RRM2B Is Frequently Amplified Across Multiple Tumor Types: Implications for DNA Repair, Cellular Survival, and Cancer Therapy

Overview

Journal Front Genet

Date 2021 Apr 19

PMID 33868369

Citations 7

Authors

Waleed Iqbal

Elena V Demidova

Samantha Serrao

Taha ValizadehAslani

Gail Rosen

Sanjeevani Arora

Affiliations

Soon will be listed here.

Abstract

plays a crucial role in DNA replication, repair and oxidative stress. While germline mutations have been implicated in mitochondrial disorders, its relevance to cancer has not been established. Here, using TCGA studies, we investigated alterations in cancer. We found that is highly amplified in multiple tumor types, particularly in -amplified tumors, and is associated with increased mRNA expression. We also observed that the chromosomal region 8q22.3-8q24, is amplified in multiple tumors, and includes , along with several other cancer-associated genes. An analysis of genes within this 8q-amplicon showed that cancers that have both -amplified along with have a distinct pattern of amplification compared to cancers that are unaltered or those that have amplifications in or only. Investigation of curated biological interactions revealed that gene products of the amplified 8q22.3-8q24 region have important roles in DNA repair, DNA damage response, oxygen sensing, and apoptosis pathways and interact functionally. Notably, -amplified cancers are characterized by mutation signatures of defective DNA repair and oxidative stress, and at least -amplified breast cancers are associated with poor clinical outcome. These data suggest alterations in RR2MB and possibly the interacting 8q-proteins could have a profound effect on regulatory pathways such as DNA repair and cellular survival, highlighting therapeutic opportunities in these cancers.

Citing Articles

Development of a novel risk signature revealing prognostic and tumor microenvironmental features in breast cancer.

Shen Y, Jiang B, Luo Y, Zhang Z Medicine (Baltimore). 2025; 104(5):e41369.

PMID: 39889154 PMC: 11789914. DOI: 10.1097/MD.0000000000041369.

RRM2 promotes liver metastasis of pancreatic cancer by stabilizing YBX1 and activating the TGF-beta pathway.

Du Z, Zhang Q, Xiang X, Li W, Yang Q, Yu H iScience. 2024; 27(10):110864.

PMID: 39398252 PMC: 11470400. DOI: 10.1016/j.isci.2024.110864.

Transcriptome- and proteome-wide association studies identify genes associated with renal cell carcinoma.

Dutta D, Guo X, Winter T, Jahagirdar O, Ha E, Susztak K Am J Hum Genet. 2024; 111(9):1864-1876.

PMID: 39137781 PMC: 11393681. DOI: 10.1016/j.ajhg.2024.07.012.

Integrative lactylation and tumor microenvironment signature as prognostic and therapeutic biomarkers in skin cutaneous melanoma.

Zhu Y, Song B, Yang Z, Peng Y, Cui Z, Chen L J Cancer Res Clin Oncol. 2023; 149(20):17897-17919.

PMID: 37955686 DOI: 10.1007/s00432-023-05483-7.

Candidate variants in DNA replication and repair genes in early-onset renal cell carcinoma patients referred for germline testing.

Demidova E, Serebriiskii I, Vlasenkova R, Kelow S, Andrake M, Hartman T BMC Genomics. 2023; 24(1):212.

PMID: 37095444 PMC: 10123997. DOI: 10.1186/s12864-023-09310-8.

References

Begg K, Tavassoli M . Inside the hypoxic tumour: reprogramming of the DDR and radioresistance. Cell Death Discov. 2020; 6:77. PMC: 7434912. DOI: 10.1038/s41420-020-00311-0. View

Jia Y, Chen L, Jia Q, Dou X, Xu N, Liao D . The well-accepted notion that gene amplification contributes to increased expression still remains, after all these years, a reasonable but unproven assumption. J Carcinog. 2016; 15:3. PMC: 4895059. DOI: 10.4103/1477-3163.182809. View

Desai A, Yan Y, Gerson S . Advances in therapeutic targeting of the DNA damage response in cancer. DNA Repair (Amst). 2018; 66-67:24-29. PMC: 6005187. DOI: 10.1016/j.dnarep.2018.04.004. View

Bornstein B, Area E, Flanigan K, Ganesh J, Jayakar P, Swoboda K . Mitochondrial DNA depletion syndrome due to mutations in the RRM2B gene. Neuromuscul Disord. 2008; 18(6):453-9. PMC: 3891825. DOI: 10.1016/j.nmd.2008.04.006. View

Byrne J, Balleine R, Fejzo M, Mercieca J, Chiew Y, Livnat Y . Tumor protein D52 (TPD52) is overexpressed and a gene amplification target in ovarian cancer. Int J Cancer. 2005; 117(6):1049-54. DOI: 10.1002/ijc.21250. View

