Abstract 36: Synthetic lethality across normal tissues is strongly associated with cancer risk, onset, and tumor suppressor specificity

Various characteristics of cancers exhibit tissue specificity, including lifetime cancer risk, onset age, and cancer driver genes. Previously, the large variation in cancer risk across human tissues was found to strongly correlate with the number of stem cell divisions and abnormal DNA methylation levels. Here, we study the role of synthetic lethality in cancer risk. Analyzing normal tissue transcriptomics data in the Genotype-Tissue Expression project, we quantify the extent of co-inactivation of cancer synthetic lethal (cSL) gene pairs and find that normal tissues with more down-regulated cSL gene pairs have lower and delayed cancer risk. Consistently, more cSL gene pairs become up-regulated in cells treated by carcinogens and throughout premalignant stages in vivo. We also show that the tissue specificity of numerous tumor suppressor genes is associated with the expression of their cSL partner genes across normal tissues. Overall, our findings support the possible role of synthetic lethality in tumorigenesis.

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Synthetic lethality across normal tissues is strongly associated with cancer risk, onset, and tumor suppressor specificity

10.1101/818922 ◽

2019 ◽

Author(s):

Kuoyuan Cheng ◽

Nishanth Ulhas Nair ◽

Joo Sang Lee ◽

Eytan Ruppin

Keyword(s):

Tumor Suppressor ◽

Cancer Risk ◽

Tissue Specificity ◽

Synthetic Lethality ◽

Driver Genes ◽

Lifetime Cancer Risk ◽

Normal Tissues ◽

Gene Pairs ◽

Stem Cell Divisions

AbstractVarious characteristics of cancers exhibit tissue-specificity, including lifetime cancer risk, onset age and cancer driver genes. Previously, the large variation in cancer risk across human tissues was found to strongly correlate with the number of stem cell divisions and abnormal DNA methylation levels occurring in them. Here we study the role of another potentially important factor, synthetic lethality, in cancer risk. Analyzing transcriptomics data in the GTEx compendium we quantify the extent of co-inactivation of cancer synthetic lethal (cSL) gene pairs in normal tissues and find that normal tissues with more down-regulated cSL gene pairs have lower and delayed cancer risk. We also show that the tissue-specificity of numerous tumor suppressor genes is strongly associated with the expression of their cSL partner genes in the corresponding normal tissues. Overall, our findings uncover the role of synthetic lethality as a novel important factor involved in tumorigenesis.

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Expanding the Biotherapeutics Realm via miR-34a: “Potent Clever Little” Agent in Breast Cancer Therapy

Current Pharmaceutical Biotechnology ◽

10.2174/1389201020666190617162042 ◽

2019 ◽

Vol 20 (8) ◽

pp. 665-673 ◽

Cited By ~ 1

Author(s):

Mohsen Mohammady ◽

Seyed I. Ghetmiri ◽

Mahtab Baharizade ◽

Mohammad H. Morowvat ◽

Susan Torabi

Keyword(s):

Breast Cancer ◽

Cancer Therapy ◽

Tumor Suppressor ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Signal Pathways ◽

Breast Cancer Therapy ◽

Female Population ◽

Therapeutic Goals ◽

Normal Tissues

Background:One of the most prevalent cancers befell to women is considered to be breast cancer (BC). It is also the deadliest among the female population after lung cancer. Additionally, several studies have demonstrated that there is an association between microRNA34-a and breast cancer.Method:We searched PubMed, Web of Science, and Google Scholar up to December 2018. Those studies which have been studied miR-34a and its tumor-suppressing capabilities were considered as the most important topics. Moreover, we extracted articles which were solely focused on microRNA-34a in breast cancer therapy. Finally, 80 articles were included.Results:In comparison with the normal tissues, down-regulation of miR-34a expression is shown considerably in tumor cells. Overexpression of miR-34a acts as a tumor suppressor by transcriptional regulating one of the signaling pathways (TP53), NOTCH, and transforming growth factor beta (TGF-β), Bcl- 2 and SIRT1genes, HDAC1 and HDAC7, Fra-1, TPD52, TLR Via CXCL10. Moreover, drug resistance declines which lead to the apoptosis, cell cycle arrest and senescence. As a result, the proliferation, invasion and metastasis of the tumor are suppressed. The Mrx34 drug contains miR-34a mimic and a lipid vector. MiR-34a as the active ingredient portrays the role of a tumor suppressor. This drug has recently entered the clinical trials studies.Conclusion:These findings suggest a robust cause for developing miR-34a as a therapeutic agent to target BC. In that scenario, miR-34a is strongly useful to introduce new therapeutic goals for BC. Moreover, this review aims to confirm the signal pathways, therapeutic and diagnostic values of miR- 34a in BC and beyond.

