scholarly journals Pervasive duplication of tumor suppressors in Afrotherians during the evolution of large bodies and reduced cancer risk

2020 ◽  
Author(s):  
Juan Manuel Vazquez ◽  
Vincent J. Lynch
Keyword(s):  
Body Size ◽  
Tumor Suppressor ◽  
Gene Duplication ◽  
Cancer Risk ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Cell Biology ◽  
Cancer Resistance ◽  
Anti Cancer ◽  
Protection Mechanisms

AbstractThe risk of developing cancer is correlated with body size and lifespan within species. Between species, however, there is no correlation between cancer and either body size or lifespan, indicating that large, long-lived species have evolved enhanced cancer protection mechanisms. Elephants and their relatives (Proboscideans) are a particularly interesting lineage for the exploration of mechanisms underlying the evolution of augmented cancer resistance because they evolved large bodies recently within a clade of smaller bodied species (Afrotherians). Here, we explore the contribution of gene duplication to body size and cancer risk in Afrotherians. Unexpectedly, we found that tumor suppresxssor duplication was pervasive in Afrotherian genomes, rather than restricted to Proboscideans. Proboscideans, however, have duplicates in unique pathways that may underlie some aspects of their remarkable anti-cancer cell biology. These data suggest that duplication of tumor suppressor genes facilitated the evolution of increased body size by compensating for decreasing intrinsic cancer risk.

scholarly journals Pervasive duplication of tumor suppressors in Afrotherians during the evolution of large bodies and reduced cancer risk

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Juan M Vazquez ◽  
Vincent J Lynch
Keyword(s):  
Body Size ◽  
Tumor Suppressor ◽  
Gene Duplication ◽  
Cancer Risk ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Cell Biology ◽  
Cancer Resistance ◽  
Anti Cancer ◽  
Protection Mechanisms

The risk of developing cancer is correlated with body size and lifespan within species. Between species, however, there is no correlation between cancer and either body size or lifespan, indicating that large, long-lived species have evolved enhanced cancer protection mechanisms. Elephants and their relatives (Proboscideans) are a particularly interesting lineage for the exploration of mechanisms underlying the evolution of augmented cancer resistance because they evolved large bodies recently within a clade of smaller bodied species (Afrotherians). Here, we explore the contribution of gene duplication to body size and cancer risk in Afrotherians. Unexpectedly, we found that tumor suppressor duplication was pervasive in Afrotherian genomes, rather than restricted to Proboscideans. Proboscideans, however, have duplicates in unique pathways that may underlie some aspects of their remarkable anti-cancer cell biology. These data suggest that duplication of tumor suppressor genes facilitated the evolution of increased body size by compensating for decreasing intrinsic cancer risk.

Methylation status of eight tumor suppressors in neuroendocrine pancreatic tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16197-e16197
Author(s):  
Oleg I. Kit ◽  
Vladimir S. Trifanov ◽  
Natalya N. Timoshkina ◽  
Dmitry Yu. Gvaldin ◽  
Milana Yu. Mesheryakova ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Methylation Status ◽  
Blood Levels ◽  
Malignant Neoplasms ◽  
Gene Promoters ◽  
Suppressor Genes ◽  
Healthy Donors ◽  
Pancreatic Net

e16197 Background: Aberrant DNA methylation is a characteristic feature of cancer, affecting gene expression and tumor phenotype. In this study, we quantified the methylation of promoters of eight tumor suppressor genes in pancreatic neuroendocrine tumors (Pan-NET). Methods: The method of pyrosequencing was used to quantity level (Met,%) of methylation of gene promoters - tumor suppressors AHRR, APC1A, DAPK, MGMT, MLH1, P16, RASSF1A, RUNX3 in tumor samples from 55 patients with pancreatic NET (G1-G3) and in the blood of 10 healthy donors. Met for each sample was calculated as the median methylation of CpG sites in triplicate. Results: Hypermethylation was observed for AHRR (75%), APC1A (25%), RASSF1A (30%). In contrast, DAPK, MGMT, MLH1, P16, RUNX3 had low methylation levels ( < 20%). The median of methylation in the blood of healthy donors for AHRR was 91% (76-98); for all other loci it did not exceed 6%. A high incidence of methylation in excess of blood levels in healthy donors was identified for RASSF1A (0.96); AHRR (0.75); MGMT (0.65); RUNX3 (0.41), APC1A (0.25). For tumor suppressor P16, only one case of increased methylation was recorded (Met = 15%), despite the fact that this phenomenon is not uncommon for NETs of other localizations. In 66% of pancreatic NET cases, hypermethylation of more than two promoters of tumor suppressor genes was noted. An association tendency was found between the presence of MEN1 mutations and the RASSF1A methylation level (p = 0.08). Correlation analysis revealed a significant level of negative association between changes in methylation of MLH1 and AHRR (p < 0.01); for the latter, the prognostic value of a high methylation status and a better prognosis for many malignant neoplasms were described. Conclusions: In the present study, significant methylation of the promoters of the APC1A, DAPK, MGMT, RASSF1A, and RUNX3 genes in well-differentiated pancreatic NETs was identified with a high frequency. At the same time, isolated cases of hypermethylation were noted for the well-known tumor suppressors MLH1 and P16.

