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Novel genetic aberrations in breast phyllodes tumours: comparison between prognostically distinct groups

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Abstract

Phyllodes tumours of the breast are uncommon fibroepithelial neoplasms which pose management challenges due to difficulties in accurate prediction of clinical behaviour, as histological assessment has its limitations. Molecular studies have improved the understanding of these rare tumours but such findings are scant. We aimed to investigate genetic aberrations in phyllodes tumours stratified according to clinical behaviour, to identify potential genes contributing to disease progression. Twenty phyllodes tumours were separated into prognostically distinct categories depending on whether they had recurred/metastasized within the follow-up period. DNA extracted from FFPE materials was subjected to Affymetrix OncoScan™ FFPE Express molecular inversion probe microarray platform for analysis of copy number changes and mutational status. Results were cross validated with Sanger sequencing, FISH and immunohistochemistry. A higher number of chromosomal aberrations were observed in cases which recurred/metastasized, with median events of 19 compared to 3.5 in cases which did not recur/metastasize. High-level amplification and homozygous deletions were detected exclusively in the former group. Regions of high-level amplification included MDM4 (1q32.1), RAF1 (3p25), EGFR (7p12) and PDZD2 (5p13.3). EGFR amplification was confirmed on FISH and accompanied by intense EGFR immunostaining. Regions of homozygous deletion included CDKN2A (9p21) and MACROD2 (20p12.1). Homozygous deletion of 9p21 which involved CDKN2A was accompanied by loss of protein expression. No mutations were identified in all samples. These findings provide insights into identifying target genes and pathways exploited by phyllodes tumours, which would aid future development of individualised therapy.

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References

  1. Belkacémi Y, Bousquet G, Marsiglia H et al (2008) Phyllodes tumor of the breast. Int J Radiat Oncol Biol Phys 70:492–500

    Article  PubMed  Google Scholar 

  2. Bernstein L, Deapen D, Ross R (1993) The descriptive epidemiology of malignant cystosarcoma phyllodes tumors of the breast. Cancer 71:3020–3024

    Article  CAS  PubMed  Google Scholar 

  3. Seow A, Koh W, Chia K, Shi L, Lee H, Shanmugaratnam S, Seow A (eds) (2004) Trends in cancer incidence in Singapore, 1968–2002, Singapore

  4. Lakhani S, Ellis I, Schnitt S, Tan P, van de Vijver M (eds) (2012) WHO classification of tumours of the breast, vol 4. International Agency for Research on Cancer, Lyon

    Google Scholar 

  5. Tan PH, Thike AA, Tan WJ, Thu MMM, Busmanis I, Li H, Chay WY, Tan MH, Phyllodes Tumour Network Singapore (2012) Predicting clinical behaviour of breast phyllodes tumours: a nomogram based on histological criteria and surgical margins. J Clin Pathol 65:69–76

    Article  PubMed  Google Scholar 

  6. Jee KJ, Gong G, Ahn SH, Park JM, Knuutila S (2003) Gain in 1q is a common abnormality in phyllodes tumours of the breast. Anal Cell Pathol 25:89–93

    CAS  PubMed  Google Scholar 

  7. Jones AM, Mitter R, Springall R et al (2008) A comprehensive genetic profile of phyllodes tumours of the breast detects important mutations, intra-tumoral genetic heterogeneity and new genetic changes on recurrence. J Pathol 214:533–544

    Article  CAS  PubMed  Google Scholar 

  8. Lu YJ, Birdsall S, Osin P, Gusterson B, Shipley J (1997) Phyllodes tumors of the breast analyzed by comparative genomic hybridization and association of increased 1q copy number with stromal overgrowth and recurrence. Genes Chromosom Cancer 20:275–281