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Functional Loss of p21/Waf-1 in a Case of Benign Canine Multicentric Melanoma

Veterinary Pathology ◽

10.1177/030098589803500202 ◽

1998 ◽

Vol 35 (2) ◽

pp. 94-101 ◽

Cited By ~ 17

Author(s):

M. G. Ritt ◽

J. Wojcieszyn ◽

J. F. Modiano

Keyword(s):

Tumor Suppressor ◽

Cell Cycle Progression ◽

Kinase Inhibitor ◽

P53 Gene ◽

Tumor Formation ◽

Cyclin Dependent Kinase ◽

P53 Expression ◽

Functional Loss ◽

Normal Tissues ◽

Cyclin Dependent Kinase Inhibitor

Mutations of tumor suppressor genes remove mechanisms that normally arrest proliferation of transformed cells, resulting in tumor formation. The p53 gene product functions as a tumor suppressor that induces p21/Waf-1, the 21-kDa product of the waf-1/cip-1/mda-6 gene. p21/Waf-1 is a pan-cyclin-dependent kinase inhibitor that arrests cell cycle progression under a variety of circumstances. We examined tissues from a dog with multiple primary pigmented proliferative lesions (benign, multicentric melanoma consisting of three distinct dermal lesions and a matrical cyst) for p21/Waf-1 and p53 expression by immunohistochemistry and immunoblotting. p21/Waf-1 and p-53 proteins were undetectable in the tumor cells and in the cyst but were present in adjacent normal tissues. Abundant cyclin-dependent kinase 4 (Cdk4), a protein related functionally to p21/Waf-1, also was present in the cyst. A somatic mutation of the waf-1 gene or of the p53 gene may have resulted in the loss of p21/Waf-1 expression in a common precursor of pigment-producing cells from the affected dog. Furthermore, this functional loss of p21/Waf-1 may play an important role in the genesis of canine benign melanoma.

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Molecular Genetics of Cancer

10.2310/im.1003 ◽

2012 ◽

Author(s):

Leif W. Ellisen

Keyword(s):

Risk Assessment ◽

Tumor Suppressor ◽

Environmental Factors ◽

Cancer Risk ◽

Tumor Progression ◽

Cancer Genomics ◽

Precancerous Lesions ◽

Expression Profiles ◽

Genetic Alterations ◽

Cancer Risk Assessment

The uncontrolled clonal expansion of a cell, which often leads to invasion of surrounding tissues and metastatic spread, produces cancer. A clear histologic and molecular genetic evolution from precancerous lesions to frankly malignant and invasive cancer has been defined for some tumors (e.g., colon and bladder cancers). In rare cases, mutations may occur and be passed on in the germline, resulting in genetic predisposition to cancer (i.e., familial cancer syndromes). Environmental factors are also thought to contribute to the development of cancer. Interactions between environmental factors and subtle germline genetic variations that distinguish individuals may in some cases constitute an important determinant of cancer risk within the general population. Finally, viral infection has been linked to the development of specific cancers. Oncogenes and proto-oncogenes, and germline genetic analysis and cancer risk assessment are covered. Also discussed are genetic alterations and abnormalities, tumor suppressor genes, tumor progression, genetic mechanisms of treatment sensitivity and resistance, and emerging trends in cancer genomics and risk assessment. Figures illustrate activation of proto-oncogenes, the Knudsen two-hit model of tumor initiation, allelic losses in tumors, the retinoblastoma gene (RB1) cell cycle pathway, the p53 cellular stress and DNA damage response pathway, microsatellite instability and DNA mismatch repair, multiple oncogenes and tumor suppressors, tumor progression, cellular senescence and telomerase activation, tumor angiogenesis, chemotherapy drug resistance, targeting of oncogenic proteins by imatinib mesylate, analysis of expression profiles using high-density microarrays, and the spectrum of risk alleles for breast cancer predisposition. Tables outline oncogene and tumor suppressor gene mutations. This chapter contains 119 references.

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CircPLEKHM3 acts as a tumor suppressor through regulation of the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis in ovarian cancer

Molecular Cancer ◽

10.1186/s12943-019-1080-5 ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 20

Author(s):