scholarly journals Inactivation of multiple tumor-suppressor genes involved in negative regulation of the cell cycle, MTS1/p16INK4A/CDKN2, MTS2/p15INK4B, p53, and Rb genes in primary lymphoid malignancies

Blood ◽  
1996 ◽  
Vol 87 (12) ◽  
pp. 4949-4958 ◽  
Author(s):  
A Hangaishi ◽  
S Ogawa ◽  
N Imamura ◽  
S Miyawaki ◽  
Y Miura ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Cell Cycle Control ◽  
Negative Regulators ◽  
Suppressor Genes ◽  
Multiple Tumor ◽  
Lymphoid Malignancies ◽  
Cell Cycle Machinery

It is now evident that the cell cycle machinery has a variety of elements negatively regulating cell cycle progression. However, among these negative regulators in cell cycle control, only 4 have been shown to be consistently involved in the development of human cancers as tumor suppressors: Rb (Retinoblastoma susceptibility protein), p53, and two recently identified cyclin-dependent kinase inhibitors, p16INK4A/MTS1 and p15INK4B/MTS2. Because there are functional interrelations among these negative regulators in the cell cycle machinery, it is particularly interesting to investigate the multiplicity of inactivations of these tumor suppressors in human cancers, including leukemias/lymphomas. To address this point, we examined inactivations of these four genes in primary lymphoid malignancies by Southern blot and polymerase chain reaction-single- strand conformation polymorphism analyses. We also analyzed Rb protein expression by Western blot analysis. The p16INK4A and p15INK4B genes were homozygously deleted in 45 and 42 of 230 lymphoid tumor specimens, respectively. Inactivations of the Rb and p53 genes were 27 of 91 and 9 of 173 specimens, respectively. Forty-one (45.1%) of 91 samples examined for inactivations of all four tumor suppressors had one or more abnormalities of these four tumor-suppressor genes, indicating that dysregulation of cell cycle control is important for tumor development. Statistical analysis of interrelations among impairments of these four genes indicated that inactivations of the individual tumor-suppressor genes might occur almost independently. In some patients, disruptions of multiple tumor-suppressor genes occurred; 4 cases with p16INK4A, p15INK4B, and Rb inactivations; 2 cases with p16INK4A, p15INK4B, and p53 inactivations; and 1 case with Rb and p53 inactivations. It is suggested that disruptions of multiple tumor suppressors in a tumor cell confer an additional growth advantage on the tumor.

scholarly journals Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma

Blood ◽  
2016 ◽  
Vol 128 (13) ◽  
pp. 1735-1744 ◽  
Author(s):  
Niels Weinhold ◽  
Cody Ashby ◽  
Leo Rasche ◽  
Shweta S. Chavan ◽  
Caleb Stein ◽  
...  
Keyword(s):  
High Risk ◽  
Tumor Suppressor ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Clonal Selection ◽  
Therapeutic Approaches ◽  
Apoptosis Resistance ◽  
Driver Genes ◽  
Suppressor Genes ◽  
Key Points

Key PointsHits in driver genes and bi-allelic events affecting tumor suppressors increase apoptosis resistance and proliferation rate–driving relapse. Excessive biallelic inactivation of tumor suppressors in high-risk cases highlights the need for TP53-independent therapeutic approaches.

Molecular Pathogenesis of MDS

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 156-160 ◽  
Author(s):  
A. Thomas Look
Keyword(s):  
Tumor Suppressor ◽  
Progenitor Cells ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Molecular Mechanisms ◽  
Point Mutations ◽  
Suppressor Genes ◽  
Hematopoietic Stem ◽  
Chromosomal Deletions ◽  
Genes Encoding

