한빛사논문
- 조회200
Dong‑Jin Han1,2,3, Sunmin Kim1,2,3, Seo‑Young Lee1,2,3, Youngbeen Moon1,2,3, Su Jung Kang1,2, Jinseon Yoo1,2,3, Hye Young Jeong1,2, Hae Jin Cho1,2, Jeong Yang Jeon1,2, Byeong Chang Sim6, Jaehoon Kim6, Seungho Lee4, Ruibin Xi5 and Tae‑Min Kim1,2,6*
1Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea.
2Cancer Research Institute, College of Medicine, The Catholic University of Korea, 222 Bandodae‑ro, Seocho‑Gu, Seoul, Korea.
3Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul, Korea.
4Department of Pharmacology, Yonsei University College of Medicine, Seoul, Republic of Korea.
5School of Mathematical Sciences and Center for Statistical Science, Peking University, Beijing, China.
6CMC Institute for Basic Medical Science, The Catholic Medical Center of The Catholic University of Korea, Seoul, Republic of Korea.
Dong-Jin Han, Sunmin Kim wish it to be known that, in their opinion, the frst two authors should be regarded as joint First Authors.
*Correspondence: Tae‑Min Kim
Abstract
Background: Determining the impact of somatic mutations requires understanding the functional relationship of genes acquiring mutations; however, it is largely unknown how mutations in functionally related genes influence each other.
Methods: We employed non-synonymous-to-synonymous or dNdS ratios to evaluate the evolutionary dependency (ED) of gene pairs, assuming a mutation in one gene of a gene pair can affect the evolutionary fitness of mutations in its partner genes as mutation context. We employed PanCancer- and tumor type-specific mutational profiles to infer the ED of gene pairs and evaluated their biological relevance with respect to gene dependency and drug sensitivity.
Results: We propose that dNdS ratios of gene pairs and their derived cdNS (context-dependent dNdS) scores as measure of ED distinguishing gene pairs either as synergistic (SYN) or antagonistic (ANT). Mutation contexts can induce substantial changes in the evolutionary fitness of mutations in the paired genes, e.g., IDH1 and IDH2 mutation contexts lead to substantial increase and decrease of dNdS ratios of ATRX indels and IDH1 missense mutations corresponding to SYN and ANT relationship with positive and negative cdNS scores, respectively. The impact of gene silencing or knock-outs on cell viability (genetic dependencies) often depends on ED, suggesting that ED can guide the selection of candidates for synthetic lethality such as TCF7L2-KRAS mutations. Using cell line-based drug sensitivity data, the effects of targeted agents on cell lines are often associated with mutations of genes exhibiting ED with the target genes, informing drug sensitizing or resistant mutations for targeted inhibitors, e.g., PRSS1 and CTCF mutations as resistant mutations to EGFR and BRAF inhibitors for lung adenocarcinomas and melanomas, respectively.
Conclusions: We propose that the ED of gene pairs evaluated by dNdS ratios can advance our understanding of the functional relationship of genes with potential biological and clinical implications.
논문정보
- Research article
- 2024년 08월 (BRIC 등록일 2024-08-28)
- 국내(교신)+국외 연구진
- 의약학 > 유전 및 유전체의학
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