Isolation and functional assessment of common, polymorphic variants of the B-MYB proto-oncogene associated with a reduced cancer risk (original) (raw)

• Short Communication
• Published: 19 November 2007
• R Bussolari2 na1,
• D Corvetta1,3,
• O Chayka1,
• G Santilli1,
• J M-M Kwok1,
• G F Amorotti2,
• G P Tonini4,
• L Iacoviello5,
• R Bertorelle6,
• C Menin6,
• M Hubank1,
• B Calabretta2 &
• …
• A Sala1

Oncogene volume 27, pages 2929–2933 (2008)Cite this article

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A Corrigendum to this article was published on 22 May 2008

Abstract

The B-MYB proto-oncogene is a transcription factor belonging to the MYB family that is frequently overexpressed or amplified in different types of human malignancies. While it is suspected that B-MYB plays a role in human cancer, there is still no direct evidence of its causative role. Looking for mutations of the B-MYB gene in human cell lines and primary cancer samples, we frequently isolated two nonsynonymous B-MYB polymorphic variants (rs2070235 and rs11556379). Compared to the wild-type protein, the B-MYB isoforms display altered conformation, impaired regulation of target genes and decreased antiapoptotic activity, suggesting that they are hypomorphic variants of the major allele. Importantly, the B-MYB polymorphisms are common; rs2070235 and rs11556379 are found, depending on the ethnic background, in 10–50% of human subjects. We postulated that, if B-MYB activity is important for transformation, the presence of common, hypomorphic variants might modify cancer risk. Indeed, the B-MYB polymorphisms are underrepresented in 419 cancer patients compared to 230 controls (odds ratio 0.53; (95%) confidence interval 0.385–0.755; _P_=0.001). This data imply that a large fraction of the human population is carrier of B-MYB alleles that might be associated with a reduced risk of developing neoplastic disease.

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References

• Ahlbory D, Appl H, Lang D, Klempnauer KH . (2005). Disruption of B-myb in DT40 cells reveals novel function for B-Myb in the response to DNA-damage. Oncogene 24: 7127–7134.
  Article CAS Google Scholar
• Bar-Shira A, Pinthus JH, Rozovsky U, Goldstei M, Sellers WR, Yaron Y et al. (2002). Multiple genes in human 20q13 chromosomal region are involved in an advanced prostate cancer xenograft. Cancer Res 62: 6803–6807.
  CAS PubMed Google Scholar
• Boutros R, Dozier C, Ducommun B . (2006). The when and wheres of CDC25 phosphatases. Curr Opin Cell Biol 18: 185–191.
  Article CAS Google Scholar
• Eckstein LA, Van Quill KR, Bui SK, Uusitalo MS, O'Brien JM . (2005). Cyclosporin a inhibits calcineurin/nuclear factor of activated T-cells signaling and induces apoptosis in retinoblastoma cells. Invest Ophthalmol Vis Sci 46: 782–790.
  Article Google Scholar
• Forozan F, Mahlamaki EH, Monni O, Chen Y, Veldman R, Jiang Y et al. (2000). Comparative genomic hybridization analysis of 38 breast cancer cell lines: a basis for interpreting complementary DNA microarray data. Cancer Res 60: 4519–4525.
  CAS Google Scholar
• Grassilli E, Salomoni P, Perrotti D, Franceschi C, Calabretta B . (1999). Resistance to apoptosis in CTLL-2 cells overexpressing B-Myb is associated with B-Myb-dependent bcl-2 induction. Cancer Res 59: 2451–2456.
  CAS PubMed Google Scholar
• Iacoviello L, Di Castelnuovo A, De Knijff P, D'Orazio A, Amore C, Arboretti R et al. (1998). Polymorphisms in the coagulation factor VII gene and the risk of myocardial infarction. N Engl J Med 338: 79–85.
  Article CAS Google Scholar
• Imyanitov EN, Togo AV, Hanson KP . (2004). Searching for cancer-associated gene polymorphisms: promises and obstacles. Cancer Lett 204: 3–14.
  Article CAS Google Scholar
• Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV et al. (2007). A ‘silent’ polymorphism in the MDR1 gene changes substrate specificity. Science 315: 525–528.
  Article CAS Google Scholar
• Masselink H, Vastenhouw N, Bernards R . (2001). B-myb rescues ras-induced premature senescence, which requires its transactivation domain. Cancer Lett 171: 87–101.
  Article CAS Google Scholar
• Nicoletti I, Migliorati G, Pagliacci MC, Grignani F, Riccardi C . (1991). A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 139: 271–279.
  Article CAS Google Scholar
• Oh IH, Reddy EP . (1999). The myb gene family in cell growth, differentiation and apoptosis. Oncogene 18: 3017–3033.
  Article CAS Google Scholar
• Oukka M, Ho IC, de la Brousse FC, Hoey T, Grusby MJ, Glimcher LH . (1998). The transcription factor NFAT4 is involved in the generation and survival of T cells. Immunity 9: 295–304.
  Article CAS Google Scholar
• Raschella G, Cesi V, Amendola R, Negroni A, Tanno B, Altavista P et al. (1999). Expression of B-myb in neuroblastoma tumors is a poor prognostic factor independent from MYCN amplification. Cancer Res 59: 3365–3368.
  CAS PubMed Google Scholar
• Sala A . (2005). B-MYB, a transcription factor implicated in regulating cell cycle, apoptosis and cancer. Eur J Cancer 41: 2479–2484.
  Article CAS Google Scholar
• Shepard JL, Amatruda JF, Stern HM, Subramanian A, Finkelstein D, Ziai J et al. (2005). A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility. Proc Natl Acad Sci USA 102: 13194–13199.
  Article CAS Google Scholar
• Sugimura H, Caporaso NE, Modali RV, Hoover RN, Resau JH, Trump BF et al. (1990). Association of rare alleles of the Harvey ras protooncogene locus with lung cancer. Cancer Res 50: 1857–1862.
  CAS PubMed Google Scholar
• Tanaka Y, Patestos NP, Maekawa T, Ishii S . (1999). B-myb is required for inner cell mass formation at an early stage of development. J Biol Chem 274: 28067–28070.
  Article CAS Google Scholar
• Tanner MM, Grenman S, Koul A, Johannsson O, Meltzer P, Pejovic T et al. (2000). Frequent amplification of chromosomal region 20q12–q13 in ovarian cancer. Clin Cancer Res 6: 1833–1839.
  CAS PubMed Google Scholar