Lei Zhang ◽

Qing Zhou ◽

Qiongzi Qiu ◽

Ling Hou ◽

Mengting Wu ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Suppressor ◽

Cancer Cells ◽

Cancer Patients ◽

Cancer Biology ◽

Ovarian Cancer Cells ◽

Ovarian Carcinomas ◽

Mesenchymal Transition ◽

Normal Tissues ◽

Endogenous Expression

Abstract Background Emerging evidence has shown that circular RNAs (circRNAs) play essential roles in cancer biology and are potential biomarkers and targets for cancer therapy. However, the expression and function of circRNAs in ovarian carcinogenesis and its progression remain elusive. Methods RNA sequencing was performed to reveal circRNA expression profiles in ovarian cancerous and normal tissues. Single-molecule RNA in-situ hybridization was used to quantify circPLEKHM3 expression in tumor tissues. Cell-based in-vitro and in-vivo assays were subsequently conducted to support the clinical findings. Results CircPLEKHM3 was identified as one of the most significantly down-regulated circRNAs in ovarian cancer tissues compared with normal tissues. Its expression was further decreased in peritoneal metastatic ovarian carcinomas compared to primary ovarian carcinomas. Patients with lower circPLEKHM3 tend to have a worse prognosis. Functionally, circPLEKHM3 overexpression inhibited cell growth, migration and epithelial–mesenchymal transition, whereas its knockdown exerted an opposite role. Further analyses showed that circPLEKHM3 sponged miR-9 to regulate the endogenous expression of BRCA1, DNAJB6 and KLF4, and consequently inactivate AKT1 signaling. In addition, AKT inhibitor MK-2206 could block the tumor-promoting effect of circPLEKHM3 depletion, and potentiate Taxol-induced growth inhibition of ovarian cancer cells. Conclusions Our findings demonstrated that circPLEKHM3 functions as a tumor suppressor in ovarian cancer cells by targeting the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis and may be used as a prognostic indicator and therapeutic target in ovarian cancer patients. The new strategy for treating ovarian cancer by a combination therapy of Taxol with MK-2206 is worth further investigation, especially in ovarian cancer patients with loss of circPLEKHM3 expression.

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Cross-species synthetic lethal interaction screening as a strategy for the identification of novel therapeutic targets in cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.11105 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 11105-11105

Author(s):

John P. Shen ◽

Rohith Srivas ◽

Ana Bojorquez-Gomez ◽

Katherine Licon ◽

Jian Feng Li ◽

...

Keyword(s):

Tumor Suppressor ◽

Tumor Suppressor Genes ◽

Synthetic Lethality ◽

Control Cell ◽

Therapeutic Targets ◽

Model Organisms ◽

Suppressor Genes ◽

Synthetic Lethal ◽

Synthetic Lethal Interactions ◽

Novel Therapeutic

11105 Background: Mutation, deletion, or epigenetic silencing of tumor suppressor genes is a near universal feature of malignant cells. However, therapeutic strategies for restoring the function of mutated or deleted genes have proven difficult. Synthetic lethality, an event in which the simultaneous perturbation of two genes results in cellular death, has been proposed as a method to selectively target cancer cells. Identifying and pharmacologically inhibiting proteins encoded by genes that are synthetic lethal with known tumor suppressor mutations should result in selective toxicity to tumor cells. Methods: To identify candidate target proteins we measured all pair-wise genetic interactions between all known orthologs of human tumor suppressor genes (162 genes) and all orthologs of druggable human proteins (~400 genes) in the model organism S. Cerevisiae. Analysis of the data uncovered 2,087 distinct synthetic lethal interactions between a tumor suppressor and druggable gene. A computational algorithm was then developed to identify those interactions which were likely to be conserved in humans based on conservation of the synthetic lethal relationship in the distant fission yeast S. pombe. Results: Our bioinformatic analysis suggested a high probability of conservation of the synthetic lethal interactions between the yeast RAD51 (ortholog of BRCA1) and RAD57 (ortholog of XRCC3) with HDA1 (a histone deacetylase; HDAC). We confirmed this by treating LN428 cells with stable lentiviral knockdown of BRCA1 or XRCC3 with the HDAC inhibitors vorinostat (SAHA) and entinostat (MS-275). Both the BRCA1 and XRCC3 knockdown cell lines were significantly more sensitive to HDAC inhibition relative to wild-type (non-silencing lentiviral control) cell line (Table). Conclusions: These results demonstrate that high-throughput approaches for screening synthetic lethal interactions in model organisms such as S. cerevisiae and S. pombecan serve as a valuable resource in helping to identify novel therapeutic targets in human cancer. [Table: see text]

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Epigenetic inactivation of the CpG demethylase TET1 as a DNA methylation feedback loop in human cancers

Scientific Reports ◽

10.1038/srep26591 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 55

Author(s):

Lili Li ◽

Chen Li ◽

Haitao Mao ◽

Zhenfang Du ◽

Wai Yee Chan ◽

...

