A novel RBBP8(p.E281*) germline mutation is a predisposing mutation in familial hereditary cancer syndrome.
Hereditary cancer
RBBP8
Tumor susceptibility genes
Journal
Journal of molecular medicine (Berlin, Germany)
ISSN: 1432-1440
Titre abrégé: J Mol Med (Berl)
Pays: Germany
ID NLM: 9504370
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
received:
14
02
2023
accepted:
29
07
2023
revised:
30
04
2023
medline:
9
10
2023
pubmed:
24
8
2023
entrez:
24
8
2023
Statut:
ppublish
Résumé
Screening tumor susceptibility genes helps in identifying powerful biomarkers for hereditary cancer monitoring, prevention, and diagnosis, providing opportunities for understanding potential molecular mechanisms and biomarkers for the precise treatment of hereditary cancer syndromes. Whole-exome sequencing of blood and bioinformatics analysis uncovered a novel RBBP8(p.E281*) germline mutation in a family with hereditary cancer syndrome, which was verified by Sanger sequencing. Cell proliferation, colony formation, cell migration, and in vivo tumorigenesis were investigated by CCK8, colony formation, Transwell, and in vivo xenograft assays. Protein localization and interaction were detected by immunofluorescence, nuclear and cytoplasmic protein extraction kits, and Co-IP. A new heterozygous germline mutation of the RBBP8(p.E281*) gene was found to be associated with familial hereditary cancer syndrome. RBBP8-WT was mainly detected in the nucleus and interacts with BRCA1. In contrast, RBBP8(p.E281*) is mainly located in the cytoplasm, with no interaction with BRCA1. RBBP8(p.E281*) variant plays an oncogenic role in the cytoplasm in addition to its loss of function in the nucleus, which promotes breast cancer proliferation, in vivo tumorigenesis, and migration. Compared with the control group, RBBP8(p.E281*) showed elevated cell death in response to cisplatin and olaparib treatment. A novel RBBP8(p.E281*) germline mutation was identified from familial hereditary cancer syndrome. RBBP8(p.E281*) is not able to enter the nucleus or interact with BRCA1 through the lost binding motif, and RBBP8(p.E281*) variant appears to promote tumorigenesis in the cytoplasm in addition to its loss of function in the nucleus. RBBP8(p.E281*) variant may promote tumor susceptibility and serve as a precision medicine biomarker in familial hereditary cancer syndrome. KEY MESSAGES: RBBP8(p.E281*) is a susceptibility gene in this familial hereditary cancer syndrome RBBP8(p.E281*) lost its ability to enter the nucleus and the BRCA1 binding motif A novel RBBP8(p.E281*) germline mutation promotes breast cancer tumorigenesis Patients with RBBP8(p.E281*) germline mutation may benefit from Olaparib, Cisplatin.
Identifiants
pubmed: 37615686
doi: 10.1007/s00109-023-02354-z
pii: 10.1007/s00109-023-02354-z
doi:
Substances chimiques
Cisplatin
Q20Q21Q62J
Biomarkers
0
RBBP8 protein, human
EC 3.1.-
Endodeoxyribonucleases
EC 3.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1255-1265Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Samadder NJ, Giridhar KV, Baffy N et al (2019) Hereditary cancer syndromes-a primer on diagnosis and management: part 1: breast-ovarian cancer syndromes. Mayo Clin Proc 94(6):1084–1098
pubmed: 31171119
doi: 10.1016/j.mayocp.2019.02.017
Liu Q, Tan YQ (2019) Advances in identification of susceptibility gene defects of hereditary colorectal cancer. J Cancer 10(3):643–653
pubmed: 30719162
pmcid: 6360424
doi: 10.7150/jca.28542
McKay GE, Zakas AL, Osman F et al (2021) Factors affecting genetic consultation in adolescent and young adult patients with sarcoma. J Natl Compr Canc Netw 1-8
Hereditary cancer syndromes and risk assessment (2019) ACOG committee opinion, Number 793. Obstet Gynecol 134(6):e143–e149
doi: 10.1097/AOG.0000000000003562
Futreal PA, Liu Q, Shattuck-Eidens D et al (1994) BRCA1 mutations in primary breast and ovarian carcinomas. Science 266(5182):120–122
pubmed: 7939630
doi: 10.1126/science.7939630
Wang Q (2016) Cancer predisposition genes: molecular mechanisms and clinical impact on personalized cancer care: examples of Lynch and HBOC syndromes. Acta Pharmacol Sin 37(2):143–149
pubmed: 26616728
doi: 10.1038/aps.2015.89
Powell SN, Kachnic LA (2003) Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. Oncogene 22(37):5784–5791
