Advertisement

Breast Cancer Research and Treatment

, Volume 162, Issue 2, pp 243–253 | Cite as

FGD5 amplification in breast cancer patients is associated with tumour proliferation and a poorer prognosis

  • Marit Valla
  • Monica Jernberg Engstrøm
  • Borgny Ytterhus
  • Åse Kristin Skain Hansen
  • Lars Andreas Akslen
  • Lars Johan Vatten
  • Signe Opdahl
  • Anna Mary Bofin
Preclinical study

Abstract

Purpose

Proliferation is a hallmark of cancer. Using a combined genomic approach, FGD5 amplification has been identified as a driver of proliferation in Luminal breast cancer. We aimed to describe FGD5 copy number change in breast cancer, and to assess a possible association with tumour proliferation and prognosis.

Methods

We used fluorescence in situ hybridization targeting FGD5 and chromosome 3 centromere (CEP3) on formalin-fixed, paraffin-embedded tissue from 430 primary breast cancers and 108 lymph node metastases, from a cohort of Norwegian breast cancer patients. We tested the association between FGD5 copy number status and proliferation (assessed by Ki67 levels and mitotic count) using Pearson’s Chi square test, and assessed the prognostic impact of FGD5 copy number change by estimating cumulative risks of death and hazard ratios.

Results

We identified FGD5 amplification (defined as FGD5/CEP3 ratio ≥2 or mean FGD5/tumour cell ≥4) in 9.5% of tumours. Mitotic count and Ki67 levels were higher in tumours with FGD5 copy number increase, compared to tumours with no copy number change. After 10 years of follow-up, cumulative risk of death from breast cancer was higher among cases with FGD5 amplification [48.1% (95% CI 33.8–64.7)], compared to non-amplified cases [27.7% (95% CI 23.4–32.6)].

Conclusions

FGD5 is a new prognostic marker in breast cancer, and increased copy number is associated with higher tumour proliferation and poorer long-term prognosis.

Keywords

Breast cancer FGD5 FISH Gene amplification Proliferation Prognosis 

Notes

Acknowledgements

The authors thank the Department of Pathology and Medical Genetics at St. Olav’s Hospital, Trondheim University Hospital, Norway for making the archives available for the study; the Cancer Registry of Norway, and the Norwegian Cause of Death Registry for providing the patient data, and Hong Yan Dai for assistance in the design of the FGD5 probe used in this study. This work was supported by the Research Council of Norway (Project No. 231297); and the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology (Project Nos. 46030001 and 46056705).

Compliance with ethical standards

Ethical standards

The study was approved by the Regional Committee for Medical and Health Sciences Research Ethics (REK, Midt-Norge, Norway, reference number 836/2009).

Conflicts of interest

The authors declare that they have no conflicts of interest.

Supplementary material

10549_2017_4125_MOESM1_ESM.docx (24 kb)
Supplementary material 1 (DOCX 25 kb)