Abstract Clonal disorders of hematopoiesis, such as myelodysplastic syndromes (MDS) and myeloproliferative diseases (MPD), affect both hematopoietic stem cells and progenitor cells within the erythroid, platelet and granulocytic lineages and can have devastating consequences in children and adults. The genetic features of these diseases often include clonal, nonrandom chromosomal deletions (e.g., 7q–, 5q–, 20q–, 6q–, 11q– and 13q–) that appear to inactivate tumor suppressor genes required for the normal development of myeloid cells (reviewed in Bench1 and Fenaux2). These putative tumor suppressors have proved to be much more difficult to identify than oncogenes activated by chromosomal translocations, the other major class of chromosomal lesions in MDS and MPD.3 Although MDS and MPD are almost certainly caused by mutations in stem/progenitor cells,4 the role of inactivated tumor suppressor genes in this process remains poorly understood. In a small portion of myeloid diseases, mutations have been identified in genes encoding factors known to be required for normal hematopoiesis, such as PU.1, RUNX1, CTNNA1 (α-catenin) and c/EBPα, and implicating these genes as tumor suppressors.5–7 Nonetheless, the identities of most deletion-associated tumor suppressors in these diseases remains elusive, despite complete sequencing of the human genome. The deleted regions detected by cytogenetic methods are generally very large, containing many hundreds of genes, thus making it hard to locate the critical affected gene or genes. It is also unclear whether dysfunctional myelopoiesis results from haploinsufficiency, associated with the deletion of one allele, or from homozygous inactivation due to additional point mutations or microdeletions of the retained wild-type allele. In general MDS have proved surprisingly resistant to conventional treatments. Targeted therapeutic advances in MDS will likely depend on a full comprehension of underlying molecular mechanisms, in particular the tumor suppressor genes lost through clonal, nonrandom chromosomal deletions, such as the 7q– and (del)5q.

scholarly journals Up-regulation of tumor suppressor genes by exogenous dhC16-Cer contributes to its anti-cancer activity in primary effusion lymphoma

Oncotarget ◽  
2017 ◽  
Vol 8 (9) ◽  
pp. 15220-15229 ◽  
Author(s):  
Yueyu Cao ◽  
Jing Qiao ◽  
Zhen Lin ◽  
Jovanny Zabaleta ◽  
Lu Dai ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Primary Effusion Lymphoma ◽  
Suppressor Genes ◽  
Anti Cancer ◽  
Cancer Activity

scholarly journals Macrophages, Inflammation, and Tumor Suppressors: ARF, a New Player in the Game

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Paqui G. Través ◽  
Alfonso Luque ◽  
Sonsoles Hortelano
Keyword(s):  
Tumor Suppressor ◽  
Immune Responses ◽  
Cancer Progression ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Molecular Mechanisms ◽  
Clinical Evidence ◽  
Macrophage Polarization ◽  
Innate Immune

The interaction between tumor progression and innate immune system has been well established in the last years. Indeed, several lines of clinical evidence indicate that immune cells such as tumor-associated macrophages (TAMs) interact with tumor cells, favoring growth, angiogenesis, and metastasis of a variety of cancers. In most tumors, TAMs show properties of an alternative polarization phenotype (M2) characterized by the expression of a series of chemokines, cytokines, and proteases that promote immunosuppression, tumor proliferation, and spreading of the cancer cells. Tumor suppressor genes have been traditionally linked to the regulation of cancer progression; however, a growing body of evidence indicates that these genes also play essential roles in the regulation of innate immunity pathways through molecular mechanisms that are still poorly understood. In this paper, we provide an overview of the immunobiology of TAMs as well as what is known about tumor suppressors in the context of immune responses. Recent advances regarding the role of the tumor suppressor ARF as a regulator of inflammation and macrophage polarization are also reviewed.

scholarly journals Transcription Factors and Methylation Drive Prognostic miRNA Dysregulation in Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Shijie Qin ◽  
Jieyun Xu ◽  
Yunmeng Yi ◽  
Sizhu Jiang ◽  
Ping Jin ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Tumor Suppressor ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Mature Mirnas ◽  
Promoter Regions ◽  
Multiple Tumor ◽  
Tumor Suppressor Mirnas ◽  
Abnormal Cell Proliferation

Many dysregulated microRNAs (miRNAs) have been suggested to serve as oncogenes or tumor suppressors to act as diagnostic and prognostic factors for HCC patients. However, the dysregulated mechanisms of miRNAs in HCC remain largely unknown. Herein, we firstly identify 114 disordered mature miRNAs in HCC, 93 of them are caused by dysregulated transcription factors, and 10 of them are driven by the DNA methylation of their promoter regions. Secondly, we find that seven up-regulated miRNAs (miR-9-5p, miR-452-5p, miR-452-3p, miR-1180-3p, miR-4746-5p, miR-3677-3 and miR-4661-5p) can promote tumorigenesis via inhibiting multiple tumor suppressor genes participated in metabolism, which may act as oncogenes, and seven down-regulated miRNAs (miR-99-5p, miR-5589-5p, miR-5589-3p, miR-139-5p, miR-139-3p, miR-101-3p and miR-125b-5p) can suppress abnormal cell proliferation via suppressing a number of oncogenes involved in cancer-related pathways, which may serve as tumor suppressors. Thirdly, our findings reveal a mechanism that transcription factor and miRNA interplay can form various regulatory loops to synergistically control the occurrence and development of HCC. Finally, our results demonstrate that this key transcription factor FOXO1 can activate a certain number of tumor suppressor miRNAs to improve the survival of HCC patients, suggesting FOXO1 as an effective therapeutic target for HCC patients. Overall, our study not only reveals the dysregulated mechanisms of miRNAs in HCC, but provides several novel prognostic biomarkers and potential therapeutic targets for HCC patients.

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