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

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.

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

2021 ◽  
Vol 7 (1) ◽  
pp. eabc2100
Author(s):  
Kuoyuan Cheng ◽  
Nishanth Ulhas Nair ◽  
Joo Sang Lee ◽  
Eytan Ruppin
Keyword(s):  
Tumor Suppressor ◽  
Cancer Risk ◽  
Tissue Specificity ◽  
Synthetic Lethality ◽  
Lifetime Cancer Risk ◽  
Normal Tissues ◽  
Gene Pairs ◽  
Stem Cell Divisions

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.

Role of stem-cell divisions in cancer risk

Nature ◽  
2017 ◽  
Vol 548 (7666) ◽  
pp. E13-E14 ◽  
Author(s):  
Cristian Tomasetti ◽  
Rick Durrett ◽  
Marek Kimmel ◽  
Amaury Lambert ◽  
Giovanni Parmigiani ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Risk ◽  
Cell Divisions ◽  
Stem Cell Divisions

scholarly journals Cancer Etiology: Variation in Cancer Risk among Tissues is Poorly Explained by the Number of Gene Mutations

2017 ◽  
Author(s):  
Miguel Lopez-Lazaro
Keyword(s):  
Stem Cell ◽  
Cancer Risk ◽  
Gene Mutations ◽  
Cancer Registries ◽  
Cancer Etiology ◽  
Driver Genes ◽  
Incidence Data ◽  
Cell Divisions ◽  
Stem Cell Divisions ◽  
Risk Of Cancer

Recent evidence indicates that the risk of being diagnosed with cancer in a tissue is strongly correlated (0.80) with the number of stem cell divisions accumulated by the tissue. Since cell division can generate random mutations during DNA replication, this correlation has been used to propose that cancer is largely caused by the accumulation of unavoidable mutations in driver genes. However, no correlation between the number of gene mutations and cancer risk across tissues has been reported. Because many somatic mutations in cancers originate prior to tumor initiation and the number of cell divisions occurring during tumor growth is similar among tissues, here I use whole genome sequencing information from 22,086 cancer samples and incidence data from the largest cancer registry in each continent to study the relationship between the number of gene mutations and the risk of cancer across 33 tissue types. Results show a weak positive correlation (mean = 0.14) between these two parameters in each of the five cancer registries. The correlation became stronger (mean = 0.50) when gender-related cancers were excluded. Results also show that 1,003 samples from 29 cancer types have zero mutations in genes. These data suggest that cancer etiology can be better explained by the accumulation of stem cell divisions than by the accumulation of gene mutations. Possible mechanisms by which the accumulation of cell divisions in stem cells increases the risk of cancer are discussed.

scholarly journals Do Mutations Turn p53 into an Oncogene?

2019 ◽  
Vol 20 (24) ◽  
pp. 6241 ◽  
Author(s):  
Consuelo Pitolli ◽  
Ying Wang ◽  
Mara Mancini ◽  
Yufang Shi ◽  
Gerry Melino ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cancer Risk ◽  
Germline Mutations

The key role of p53 as a tumor suppressor became clear when it was realized that this gene is mutated in 50% of human sporadic cancers, and germline mutations expose carriers to cancer risk throughout their lifespan. Mutations in this gene not only abolish the tumor suppressive functions of p53, but also equip the protein with new pro-oncogenic functions. Here, we review the mechanisms by which these new functions gained by p53 mutants promote tumorigenesis.

scholarly journals Peto's paradox and human cancers

2015 ◽  
Vol 370 (1673) ◽  
pp. 20150104 ◽  
Author(s):  
Robert Noble ◽  
Oliver Kaltz ◽  
Michael E. Hochberg
Keyword(s):  
Stem Cell ◽  
Natural Selection ◽  
Cancer Risk ◽  
Cancer Incidence ◽  
Human Cancer ◽  
Independent Effect ◽  
Anatomical Site ◽  
Lifetime Cancer Risk ◽  
Cell Divisions ◽  
Stem Cell Divisions

Peto's paradox is the lack of the expected trend in cancer incidence as a function of body size and lifespan across species. The leading hypothesis to explain this pattern is natural selection for differential cancer prevention in larger, longer lived species. We evaluate whether a similar effect exists within species, specifically humans. We begin by reanalysing a recently published dataset to separate the effects of stem cell number and replication rate, and show that each has an independent effect on cancer risk. When considering the lifetime number of stem cell divisions in an extended dataset, and removing cases associated with other diseases or carcinogens, we find that lifetime cancer risk per tissue saturates at approximately 0.3–1.3% for the types considered. We further demonstrate that grouping by anatomical site explains most of the remaining variation. Our results indicate that cancer risk depends not only on the number of stem cell divisions but varies enormously (approx. 10 000 times) depending on anatomical site. We conclude that variation in risk of human cancer types is analogous to the paradoxical lack of variation in cancer incidence among animal species and may likewise be understood as a result of evolution by natural selection.

scholarly journals NDR1 functions as tumor suppressor in glioblastoma by phosphoralation of YAP

2021 ◽  
Author(s):  
Bin Chen ◽  
Bin Liu ◽  
Tao Yu ◽  
Yunfeng Han ◽  
Chao Wu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Flow Cytometry ◽  
Tumor Suppressor ◽  
Hippo Pathway ◽  
Tumor Model ◽  
Hippo Signaling ◽  
Lower Survival Rate ◽  
Normal Tissues ◽  
Cycle Arrest