    Article  CAS  PubMed  Google Scholar 

  9. Ang MK, Ooi AS, Thike AA, Tan P, Zhang Z, Dykema K, Furge K, Teh BT, Tan PH (2011) Molecular classification of breast phyllodes tumors: validation of the histologic grading scheme and insights into malignant progression. Breast Cancer Res Treat 129:319–329

    Article  PubMed  Google Scholar 

  10. Wang ZC, Buraimoh A, Iglehart JD, Richardson AL (2006) Genome-wide analysis for loss of heterozygosity in primary and recurrent phyllodes tumor and fibroadenoma of breast using single nucleotide polymorphism arrays. Breast Cancer Res Treat 97:301–309

    Article  CAS  PubMed  Google Scholar 

  11. Laé M, Vincent-Salomon A, Savignoni A, Huon I, Fréneaux P, Sigal-Zafrani B, Aurias A, Sastre-Garau X, Couturier J (2007) Phyllodes tumors of the breast segregate in two groups according to genetic criteria. Mod Pathol 20:435–444

    Article  PubMed  Google Scholar 

  12. Kersting C, Kuijper A, Schmidt H et al (2006) Amplifications of the epidermal growth factor receptor gene (egfr) are common in phyllodes tumors of the breast and are associated with tumor progression. Lab Invest 86:54–61

    Article  CAS  PubMed  Google Scholar 

  13. Korcheva VB, Levine J, Beadling C, Warrick A, Countryman G, Olson NR, Heinrich MC, Corless CL, Troxell ML (2011) Immunohistochemical and molecular markers in breast phyllodes tumors. AIMM 19:119–125

    CAS  PubMed  Google Scholar 

  14. Gatalica Z, Finkelstein S, Lucio E, Tawfik O, Palazzo J, Hightower B, Eyzaguirre E (2001) p53 protein expression and gene mutation in phyllodes tumors of the breast. Pathol Res Pract 197:183–187

    Article  CAS  PubMed  Google Scholar 

  15. Wang Y, Cottman M, Schiffman JD (2012) Molecular inversion probes: a novel microarray technology and its application in cancer research. Cancer Genet 205:341–355

    Article  CAS  PubMed  Google Scholar 

  16. Schiffman JD, Hodgson JG, VandenBerg SR et al (2010) Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas. Cancer Res 70:512–519

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Wang Y, Moorhead M, Karlin-Neumann G et al (2007) Analysis of molecular inversion probe performance for allele copy number determination. Genome Biol 8:R246

    Article  PubMed Central  PubMed  Google Scholar 

  18. Tan PH, Jayabaskar T, Chuah KL, Lee HY, Tan Y, Hilmy M, Hung H, Selvarajan S, Bay BH (2005) Phyllodes tumors of the breast: the role of pathologic parameters. Am J Clin Pathol 123:529–540

    Article  PubMed  Google Scholar 

  19. Diskin S, Hou C, Glessner J et al (2009) Copy number variation at 1q21.1 associated with neuroblastoma. Nature 459:987–991

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Dong H, Zhang H, Liang J et al (2011) Digital karyotyping reveals probable target genes at 7q21.3 locus in hepatocellular carcinoma. BMC Med Genomics 4:60

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Arco A, Favaloro A, Gioffrè M, Santoro G, Speciale F, Vermiglio G, Cutroneo G (2012) Sarcoglycans in the normal and pathological breast tissue of humans: an immunohistochemical and molecular study. Cells Tissues Organs 195:550–562

    Article  CAS  PubMed  Google Scholar 

  22. Orsetti B, Nugoli M, Cervera N et al (2006) Genetic profiling of chromosome 1 in breast cancer: mapping of regions of gains and losses and identification of candidate genes on 1q. Br J Cancer 95:1439–1447

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Simon R, Richter J, Wagner U et al (2001) High-throughput tissue microarray analysis of 3p25 (RAF1) and 8p12 (FGFR1) copy number alterations in urinary bladder cancer. Cancer Res 61:4514–4519

