Identifying Modules of Cooperating Cancer Drivers

Overview

Journal Mol Syst Biol

Specialty Molecular Biology

Date 2021 Mar 26

PMID 33769711

Citations 9

Authors

Michael I Klein

Vincent L Cannataro

Jeffrey P Townsend

Scott Newman

David F Stern

Hongyu Zhao

Affiliations

Soon will be listed here.

Abstract

Identifying cooperating modules of driver alterations can provide insights into cancer etiology and advance the development of effective personalized treatments. We present Cancer Rule Set Optimization (CRSO) for inferring the combinations of alterations that cooperate to drive tumor formation in individual patients. Application to 19 TCGA cancer types revealed a mean of 11 core driver combinations per cancer, comprising 2-6 alterations per combination and accounting for a mean of 70% of samples per cancer type. CRSO is distinct from methods based on statistical co-occurrence, which we demonstrate is a suboptimal criterion for investigating driver cooperation. CRSO identified well-studied driver combinations that were not detected by other approaches and nominated novel combinations that correlate with clinical outcomes in multiple cancer types. Novel synergies were identified in NRAS-mutant melanomas that may be therapeutically relevant. Core driver combinations involving NFE2L2 mutations were identified in four cancer types, supporting the therapeutic potential of NRF2 pathway inhibition. CRSO is available at https://github.com/mikekleinsgit/CRSO/.

Citing Articles

Rare Drivers at Low Prevalence with High Cancer Effects in T-Cell and B-Cell Pediatric Acute Lymphoblastic Leukemia.

Mandell J, Diviti S, Xu M, Townsend J Int J Mol Sci. 2024; 25(12).

PMID: 38928295 PMC: 11203805. DOI: 10.3390/ijms25126589.

Prevalence and Associations of Co-occurrence of Mutations and Chromosome 3q26 Amplification in Lung Cancer.

Liu J, Liu S, Li D, Li H, Zhang F Glob Med Genet. 2024; 11(2):150-158.

PMID: 38628662 PMC: 11018393. DOI: 10.1055/s-0044-1786004.

Pairwise and higher-order epistatic effects among somatic cancer mutations across oncogenesis.

Alfaro-Murillo J, Townsend J Math Biosci. 2023; 366:109091.

PMID: 37996064 PMC: 10847963. DOI: 10.1016/j.mbs.2023.109091.

Estimation of Neutral Mutation Rates and Quantification of Somatic Variant Selection Using cancereffectsizeR.

Mandell J, Cannataro V, Townsend J Cancer Res. 2022; 83(4):500-505.

PMID: 36469362 PMC: 9929515. DOI: 10.1158/0008-5472.CAN-22-1508.

Big data in basic and translational cancer research.

Jiang P, Sinha S, Aldape K, Hannenhalli S, Sahinalp C, Ruppin E Nat Rev Cancer. 2022; 22(11):625-639.

PMID: 36064595 PMC: 9443637. DOI: 10.1038/s41568-022-00502-0.

References

Liu C, Wang C, Wang K, Liu L, Shen Q, Yan K . SMYD3 as an oncogenic driver in prostate cancer by stimulation of androgen receptor transcription. J Natl Cancer Inst. 2013; 105(22):1719-28. DOI: 10.1093/jnci/djt304. View

Mina M, Raynaud F, Tavernari D, Battistello E, Sungalee S, Saghafinia S . Conditional Selection of Genomic Alterations Dictates Cancer Evolution and Oncogenic Dependencies. Cancer Cell. 2017; 32(2):155-168.e6. DOI: 10.1016/j.ccell.2017.06.010. View

Leiserson M, Wu H, Vandin F, Raphael B . CoMEt: a statistical approach to identify combinations of mutually exclusive alterations in cancer. Genome Biol. 2015; 16:160. PMC: 4531541. DOI: 10.1186/s13059-015-0700-7. View

Chen X, Lun L, Hou H, Tian R, Zhang H, Zhang Y . The Value of lncRNA HULC as a Prognostic Factor for Survival of Cancer Outcome: A Meta-Analysis. Cell Physiol Biochem. 2017; 41(4):1424-1434. DOI: 10.1159/000468005. View