Abstract Purpose: The NDR1(Nuclear Dbf2-related) kinase is a member of the NDR/LATS family which was a supplementary of Hippo pathway. However, whether NDR1 could inhibit glioblastoma (GBM) growth by phosphorylating YAP remains unknown. Meanwhile, the role of NDR1 in GBM was not clear. The purpose of this study was to investigate the role of NDR1-YAP pathway in GBM. Materials and Methods: Bioinformation analysis and immunohistochemistry was performed to identify the expression of NDR1 in GBM. The effect of NDR1 on cell proliferation and cell cycle was analyzed utilizing cck-8, clone formation, immunofluorescence and flow cytometry respectively. In addition, the xenograft tumor model was established as well. Protein interaction was examined by Co-ip and immunofluorescence. Results: Bioinformation analysis and immunohistochemistry of our petients’ tumor tissues showed that expression of NDR1 in tumor tissue was relatively lower than that in normal tissues and was positively related to lower survival rate. NDR1 could markedly reduce the proliferation, colony formation of U87 and U251. Furthermore, the results of flow cytometry showed that NDR1 led to cell cycle arrest at the G1 phase. Tumor growth was also inhibited in xenograft nude mouse models in NDR1-OE group. Western blotting and immunofluorescence showed that NDR1 could integrate with and phophoralate YAP at S127 site. Meanwhile, NDR1 could mediate apopptosis process. Conclusion: In summary, our findings pointed out that NDR1 functions as a tumor suppressor in GBM. NDR1 was identified as a novel regulator of YAP, which give us a in depth comprehension in Hippo signaling pathway.

scholarly journals MicroRNA-520b Functions as a Tumor Suppressor in Colorectal Cancer by Inhibiting Defective in Cullin Neddylation 1 Domain Containing 1 (DCUN1D1)

2018 ◽  
Vol 26 (4) ◽  
pp. 593-604 ◽  
Author(s):  
Jing Xiao ◽  
Guang Li ◽  
Jingyu Zhou ◽  
Shalong Wang ◽  
Dongcai Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Epithelial Mesenchymal Transition ◽  
Epithelial Cell Line ◽  
Intestinal Epithelial ◽  
Mesenchymal Transition ◽  
Small Noncoding Rnas ◽  
Normal Tissues ◽  
Novel Target

MicroRNAs (miRs), a class of small noncoding RNAs, are important regulators for gene expression through directly binding to the 3′-untranslated region (3′-UTR) of their target mRNA. Recently, downregulation of miR-520b has been observed in several common human cancers. However, the exact role of miR-520b in colorectal cancer (CRC) has not previously been studied. In this study, our data showed that miR-520b was significantly downregulated in CRC and cell lines when compared with adjacent normal tissues and a normal intestinal epithelial cell line. Low expression of miR-520b was notably associated with the malignant progress and a shorter survival time for CRC patients. Restoration of miR-520b inhibited cell proliferation, migration, invasion, and epithelial‐mesenchymal transition (EMT) in CRC cells. Defective in cullin neddylation 1 domain containing 1 (DCUN1D1) was then identified as a novel target gene of miR-520b in CRC cells. The expression of DCUN1D1 was significantly increased in CRC, with a negative correlation to miR-520b expression in CRC tissues. Moreover, a high expression of DCUN1D1 was significantly associated with the malignant progress and a poor prognosis for CRC patients. Furthermore, overexpression of DCUN1D1 rescued the miR-520b-mediated malignant phenotypes and EMT in CRC cells. The data demonstrate that miR-520b functions as a tumor suppressor in CRC through targeting DCUN1D1, suggesting that miR-520b may become a potential therapeutic target for the treatment of CRC.

scholarly journals Cross-species identification of cancer-resistance associated genes uncovers their relevance to human cancer risk

2021 ◽  
Author(s):  
Nishanth Ulhas Nair ◽  
Kuoyuan Cheng ◽  
Lamis Naddaf ◽  
Elad Sharon ◽  
Lipika R Pal ◽  
...  
Keyword(s):  
Cancer Risk ◽  
Metabolic Pathways ◽  
Human Cancer ◽  
Cancer Resistance ◽  
Loss Of Function ◽  
Driver Genes ◽  
Lifetime Cancer Risk ◽  
Cancer Driver ◽  
Evolutionarily Conserved ◽  
Resistance Score

Cancer is an evolutionarily conserved disease that occurs in a wide variety of species. We applied a comparative genomics approach to systematically characterize the genes whose conservation levels significantly correlates positively (PC) or negatively (NC) with a broad spectrum of cancer-resistance estimates, computed across almost 200 vertebrate species. PC genes are enriched in pathways relevant to tumor suppression including cell cycle, DNA repair, and immune response, while NC genes are enriched with a host of metabolic pathways. The conservation levels of the PC and NC genes in a species serve to build the first genomics-based predictor of its cancer resistance score. We find that PC genes are less tolerant to loss of function (LoF) mutations, are enriched in cancer driver genes and are associated with germline mutations that increase human cancer risk. Furthermore, their expression levels are associated with lifetime cancer risk across human tissues. Finally, their knockout in mice results in increased cancer incidence. In sum, we find that many genes associated with cancer resistance across species are implicated in human cancers, pointing to several additional candidate genes that may have a functional role in human cancer.

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