pubmed: 12947386
doi: 10.1038/sj.onc.1206678
Yurgelun MB, Kulke MH, Fuchs CS et al (2017) Cancer susceptibility gene mutations in individuals with colorectal cancer. J Clin Oncol 35(10):1086–1095
pubmed: 28135145
pmcid: 5455355
doi: 10.1200/JCO.2016.71.0012
Lynch HT, Snyder CL, Shaw TG et al (2015) Milestones of Lynch syndrome: 1895–2015. Nat Rev Cancer 15(3):181–194
pubmed: 25673086
doi: 10.1038/nrc3878
Thariat J, Chevalier F, Orbach D et al (2021) Avoidance or adaptation of radiotherapy in patients with cancer with Li-Fraumeni and heritable TP53-related cancer syndromes. Lancet Oncol 22(12):e562–e574
pubmed: 34856153
doi: 10.1016/S1470-2045(21)00425-3
Huang R, Zhou PK (2021) DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy. Signal Transduct Target Ther 6(1):254
pubmed: 34238917
pmcid: 8266832
doi: 10.1038/s41392-021-00648-7
Perkhofer L, Gout J, Roger E et al (2021) DNA damage repair as a target in pancreatic cancer: state-of-the-art and future perspectives. Gut 70(3):606–617
pubmed: 32855305
doi: 10.1136/gutjnl-2019-319984
Mehibel M, Xu Y, Li CG et al (2021) Eliminating hypoxic tumor cells improves response to PARP inhibitors in homologous recombination-deficient cancer models. J Clin Invest 131(11)
Heeke AL, Xiu J, Elliott A et al (2020) Actionable co-alterations in breast tumors with pathogenic mutations in the homologous recombination DNA damage repair pathway. Breast Cancer Res Treat 184(2):265–275
pubmed: 32776290
doi: 10.1007/s10549-020-05849-2
Palicelli A, Croci S, Bisagni A et al (2022) What do we have to know about PD-L1 expression in prostate cancer? A systematic literature review (part 6): correlation of PD-L1 expression with the status of mismatch repair system, BRCA, PTEN, and other genes. Biomedicines 10(2)
Locke AJ, Hossain L, McCrostie G et al (2021) SUMOylation mediates CtIP’s functions in DNA end resection and replication fork protection. Nucleic Acids Res 49(2):928–953
pubmed: 33406258
pmcid: 7826263
doi: 10.1093/nar/gkaa1232
Howard SM, Ceppi I, Anand R et al (2020) The internal region of CtIP negatively regulates DNA end resection. Nucleic Acids Res 48(10):5485–5498
pubmed: 32347940
pmcid: 7261161
doi: 10.1093/nar/gkaa273
Mohiuddin M, Rahman MM, Sale JE et al (2019) CtIP-BRCA1 complex and MRE11 maintain replication forks in the presence of chain terminating nucleoside analogs. Nucleic Acids Res 47(6):2966–2980
pubmed: 30657944
pmcid: 6451104
doi: 10.1093/nar/gkz009
Przetocka S, Porro A, Bolck HA et al (2018) CtIP-mediated fork protection synergizes with BRCA1 to suppress genomic instability upon DNA replication stress. Mol Cell 72(3):568–582
pubmed: 30344097
doi: 10.1016/j.molcel.2018.09.014
Stroik S, Kurtz K, Hendrickson EA (2019) CtIP is essential for telomere replication. Nucleic Acids Res 47(17):8927–8940
pubmed: 31378812
pmcid: 6755089
doi: 10.1093/nar/gkz652
Molloy DP, Barral PM, Bremner KH et al (2001) Structural determinants outside the PXDLS sequence affect the interaction of adenovirus E1A, C-terminal interacting protein and Drosophila repressors with C-terminal binding protein. Biochim Biophys Acta 1546(1):55–70
pubmed: 11257508
doi: 10.1016/S0167-4838(00)00071-6
Yu X, Wu LC, Bowcock AM et al (1998) The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression. J Biol Chem 273(39):25388–25392
pubmed: 9738006
doi: 10.1074/jbc.273.39.25388
Li S, Chen PL, Subramanian T et al (1999) Binding of CtIP to the BRCT repeats of BRCA1 involved in the transcription regulation of p21 is disrupted upon DNA damage. J Biol Chem 274(16):11334–11338
pubmed: 10196224
doi: 10.1074/jbc.274.16.11334
Guirouilh-Barbat J, Gelot C, Xie A et al (2016) 53BP1 Protects against CtIP-dependent capture of ectopic chromosomal sequences at the junction of distant double-strand breaks. PLoS Genet 12(10):e1006230
pubmed: 27798638
pmcid: 5087911
doi: 10.1371/journal.pgen.1006230
Anglada T, Genesca A, Martin M (2020) Age-associated deficient recruitment of 53BP1 in G1 cells directs DNA double-strand break repair to BRCA1/CtIP-mediated DNA-end resection. Aging (Albany NY) 12(24):24872–24893
pubmed: 33361520
pmcid: 7803562
doi: 10.18632/aging.202419
Bakr A, Kocher S, Volquardsen J et al (2016) Impaired 53BP1/RIF1 DSB mediated end-protection stimulates CtIP-dependent end resection and switches the repair to PARP1-dependent end joining in G1. Oncotarget 7(36):57679–57693