Luis Manzano J, Layos L, Buges C, de Los Llanos Gil M, Vila L, Martinez-Balibrea E . Resistant mechanisms to BRAF inhibitors in melanoma. Ann Transl Med. 2016; 4(12):237. PMC: 4930524. DOI: 10.21037/atm.2016.06.07. View

Lawrence M, Stojanov P, Polak P, Kryukov G, Cibulskis K, Sivachenko A . Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013; 499(7457):214-218. PMC: 3919509. DOI: 10.1038/nature12213. View

Villanueva J, Infante J, Krepler C, Reyes-Uribe P, Samanta M, Chen H . Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. Cell Rep. 2013; 4(6):1090-9. PMC: 3956616. DOI: 10.1016/j.celrep.2013.08.023. View

Cannataro V, Gaffney S, Townsend J . Effect Sizes of Somatic Mutations in Cancer. J Natl Cancer Inst. 2018; 110(11):1171-1177. PMC: 6235682. DOI: 10.1093/jnci/djy168. View

Klec C, Gutschner T, Panzitt K, Pichler M . Involvement of long non-coding RNA HULC (highly up-regulated in liver cancer) in pathogenesis and implications for therapeutic intervention. Expert Opin Ther Targets. 2019; 23(3):177-186. DOI: 10.1080/14728222.2019.1570499. View

10.

Shen B, Tan M, Mu X, Qin Y, Zhang F, Liu Y . Upregulated SMYD3 promotes bladder cancer progression by targeting BCLAF1 and activating autophagy. Tumour Biol. 2015; 37(6):7371-81. DOI: 10.1007/s13277-015-4410-2. View

11.

Nojiri S, Joh T . Albumin suppresses human hepatocellular carcinoma proliferation and the cell cycle. Int J Mol Sci. 2014; 15(3):5163-74. PMC: 3975446. DOI: 10.3390/ijms15035163. View

12.

Hofree M, Shen J, Carter H, Gross A, Ideker T . Network-based stratification of tumor mutations. Nat Methods. 2013; 10(11):1108-15. PMC: 3866081. DOI: 10.1038/nmeth.2651. View

13.

Li Y, Liu J, Zhou J, Chen R, Cen C . LncRNA HULC induces the progression of osteosarcoma by regulating the miR-372-3p/HMGB1 signalling axis. Mol Med. 2020; 26(1):26. PMC: 7081592. DOI: 10.1186/s10020-020-00155-5. View

14.

Liu Z, Deng M, Wu L, Zhang S . An integrative investigation on significant mutations and their down-stream pathways in lung squamous cell carcinoma reveals CUL3/KEAP1/NRF2 relevant subtypes. Mol Med. 2020; 26(1):48. PMC: 7240936. DOI: 10.1186/s10020-020-00166-2. View

15.

. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015; 517(7536):576-82. PMC: 4311405. DOI: 10.1038/nature14129. View

16.

Grossman R, Heath A, Ferretti V, Varmus H, Lowy D, Kibbe W . Toward a Shared Vision for Cancer Genomic Data. N Engl J Med. 2016; 375(12):1109-12. PMC: 6309165. DOI: 10.1056/NEJMp1607591. View

17.

Rojo de la Vega M, Chapman E, Zhang D . NRF2 and the Hallmarks of Cancer. Cancer Cell. 2018; 34(1):21-43. PMC: 6039250. DOI: 10.1016/j.ccell.2018.03.022. View

18.

Ghafouri-Fard S, Esmaeili M, Taheri M, Samsami M . Highly upregulated in liver cancer (HULC): An update on its role in carcinogenesis. J Cell Physiol. 2020; 235(12):9071-9079. DOI: 10.1002/jcp.29765. View

19.

Mazur P, Reynoird N, Khatri P, Jansen P, Wilkinson A, Liu S . SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature. 2014; 510(7504):283-7. PMC: 4122675. DOI: 10.1038/nature13320. View

20.

Mermel C, Schumacher S, Hill B, Meyerson M, Beroukhim R, Getz G . GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011; 12(4):R41. PMC: 3218867. DOI: 10.1186/gb-2011-12-4-r41. View