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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 l...

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Autores principales: Cheng, Kuoyuan, Nair, Nishanth Ulhas, Lee, Joo Sang, Ruppin, Eytan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775773/
https://www.ncbi.nlm.nih.gov/pubmed/33523837
http://dx.doi.org/10.1126/sciadv.abc2100
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author Cheng, Kuoyuan
Nair, Nishanth Ulhas
Lee, Joo Sang
Ruppin, Eytan
author_facet Cheng, Kuoyuan
Nair, Nishanth Ulhas
Lee, Joo Sang
Ruppin, Eytan
author_sort Cheng, Kuoyuan
collection PubMed
description 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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spelling pubmed-77757732021-01-14 Synthetic lethality across normal tissues is strongly associated with cancer risk, onset, and tumor suppressor specificity Cheng, Kuoyuan Nair, Nishanth Ulhas Lee, Joo Sang Ruppin, Eytan Sci Adv Research Articles 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. American Association for the Advancement of Science 2021-01-01 /pmc/articles/PMC7775773/ /pubmed/33523837 http://dx.doi.org/10.1126/sciadv.abc2100 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/ https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Research Articles
Cheng, Kuoyuan
Nair, Nishanth Ulhas
Lee, Joo Sang
Ruppin, Eytan
Synthetic lethality across normal tissues is strongly associated with cancer risk, onset, and tumor suppressor specificity
title Synthetic lethality across normal tissues is strongly associated with cancer risk, onset, and tumor suppressor specificity
title_full Synthetic lethality across normal tissues is strongly associated with cancer risk, onset, and tumor suppressor specificity
title_fullStr Synthetic lethality across normal tissues is strongly associated with cancer risk, onset, and tumor suppressor specificity
title_full_unstemmed Synthetic lethality across normal tissues is strongly associated with cancer risk, onset, and tumor suppressor specificity
title_short Synthetic lethality across normal tissues is strongly associated with cancer risk, onset, and tumor suppressor specificity
title_sort synthetic lethality across normal tissues is strongly associated with cancer risk, onset, and tumor suppressor specificity
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775773/
https://www.ncbi.nlm.nih.gov/pubmed/33523837
http://dx.doi.org/10.1126/sciadv.abc2100
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