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Acknowledgements

We thank Gianluca Sala, John Anderson, Pete Scambler and Nazneen Rahman for critical reading of the manuscript. This study was supported by the Neuroblastoma Society UK and SPARKS (to AS), the Italian Neuroblastoma Foundation (to GT), the Fondazione Cassa di Risparmio di Modena (to BC), the Ministry of University and Research (MIUR, Rome, Italy) Programma Triennale di Ricerca (Decreto no. 1588 to LI).

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Author notes

1. R Schwab and R Bussolari: These authors contributed equally to this work.

Authors and Affiliations

1. Molecular Haematology and Cancer Biology Unit, UCL Institute of Child Health, London, UK
   R Schwab, D Corvetta, O Chayka, G Santilli, J M-M Kwok, M Hubank & A Sala
2. Department of Biomedical Sciences, Universita di Modena e Reggio Emilia, Modena, Italy
   R Bussolari, G F Amorotti & B Calabretta
3. Dipartimento di Medicina Sperimentale Sezione di Biochimica, Biochimica Clinica e Biochimica dell'Esercizio Fisico Università degli Studi di Parma, Parma, Italy
   D Corvetta
4. Translational Paediatric Oncology, National Institute for Cancer Research (IST), Genoa, Italy
   G P Tonini
5. Laboratory of Genetic and Environmental Epidemiology, John Paul II Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy
   L Iacoviello
6. Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto (IOV), IRCCS, Padova, Italy
   R Bertorelle & C Menin

Authors

1. R Schwab
2. R Bussolari
3. D Corvetta
4. O Chayka
5. G Santilli
6. J M-M Kwok
7. G F Amorotti
8. G P Tonini
9. L Iacoviello
10. R Bertorelle
11. C Menin
12. M Hubank
13. B Calabretta
14. A Sala

Corresponding author

Correspondence toA Sala.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Schwab, R., Bussolari, R., Corvetta, D. et al. Isolation and functional assessment of common, polymorphic variants of the B-MYB proto-oncogene associated with a reduced cancer risk.Oncogene 27, 2929–2933 (2008). https://doi.org/10.1038/sj.onc.1210947

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• Received: 10 July 2007
• Revised: 08 October 2007
• Accepted: 22 October 2007
• Published: 19 November 2007
• Issue date: 01 May 2008
• DOI: https://doi.org/10.1038/sj.onc.1210947

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