healthcare System between 2000-2016. Total RNA was extracted from high-grade cancer areas in PNBX cores, followed by RNA sequencing and/or copy number analysis using OncoScan. Multivariate logistic regression analyses permitted calculation of odds ratios for CIN status (high versus low) in an expanded GLA-VA PNBX cohort (n = 121). Results: The CIN70 signature was significantly enriched in primary tumors and CRPC metastases from M1 PC cases. An intersection of gene signatures comprised of differentially expressed genes (DEGs) generated through comparison of M1 versus M0 PNBX and primary CRPC tumors versus metastases revealed a 157-gene "metastasis" signature that was further distilled to 7-genes (PC-CIN) regulating centrosomes, chromosomal segregation, and mitotic spindle assembly. High PC-CIN scores correlated with CRPC, PC-death and all-cause mortality in the expanded GLA-VA PNBX cohort. Interestingly, approximately 1/3 of M1 PNBX cases exhibited low CIN, illuminating differential pathways of lethal PC progression. Conclusions: Measuring CIN in PNBX by transcriptome profiling is feasible, and the PC-CIN signature may identify patients with a high risk of lethal progression at the time of diagnosis.

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Identification of Drivers of Aneuploidy in Breast Tumors

Cited by 52 publications

References 50 publications

Meiosis related cancer-testis genes correlate with tumor aneuploidy and immune infiltration in 21 cancer types

Meiosis related cancer-testis genes correlate with tumor aneuploidy and immune infiltration in 21 cancer types

Co-regulation and functional cooperativity of FOXM1 and RHNO1 bidirectional genes in ovarian cancer

Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential

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