Pan-cancer clinical impact of latent drivers from double mutations

Bengi Ruken Yavuz, Chung Jung Tsai, Ruth Nussinov, Nurcan Tuncbag*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Here, we discover potential ‘latent driver’ mutations in cancer genomes. Latent drivers have low frequencies and minor observable translational potential. As such, to date they have escaped identification. Their discovery is important, since when paired in cis, latent driver mutations can drive cancer. Our comprehensive statistical analysis of the pan-cancer mutation profiles of ~60,000 tumor sequences from the TCGA and AACR-GENIE cohorts identifies significantly co-occurring potential latent drivers. We observe 155 same gene double mutations of which 140 individual components are cataloged as latent drivers. Evaluation of cell lines and patient-derived xenograft response data to drug treatment indicate that in certain genes double mutations may have a prominent role in increasing oncogenic activity, hence obtaining a better drug response, as in PIK3CA. Taken together, our comprehensive analyses indicate that same-gene double mutations are exceedingly rare phenomena but are a signature for some cancer types, e.g., breast, and lung cancers. The relative rarity of doublets can be explained by the likelihood of strong signals resulting in oncogene-induced senescence, and by doublets consisting of non-identical single residue components populating the background mutational load, thus not identified.

Original languageEnglish
Article number202
JournalCommunications Biology
Volume6
Issue number1
DOIs
StatePublished - Dec 2023

Funding

FundersFunder number
TUBA-GEBIP
UNESCO-L’Oréal International Rising Talent Fellowship
National Institutes of HealthHHSN261201500003I
U.S. Department of Health and Human Services
National Cancer Institute
NIH Clinical Center
Government of South Australia
Türkiye Bilimsel ve Teknolojik Araştırma Kurumu121E245, 117E192

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