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

Kuoyuan Cheng, Nishanth Ulhas Nair, Joo Sang Lee, Eytan Ruppin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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.

Original languageEnglish
Article numbereabc2100
JournalScience advances
Volume7
Issue number1
DOIs
StatePublished - 1 Jan 2021
Externally publishedYes

Funding

FundersFunder number
National Cancer InstituteZIABC011802

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