    CAS  PubMed  Google Scholar 

  24. Ikeda S, Sumii H, Akiyama K, Watanabe S, Ito S, Inoue H, Takechi H, Tanabe G, Oda T (1989) Amplification of both c-myc and c-raf-1 oncogenes in a human osteosarcoma. Jpn J Cancer Res 80:6–9

    Article  CAS  PubMed  Google Scholar 

  25. Gamwell L, Gambaro K, Merziotis M et al (2013) Small cell ovarian carcinoma: genomic stability and responsiveness to therapeutics. Orphanet J Rare Dis 8:33

    Article  PubMed Central  PubMed  Google Scholar 

  26. Karim RZ, Gerega SK, Yang YH, Spillane A, Carmalt H, Scolyer RA, Lee CS (2010) p16 and pRb immunohistochemical expression increases with increasing tumour grade in mammary phyllodes tumours. Histopathology 56:868–875

    Article  PubMed  Google Scholar 

  27. Davison EJ, Tarpey PS, Fiegler H, Tomlinson IPM, Carter NP (2005) Deletion at chromosome band 20p12.1 in colorectal cancer revealed by high resolution array comparative genomic hybridization. Genes Chromosom Cancer 44:384–391

    Article  CAS  PubMed  Google Scholar 

  28. Tada M, Kanai F, Tanaka Y et al (2010) Prognostic significance of genetic alterations detected by high-density single nucleotide polymorphism array in gastric cancer. Cancer Sci 101:1261–1269

    Article  CAS  PubMed  Google Scholar 

  29. Bradley W, Raelson J, Dubois D et al (2010) Hotspots of large rare deletions in the human genome. PLoS One 5:10

    Google Scholar 

  30. Johnson CE, Gorringe KL, Thompson ER, Opeskin K, Boyle SE, Wang Y, Hill P, Mann GB, Campbell IG (2012) Identification of copy number alterations associated with the progression of DCIS to invasive ductal carcinoma. Breast Cancer Res Treat 133:889–898

    Article  CAS  PubMed  Google Scholar 

  31. Teng YHF, Tan WJ, Thike AA et al (2011) Mutations in the epidermal growth factor receptor (EGFR) gene in triple negative breast cancer: possible implications for targeted therapy. Breast Cancer Res 13:R35

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Corless C, McGreevey L, Haley A, Town A, Heinrich M (2002) KIT mutations are common in incidental gastrointestinal stromal tumours one centimeter or less in size. Am J Pathol 160:1567–1572

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Institute of Bioengineering and Nanotechnology (Biomedical Research Council, Agency for Science, Technology and Research, Singapore). The authors would like to thank Professor Bin Tean Teh of the National Cancer Centre Singapore and Duke-NUS Graduate Medical School for his valuable input. W. J. Tan is a recipient of the NUS Research Scholarship.

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None declared.

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Authors and Affiliations

  1. Department of Pathology, Singapore General Hospital, 20 College Road, Academia, Diagnostics Tower, Singapore, 169856, Singapore

    Wai Jin Tan, Aye Aye Thike, Jeffrey Chun Tatt Lim, Sie Yong Tan, Valerie Cui Yun Koh, Tse Hui Lim & Puay Hoon Tan

  2. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, MD10, 4 Medical Drive, Singapore, 117594, Singapore

    Wai Jin Tan, Boon Huat Bay & Puay Hoon Tan

  3. Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore, 138669, Singapore

    Johnathan C. Lai & Min-Han Tan

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  1. Wai Jin Tan
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Correspondence to Puay Hoon Tan.

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Tan, W.J., Lai, J.C., Thike, A.A. et al. Novel genetic aberrations in breast phyllodes tumours: comparison between prognostically distinct groups. Breast Cancer Res Treat 145, 635–645 (2014). https://doi.org/10.1007/s10549-014-2982-y

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  • DOI: https://doi.org/10.1007/s10549-014-2982-y

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