Keyword(s):

Tumor Suppressor ◽

Feedback Loop ◽

Catalytic Domain ◽

Ectopic Expression ◽

Suppressor Gene ◽

Cpg Methylation ◽

Primary Tumors ◽

Normal Tissues ◽

Tet Proteins ◽

Induced Apoptosis

Abstract Promoter CpG methylation is a fundamental regulatory process of gene expression. TET proteins are active CpG demethylases converting 5-methylcytosine to 5-hydroxymethylcytosine, with loss of 5 hmC as an epigenetic hallmark of cancers, indicating critical roles of TET proteins in epigenetic tumorigenesis. Through analysis of tumor methylomes, we discovered TET1 as a methylated target, and further confirmed its frequent downregulation/methylation in cell lines and primary tumors of multiple carcinomas and lymphomas, including nasopharyngeal, esophageal, gastric, colorectal, renal, breast and cervical carcinomas, as well as non-Hodgkin, Hodgkin and nasal natural killer/T-cell lymphomas, although all three TET family genes are ubiquitously expressed in normal tissues. Ectopic expression of TET1 catalytic domain suppressed colony formation and induced apoptosis of tumor cells of multiple tissue types, supporting its role as a broad bona fide tumor suppressor. Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9. As only infrequent mutations of TET1 have been reported, compared to TET2, epigenetic silencing therefore appears to be the dominant mechanism for TET1 inactivation in cancers, which also forms a feedback loop of CpG methylation during tumorigenesis.

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MYCN Amplification and ATRX Mutations are Incompatible in Neuroblastoma

10.1101/379636 ◽

2018 ◽

Author(s):

Maged Zeineldin ◽

Sara Federico ◽

Xiang Chen ◽

Yiping Fan ◽

Beisi Xu ◽

...

Keyword(s):

High Risk ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Synthetic Lethality ◽

Reactive Oxygen Species Generation ◽

Suppressor Gene ◽

Metabolic Reprogramming ◽

Mycn Amplification ◽

Replicative Stress ◽

Chaperone Complex

SUMMARYAggressive cancers often have activating mutations in growth-controlling oncogenes and inactivating mutations in tumor-suppressor genes. In neuroblastoma, amplification of the MYCN oncogene and inactivation of the ATRX tumor-suppressor gene correlate with high-risk disease and poor prognosis. Here we show that ATRX mutations and MYCN amplification are mutually exclusive across all ages and stages in neuroblastoma. Using human cell lines and mouse models, we found that elevated MYCN expression and ATRX mutations are incompatible. Elevated MYCN levels promote metabolic reprogramming, mitochondrial dysfunction, reactive-oxygen species generation, and DNA-replicative stress. The combination of replicative stress caused by defects in the ATRX–histone chaperone complex and that induced by MYCN-mediated metabolic reprogramming leads to synthetic lethality. Therefore, ATRX and MYCN represent an unusual example, where inactivation of a tumor-suppressor gene and activation of an oncogene are incompatible. This synthetic lethality may eventually be exploited to improve outcomes for patients with high-risk neuroblastoma.

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Assessment of tumor suppressor gene methylation for breast cancer risk screening

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.1004 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 1004-1004

Author(s):

D. Euhus ◽

R. Ashfaq ◽

D. Bu ◽

A. M. Leitch ◽

C. Lewis

Keyword(s):

Breast Cancer ◽

High Risk ◽

Breast Cancer Risk ◽

Tumor Suppressor ◽

Cancer Risk ◽

Tumor Suppressor Gene ◽

Lower Risk ◽

Suppressor Gene ◽

Gene Copies ◽

Wide Range

1004 Background: Tumor suppressor gene (TSG) methylation is frequently detected in benign proliferative breast tissue suggesting that it occurs early in breast carcinogenesis. If it can be screen-detected and is associated with breast cancer risk it could be exploited for breast cancer prevention. Methods: Nipple duct lavage (NDL) samples, obtained from 150 women selected to represent a wide range of breast cancer risk, were evaluated by quantitative methylation-specific real time PCR. High risk breasts were defined as those contralateral to a breast cancer (N = 63) and those of women with a 5-year Gail risk ≥ twice the age- and race-matched general population risk (N = 64). The prevelence of TSG methylation and marked atypia was compared for high risk and lower risk breasts using Chi-square. Data for breasts ipsilateral to a breast cancer are shown for comparison, but not included in the calculations for the high risk category. Results: Samples with adequate cellularity were obtained for 219 breasts (76%). The proportion of healthy breasts with ≥ 1% of the gene copies methylated was 13% for Cyclin D2, 19% for APC, 19% for HIN-1, 16% for RASSF1A, and 9% for RAR-beta. RAR-beta provided the best risk discrimination as 15% of high risk breasts were methylated at a level that exceeded the 95th percentile of the lower risk breasts (0.9% of gene copies methylated, P = 0.05). For the table , methylation fractions for all five genes were summed and the threshold for classifying a breast as positive was set to the 95th percentile of the lower risk breasts (methylation sum = 25.0%). Both methylation and marked atypia provide some discrimination between high and lower risk breasts; the combination, however, provides the best discrimination (24% marker positive for high risk versus 9% for lower risk, P = 0.02). Conclusions: TSG methylation in NDL samples is a marker of breast cancer risk that is complementary to cytology. [Table: see text] [Table: see text]

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