Scanlon S, Glazer P . Multifaceted control of DNA repair pathways by the hypoxic tumor microenvironment. DNA Repair (Amst). 2015; 32:180-189. PMC: 4522377. DOI: 10.1016/j.dnarep.2015.04.030. View

Qi J, Liu L, Cao J, An G, Li S, Li G . E2F1 regulates p53R2 gene expression in p53-deficient cells. Mol Cell Biochem. 2014; 399(1-2):179-88. DOI: 10.1007/s11010-014-2244-7. View

Yanamoto S, Kawasaki G, Yoshitomi I, Mizuno A . Expression of p53R2, newly p53 target in oral normal epithelium, epithelial dysplasia and squamous cell carcinoma. Cancer Lett. 2003; 190(2):233-43. DOI: 10.1016/s0304-3835(02)00588-8. View

Christoph F, Schmidt B, Schmitz-Drager B, Schulz W . Over-expression and amplification of the c-myc gene in human urothelial carcinoma. Int J Cancer. 1999; 84(2):169-73. DOI: 10.1002/(sici)1097-0215(19990420)84:2<169::aid-ijc13>3.0.co;2-f. View

10.

Okumura H, Natsugoe S, Yokomakura N, Kita Y, Matsumoto M, Uchikado Y . Expression of p53R2 is related to prognosis in patients with esophageal squamous cell carcinoma. Clin Cancer Res. 2006; 12(12):3740-5. DOI: 10.1158/1078-0432.CCR-05-2416. View

11.

Bruch J, Wohr G, Hautmann R, Mattfeldt T, Bruderlein S, Moller P . Chromosomal changes during progression of transitional cell carcinoma of the bladder and delineation of the amplified interval on chromosome arm 8q. Genes Chromosomes Cancer. 1998; 23(2):167-74. DOI: 10.1002/(sici)1098-2264(199810)23:2<167::aid-gcc10>3.0.co;2-l. View

12.

Piao C, Youn C, Jin M, Yoon S, Chang I, Lee J . MEK2 regulates ribonucleotide reductase activity through functional interaction with ribonucleotide reductase small subunit p53R2. Cell Cycle. 2012; 11(17):3237-49. PMC: 3466523. DOI: 10.4161/cc.21591. View

13.

Okumura H, Natsugoe S, Matsumoto M, Mataki Y, Takatori H, Ishigami S . The predictive value of p53, p53R2, and p21 for the effect of chemoradiation therapy on oesophageal squamous cell carcinoma. Br J Cancer. 2005; 92(2):284-9. PMC: 2361856. DOI: 10.1038/sj.bjc.6602322. View

14.

Chae Y, Anker J, Carneiro B, Chandra S, Kaplan J, Kalyan A . Genomic landscape of DNA repair genes in cancer. Oncotarget. 2016; 7(17):23312-21. PMC: 5029628. DOI: 10.18632/oncotarget.8196. View

15.

Chen J, Xiao Y, Cai X, Liu J, Chen K, Zhang X . Overexpression of p53R2 is associated with poor prognosis in lung sarcomatoid carcinoma. BMC Cancer. 2017; 17(1):855. PMC: 5731091. DOI: 10.1186/s12885-017-3811-6. View

16.

Foskolou I, Hammond E . RRM2B: An oxygen-requiring protein with a role in hypoxia. Mol Cell Oncol. 2017; 4(5):e1335272. PMC: 5644472. DOI: 10.1080/23723556.2017.1335272. View

17.

Shaibani A, Shchelochkov O, Zhang S, Katsonis P, Lichtarge O, Wong L . Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B. Arch Neurol. 2009; 66(8):1028-32. PMC: 2747647. DOI: 10.1001/archneurol.2009.139. View

18.

Yong Z, Zaini Z, Kallarakkal T, Karen-Ng L, Abdul Rahman Z, Ismail S . Genetic alterations of chromosome 8 genes in oral cancer. Sci Rep. 2014; 4:6073. PMC: 4133705. DOI: 10.1038/srep06073. View

19.

Chernov M, Stark G . The p53 activation and apoptosis induced by DNA damage are reversibly inhibited by salicylate. Oncogene. 1997; 14(21):2503-10. DOI: 10.1038/sj.onc.1201104. View

20.

Parris T, Kovacs A, Hajizadeh S, Nemes S, Semaan M, Levin M . Frequent MYC coamplification and DNA hypomethylation of multiple genes on 8q in 8p11-p12-amplified breast carcinomas. Oncogenesis. 2014; 3:e95. PMC: 4038389. DOI: 10.1038/oncsis.2014.8. View