pubmed: 27494840
pmcid: 5295381
doi: 10.18632/oncotarget.11023
Aparicio T, Baer R, Gottesman M et al (2016) MRN, CtIP, and BRCA1 mediate repair of topoisomerase II-DNA adducts. J Cell Biol 212(4):399–408
pubmed: 26880199
pmcid: 4754713
doi: 10.1083/jcb.201504005
Rozier L, Guo Y, Peterson S et al (2013) The MRN-CtIP pathway is required for metaphase chromosome alignment. Mol Cell 49(6):1097–1107
pubmed: 23434370
pmcid: 3615147
doi: 10.1016/j.molcel.2013.01.023
Fusco C, Reymond A, Zervos AS (1998) Molecular cloning and characterization of a novel retinoblastoma-binding protein. Genomics 51(3):351–358
pubmed: 9721205
doi: 10.1006/geno.1998.5368
Zarrizi R, Higgs MR, Vossgrone K et al (2020) Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability. J Clin Invest 130(8):4069–4080
pubmed: 32379725
pmcid: 7410048
Yadav S, Anbalagan M, Baddoo M et al (2020) Somatic mutations in the DNA repairome in prostate cancers in African Americans and Caucasians. Oncogene 39(21):4299–4311
pubmed: 32300177
pmcid: 7239769
doi: 10.1038/s41388-020-1280-x
Fiala EM, Ortiz MV, Kennedy JA et al (2020) 11p15.5 epimutations in children with Wilms tumor and hepatoblastoma detected in peripheral blood. Cancer 126(13):3114-3121
Wang J, Ding Q, Fujimori H et al (2016) Loss of CtIP disturbs homologous recombination repair and sensitizes breast cancer cells to PARP inhibitors. Oncotarget 7(7):7701–7714
pubmed: 26713604
doi: 10.18632/oncotarget.6715
Chen PL, Liu F, Cai S et al (2005) Inactivation of CtIP leads to early embryonic lethality mediated by G1 restraint and to tumorigenesis by haploid insufficiency. Mol Cell Biol 25(9):3535–3542
pubmed: 15831459
pmcid: 1084307
doi: 10.1128/MCB.25.9.3535-3542.2005
Soria-Bretones I, Saez C, Ruiz-Borrego M et al (2013) Prognostic value of CtIP/RBBP8 expression in breast cancer. Cancer Med 2(6):774–783
pubmed: 24403251
pmcid: 3892382
doi: 10.1002/cam4.141
Wu M, Soler DR, Abba MC et al (2007) CtIP silencing as a novel mechanism of tamoxifen resistance in breast cancer. Mol Cancer Res 5(12):1285–1295
pubmed: 18171986
doi: 10.1158/1541-7786.MCR-07-0126
Yu Y, Chen L, Zhao G et al (2020) RBBP8/CtIP suppresses P21 expression by interacting with CtBP and BRCA1 in gastric cancer. Oncogene 39(6):1273–1289
pubmed: 31636387
doi: 10.1038/s41388-019-1060-7
Ren J, Wu Y, Wang Y et al (2021) CtIP suppresses primary microRNA maturation and promotes metastasis of colon cancer cells in a xenograft mouse model. J Biol Chem 296:100707
pubmed: 33901493
pmcid: 8164041
doi: 10.1016/j.jbc.2021.100707
Wong AK, Ormonde PA, Pero R et al (1998) Characterization of a carboxy-terminal BRCA1 interacting protein. Oncogene 17(18):2279–2285
pubmed: 9811458
doi: 10.1038/sj.onc.1202150
Zhang W, Song Y, He X et al (2020) Prognosis value of RBBP8 expression in plasma cell myeloma. Cancer Gene Ther 27(1–2):22–29
pubmed: 30622325
doi: 10.1038/s41417-018-0069-3
Vilkki S, Launonen V, Karhu A et al (2002) Screening for microsatellite instability target genes in colorectal cancers. J Med Genet 39(11):785–789
pubmed: 12414815
pmcid: 1735006
doi: 10.1136/jmg.39.11.785
Reczek CR, Shakya R, Miteva Y et al (2016) The DNA resection protein CtIP promotes mammary tumorigenesis. Oncotarget 7(22):32172–32183
pubmed: 27058754
pmcid: 5078005
doi: 10.18632/oncotarget.8605
Gaymes TJ, Mohamedali AM, Patterson M et al (2013) Microsatellite instability induced mutations in DNA repair genes CtIP and MRE11 confer hypersensitivity to poly (ADP-ribose) polymerase inhibitors in myeloid malignancies. Haematologica 98(9):1397–1406
pubmed: 23349304
pmcid: 3762096
doi: 10.3324/haematol.2012.079251
Ray CA, Callen E, Ding X et al (2016) Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature 535(7612):382–387
doi: 10.1038/nature18325
Jackson LM, Dhoonmoon A, Hale A et al (2021) Loss of MED12 activates the TGFbeta pathway to promote chemoresistance and replication fork stability in BRCA-deficient cells. Nucleic Acids Res 49(22):12855–12869
pubmed: 34871431
pmcid: 8682781
doi: 10.1093/nar/gkab1184
Mirza MR, Avall LE, Birrer MJ et al (2019) Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial. Lancet Oncol 20(10):1409–1419
pubmed: 31474354
doi: 10.1016/S1470-2045(19)30515-7