Transcriptional Immune Suppression and Up-regulation of Double-stranded DNA Damage and Repair Repertoires in EcDNA-containing Tumors

Overview

Journal Elife

Specialty Biology

Date 2024 Jun 19

PMID 38896472

Authors

Miin S Lin

Se-Young Jo

Jens Luebeck

Howard Y Chang

Sihan Wu

Paul S Mischel

Vineet Bafna

Affiliations

Soon will be listed here.

Abstract

Extrachromosomal DNA is a common cause of oncogene amplification in cancer. The non-chromosomal inheritance of ecDNA enables tumors to rapidly evolve, contributing to treatment resistance and poor outcome for patients. The transcriptional context in which ecDNAs arise and progress, including chromosomally-driven transcription, is incompletely understood. We examined gene expression patterns of 870 tumors of varied histological types, to identify transcriptional correlates of ecDNA. Here, we show that ecDNA-containing tumors impact four major biological processes. Specifically, ecDNA-containing tumors up-regulate DNA damage and repair, cell cycle control, and mitotic processes, but down-regulate global immune regulation pathways. Taken together, these results suggest profound alterations in gene regulation in ecDNA-containing tumors, shedding light on molecular processes that give rise to their development and progression.

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References

Li Y, James S, Wyllie D, Wynne C, Czibula A, Bukhari A . TMEM203 is a binding partner and regulator of STING-mediated inflammatory signaling in macrophages. Proc Natl Acad Sci U S A. 2019; 116(33):16479-16488. PMC: 6697806. DOI: 10.1073/pnas.1901090116. View

McGrail D, Pilie P, Rashid N, Voorwerk L, Slagter M, Kok M . High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann Oncol. 2021; 32(5):661-672. PMC: 8053682. DOI: 10.1016/j.annonc.2021.02.006. View

Nathanson D, Gini B, Mottahedeh J, Visnyei K, Koga T, Gomez G . Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA. Science. 2013; 343(6166):72-6. PMC: 4049335. DOI: 10.1126/science.1241328. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Kim H, Nguyen N, Turner K, Wu S, Gujar A, Luebeck J . Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers. Nat Genet. 2020; 52(9):891-897. PMC: 7484012. DOI: 10.1038/s41588-020-0678-2. View

Feng Y, Zhang T, Wang Y, Xie M, Ji X, Luo X . Homeobox Genes in Cancers: From Carcinogenesis to Recent Therapeutic Intervention. Front Oncol. 2021; 11:770428. PMC: 8551923. DOI: 10.3389/fonc.2021.770428. View

He L, Guo Z, Wang W, Tian S, Lin R . FUT2 inhibits the EMT and metastasis of colorectal cancer by increasing LRP1 fucosylation. Cell Commun Signal. 2023; 21(1):63. PMC: 10041739. DOI: 10.1186/s12964-023-01060-0. View

Rizvi N, Hellmann M, Snyder A, Kvistborg P, Makarov V, Havel J . Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015; 348(6230):124-8. PMC: 4993154. DOI: 10.1126/science.aaa1348. View

Sanborn J, Salama S, Grifford M, Brennan C, Mikkelsen T, Jhanwar S . Double minute chromosomes in glioblastoma multiforme are revealed by precise reconstruction of oncogenic amplicons. Cancer Res. 2013; 73(19):6036-45. PMC: 3800429. DOI: 10.1158/0008-5472.CAN-13-0186. View

10.

Feng Z, Li L, Zeng Q, Zhang Y, Tu Y, Chen W . Silencing Inhibits the Proliferation and Metastasis of Gastric Cancer. J Cancer. 2022; 13(2):565-578. PMC: 8771524. DOI: 10.7150/jca.62033. View

11.

Bagaev A, Kotlov N, Nomie K, Svekolkin V, Gafurov A, Isaeva O . Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. Cancer Cell. 2021; 39(6):845-865.e7. DOI: 10.1016/j.ccell.2021.04.014. View

12.

Ng P, Henikoff S . SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003; 31(13):3812-4. PMC: 168916. DOI: 10.1093/nar/gkg509. View

13.

Samson N, Ablasser A . The cGAS-STING pathway and cancer. Nat Cancer. 2022; 3(12):1452-1463. DOI: 10.1038/s43018-022-00468-w. View

14.

van Leen E, Bruckner L, Henssen A . The genomic and spatial mobility of extrachromosomal DNA and its implications for cancer therapy. Nat Genet. 2022; 54(2):107-114. DOI: 10.1038/s41588-021-01000-z. View

15.

Sondka Z, Bamford S, Cole C, Ward S, Dunham I, Forbes S . The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers. Nat Rev Cancer. 2018; 18(11):696-705. PMC: 6450507. DOI: 10.1038/s41568-018-0060-1. View

16.

Fouquin A, Guirouilh-Barbat J, Lopez B, Hall J, Amor-Gueret M, Pennaneach V . PARP2 controls double-strand break repair pathway choice by limiting 53BP1 accumulation at DNA damage sites and promoting end-resection. Nucleic Acids Res. 2017; 45(21):12325-12339. PMC: 5716083. DOI: 10.1093/nar/gkx881. View

17.

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

18.

Liberzon A, Subramanian A, Pinchback R, Thorvaldsdottir H, Tamayo P, Mesirov J . Molecular signatures database (MSigDB) 3.0. Bioinformatics. 2011; 27(12):1739-40. PMC: 3106198. DOI: 10.1093/bioinformatics/btr260. View

19.

Aran D, Sirota M, Butte A . Systematic pan-cancer analysis of tumour purity. Nat Commun. 2015; 6:8971. PMC: 4671203. DOI: 10.1038/ncomms9971. View

20.

Zhu A, Ibrahim J, Love M . Heavy-tailed prior distributions for sequence count data: removing the noise and preserving large differences. Bioinformatics. 2018; 35(12):2084-2092. PMC: 6581436. DOI: 10.1093/bioinformatics/bty895. View