References

  1. 1.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. doi: 10.1016/j.cell.2011.02.013 CrossRefPubMedGoogle Scholar
  2. 2.
    Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, Thurlimann B, Senn HJ, Panel M (2015) Tailoring therapies-improving the management of early breast cancer: St Gallen International Expert Consensus on the primary therapy of early breast cancer 2015. Ann Oncol 26:1533–1546. doi: 10.1093/annonc/mdv221 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Cancer Genome Atlas N (2012) Comprehensive molecular portraits of human breast tumours. Nature 490:61–70. doi: 10.1038/nature11412 CrossRefGoogle Scholar
  4. 4.
    Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Graf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S, Group M, Langerod A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Borresen-Dale AL, Brenton JD, Tavare S, Caldas C, Aparicio S (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486:346–352. doi: 10.1038/nature10983 PubMedPubMedCentralGoogle Scholar
  5. 5.
    Gatza ML, Silva GO, Parker JS, Fan C, Perou CM (2014) An integrated genomics approach identifies drivers of proliferation in luminal-subtype human breast cancer. Nat Genet 46:1051–1059. doi: 10.1038/ng.3073 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Weizmann Institute of Science (2016) GeneCards. The Human Gene Database. http://www.genecards.org
  7. 7.
    Pasteris NG, Cadle A, Logie LJ, Porteous ME, Schwartz CE, Stevenson RE, Glover TW, Wilroy RS, Gorski JL (1994) Isolation and characterization of the faciogenital dysplasia (Aarskog-Scott syndrome) gene: a putative Rho/Rac guanine nucleotide exchange factor. Cell 79:669–678CrossRefPubMedGoogle Scholar
  8. 8.
    Braga E, Senchenko V, Bazov I, Loginov W, Liu J, Ermilova V, Kazubskaya T, Garkavtseva R, Mazurenko N, Kisseljov F, Lerman MI, Klein G, Kisselev L, Zabarovsky ER (2002) Critical tumor-suppressor gene regions on chromosome 3P in major human epithelial malignancies: allelotyping and quantitative real-time PCR. Int J Cancer 100:534–541. doi: 10.1002/ijc.10511 CrossRefPubMedGoogle Scholar
  9. 9.
    Braga E, Pugacheva E, Bazov I, Ermilova V, Kazubskaya T, Mazurenko N, Kisseljov F, Liu J, Garkavtseva R, Zabarovsky E, Kisselev L (1999) Comparative allelotyping of the short arm of human chromosome 3 in epithelial tumors of four different types. FEBS Lett 454:215–219CrossRefPubMedGoogle Scholar
  10. 10.
    Kok K, Naylor SL, Buys CH (1997) Deletions of the short arm of chromosome 3 in solid tumors and the search for suppressor genes. Adv Cancer Res 71:27–92CrossRefPubMedGoogle Scholar
  11. 11.
    Senchenko VN, Kisseljova NP, Ivanova TA, Dmitriev AA, Krasnov GS, Kudryavtseva AV, Panasenko GV, Tsitrin EB, Lerman MI, Kisseljov FL, Kashuba VI, Zabarovsky ER (2013) Novel tumor suppressor candidates on chromosome 3 revealed by NotI-microarrays in cervical cancer. Epigenetics: official journal of the DNA Methylation Society 8:409–420. doi: 10.4161/epi.24233 CrossRefGoogle Scholar
  12. 12.
    Dmitriev AA, Kashuba VI, Haraldson K, Senchenko VN, Pavlova TV, Kudryavtseva AV, Anedchenko EA, Krasnov GS, Pronina IV, Loginov VI, Kondratieva TT, Kazubskaya TP, Braga EA, Yenamandra SP, Ignatjev I, Ernberg I, Klein G, Lerman MI, Zabarovsky ER (2012) Genetic and epigenetic analysis of non-small cell lung cancer with NotI-microarrays. Epigenetics: Official Journal of the DNA Methylation Society 7:502–513. doi: 10.4161/epi.19801 CrossRefGoogle Scholar
  13. 13.
    Dmitriev AA, Rudenko EE, Kudryavtseva AV, Krasnov GS, Gordiyuk VV, Melnikova NV, Stakhovsky EO, Kononenko OA, Pavlova LS, Kondratieva TT, Alekseev BY, Braga EA, Senchenko VN, Kashuba VI (2014) Epigenetic alterations of chromosome 3 revealed by NotI-microarrays in clear cell renal cell carcinoma. BioMed Res Int 2014:735292. doi: 10.1155/2014/735292 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Engstrom MJ, Opdahl S, Hagen AI, Romundstad PR, Akslen LA, Haugen OA, Vatten LJ, Bofin AM (2013) Molecular subtypes, histopathological grade and survival in a historic cohort of breast cancer patients. Breast Cancer Res Treat 140:463–473. doi: 10.1007/s10549-013-2647-2 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Blows FM, Driver KE, Schmidt MK, Broeks A, van Leeuwen FE, Wesseling J, Cheang MC, Gelmon K, Nielsen TO, Blomqvist C, Heikkila P, Heikkinen T, Nevanlinna H, Akslen LA, Begin LR, Foulkes WD, Couch FJ, Wang X, Cafourek V, Olson JE, Baglietto L, Giles GG, Severi G, McLean CA, Southey MC, Rakha E, Green AR, Ellis IO, Sherman ME, Lissowska J, Anderson WF, Cox A, Cross SS, Reed MW, Provenzano E, Dawson SJ, Dunning AM, Humphreys M, Easton DF, Garcia-Closas M, Caldas C, Pharoah PD, Huntsman D (2010) Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med. 7:e1000279. doi: 10.1371/journal.pmed.1000279 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS, Perou CM, Ellis MJ, Nielsen TO (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101:736–750. doi: 10.1093/jnci/djp082 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, Statistics Subcommittee of NCIEWGoCD (2006) REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100:229–235. doi: 10.1007/s10549-006-9242-8 CrossRefPubMedGoogle Scholar
  18. 18.
    Cole SR, Hernan MA (2002) Fallibility in estimating direct effects. Int J Epidemiol 31:163–165CrossRefPubMedGoogle Scholar
  19. 19.
    Hoadley KA, Yau C, Wolf DM, Cherniack AD, Tamborero D, Ng S, Leiserson MD, Niu B, McLellan MD, Uzunangelov V, Zhang J, Kandoth C, Akbani R, Shen H, Omberg L, Chu A, Margolin AA, Van’t Veer LJ, Lopez-Bigas N, Laird PW, Raphael BJ, Ding L, Robertson AG, Byers LA, Mills GB, Weinstein JN, Van Waes C, Chen Z, Collisson EA, Cancer Genome Atlas Research N, Benz CC, Perou CM, Stuart JM (2014) Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 158:929–944. doi: 10.1016/j.cell.2014.06.049 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Nielsen TO, Parker JS, Leung S, Voduc D, Ebbert M, Vickery T, Davies SR, Snider J, Stijleman IJ, Reed J, Cheang MC, Mardis ER, Perou CM, Bernard PS, Ellis MJ (2010) A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor-positive breast cancer. Clin Cancer Res 16:5222–5232. doi: 10.1158/1078-0432.CCR-10-1282 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Viale G, Slaets L, Bogaerts J, Rutgers E, van’t Veer L, Piccart-Gebhart MJ, de Snoo FA, Stork-Sloots L, Russo L, Dell’Orto P, van den Akker J, Glas A, Cardoso F, TRANSBIG Consortium & the MINDACT Investigators (2014) High concordance of protein (by IHC), gene (by FISH; HER2 only), and microarray readout (by TargetPrint) of ER, PgR, and HER2: results from the EORTC 10041/BIG 03-04 MINDACT trial. Ann Oncol 25:816–823. doi: 10.1093/annonc/mdu026 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10:5367–5374. doi: 10.1158/1078-0432.CCR-04-0220 CrossRefPubMedGoogle Scholar
  23. 23.
    Knutsvik G, Stefansson IM, Aziz S, Arnes J, Eide J, Collett K, Akslen LA (2014) Evaluation of Ki67 expression across distinct categories of breast cancer specimens: a population-based study of matched surgical specimens, core needle biopsies and tissue microarrays. PLoS ONE 9:e112121. doi: 10.1371/journal.pone.0112121 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Albertson DG (2006) Gene amplification in cancer. Trends Genet 22:447–455. doi: 10.1016/j.tig.2006.06.007 CrossRefPubMedGoogle Scholar
  25. 25.
    Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thurlimann B, Senn HJ, Panel M (2013) Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2013. Ann Oncol 24:2206–2223. doi: 10.1093/annonc/mdt303 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF, American Society of Clinical O, College of American P (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31:3997–4013. doi: 10.1200/JCO.2013.50.9984 CrossRefPubMedGoogle Scholar
  27. 27.
    Rakha EA, Pinder SE, Bartlett JM, Ibrahim M, Starczynski J, Carder PJ, Provenzano E, Hanby A, Hales S, Lee AH, Ellis IO, National Coordinating Committee for Breast P (2015) Updated UK Recommendations for HER2 assessment in breast cancer. J Clin Pathol 68:93–99. doi: 10.1136/jclinpath-2014-202571 CrossRefPubMedGoogle Scholar
  28. 28.
    Batistatou A, Televantou D, Bobos M, Eleftheraki AG, Kouvaras E, Chrisafi S, Koukoulis GK, Malamou-Mitsi V, Fountzilas G (2013) Evaluation of current prognostic and predictive markers in breast cancer: a validation study of tissue microarrays. Anticancer Res 33:2139–2145PubMedGoogle Scholar
  29. 29.
    Dekker TJ, Borg ST, Hooijer GK, Meijer SL, Wesseling J, Boers JE, Schuuring E, Bart J, van Gorp J, Mesker WE, Kroep JR, Smit VT, van de Vijver MJ (2012) Determining sensitivity and specificity of HER2 testing in breast cancer using a tissue micro-array approach. Breast Cancer Res 14:R93. doi: 10.1186/bcr3208 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Camp RL, Charette LA, Rimm DL (2000) Validation of tissue microarray technology in breast carcinoma. Lab Invest 80:1943–1949CrossRefPubMedGoogle Scholar
  31. 31.
    Gazit R, Mandal PK, Ebina W, Ben-Zvi A, Nombela-Arrieta C, Silberstein LE, Rossi DJ (2014) Fgd5 identifies hematopoietic stem cells in the murine bone marrow. J Exp Med 211:1315–1331. doi: 10.1084/jem.20130428 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kurogane Y, Miyata M, Kubo Y, Nagamatsu Y, Kundu RK, Uemura A, Ishida T, Quertermous T, Hirata K, Rikitake Y (2012) FGD5 mediates proangiogenic action of vascular endothelial growth factor in human vascular endothelial cells. Arterioscler Thromb Vasc Biol 32:988–996. doi: 10.1161/ATVBAHA.111.244004 CrossRefPubMedGoogle Scholar
  33. 33.
    Nakhaei-Nejad M, Haddad G, Zhang QX, Murray AG (2012) Facio-genital dysplasia-5 regulates matrix adhesion and survival of human endothelial cells. Arterioscler Thromb Vasc Biol 32:2694–2701. doi: 10.1161/ATVBAHA.112.300074 CrossRefPubMedGoogle Scholar
  34. 34.
    Baak JP, van Diest PJ, Voorhorst FJ, van der Wall E, Beex LV, Vermorken JB, Janssen EA, Gudlaugsson E, collaborators of the Multicenter Morphometric Mammary Carcinoma P (2007) The prognostic value of proliferation in lymph-node-negative breast cancer patients is age dependent. Eur J Cancer 43:527–535. doi: 10.1016/j.ejca.2006.10.001 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Marit Valla
    • 1
  • Monica Jernberg Engstrøm
    • 1
    • 2
  • Borgny Ytterhus
    • 3
  • Åse Kristin Skain Hansen
    • 3
  • Lars Andreas Akslen
    • 4
    • 5
  • Lars Johan Vatten
    • 1
  • Signe Opdahl
    • 1
  • Anna Mary Bofin
    • 3
  1. 1.Department of Public Health and General Practice, Faculty of MedicineNorwegian University of Science and TechnologyTrondheimNorway
  2. 2.Department of Breast and Endocrine Surgery, St. Olav’s HospitalTrondheim University HospitalTrondheimNorway
  3. 3.Department of Laboratory Medicine, Children’s and Women’s Health, Faculty of MedicineNorwegian University of Science and TechnologyTrondheimNorway
  4. 4.Department of Clinical Medicine, Centre for Cancer Biomarkers CCBIOUniversity of BergenBergenNorway
  5. 5.Department of PathologyHaukeland University HospitalBergenNorway

Personalised recommendations