Genomic profile of breast sarcomas: a comparison with malignant phyllodes tumours

  • Sue Zann Lim
  • Cedric Chuan Young Ng
  • Vikneswari Rajasegaran
  • Peiyong Guan
  • Sathiyamoorthy Selvarajan
  • Aye Aye Thike
  • Nur Diyana Binte Md Nasir
  • Valerie Cui Yun Koh
  • Benita Kiat Tee Tan
  • Kong Wee Ong
  • Bin Tean Teh
  • Puay Hoon Tan
Preclinical study



We aimed to investigate the genomic profile of breast sarcomas (BS) and compare with that of malignant phyllodes tumours (MPT).


DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) specimens from 17 cases of BS diagnosed at Singapore General Hospital from January 1991 to December 2014. Targeted deep sequencing and copy number variation (CNV) analysis on 16 genes, which included recurrently mutated genes in phyllodes tumours and genes associated with breast cancer, were performed on these samples. Genetic alterations (GA) observed were summarised and analysed.


Nine cases met the quality control requirements for both targeted deep sequencing and CNV analysis. Three (33.33%) were angiosarcomas and 6 (66.67%) were non-angiosarcomas. In the non-angiosarcoma group, 83.33% (n = 5) of the patients had GA in the TERT gene. The other commonly mutated genes in this group of tumours were MED12 (n = 4, 66.67%), BCOR (n = 4, 66.67%), KMT2D (n = 3, 50%), FLNA (n = 3, 50%) and NF1 (n = 3, 50%). In contrast, none of the angiosarcomas had mutations or copy number alterations in TERT, MED12, BCOR, FLNA or NF1. Eighty percent of patients with GA in TERT (n = 5) had concurrent mutations in MED12. Sixty percent (n = 3) of these cases also demonstrated GA in NF1, PIK3CA or EGFR which are known cancer driver genes.


The non-angiosarcoma group of BS was found to share similar GA as those described for MPT, which may suggest a common origin and support their consideration as a similar group of tumours with regard to management and prognostication.


Mesenchymal Genomic profile TERT MED12 NF1 



This work was supported by funding from the Singapore General Hospital Research Grant 2016.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional research board.


  1. 1.
    Pollard SG, Marks PV, Temple LN, Thompson HH (1990) Breast sarcoma. A clinicopathologic review of 25 cases. Cancer 66:941–944.;2-B CrossRefPubMedGoogle Scholar
  2. 2.
    Terrier P, Terrier-Lacombe MJ, Mouriesse H, Friedman S, Spielmann M, Contesso G (1989) Primary breast sarcoma: a review of 33 cases with immunohistochemistry and prognostic factors. Breast Cancer Res Treat 13(1):39–48. CrossRefPubMedGoogle Scholar
  3. 3.
    Lim SZ, Selvarajan S, Thike AA, Nasir ND, Tan BK, Ong KW, Tan PH (2016) Breast sarcomas and malignant phyllodes tumours: comparison of clinicopathological features, treatment strategies, prognostic factors and outcomes. Breast Cancer Res Treat 159:229–244. CrossRefPubMedGoogle Scholar
  4. 4.
    Bousquet G, Confavreux C, Magné N, de Lara CT, Poortmans P, Senkus E, de Lafontan B, Bolla M, Largillier R, Lagneau E, Kadish S, Lemanski C, Ozsahin M, Belkacémi Y (2007) Outcome and prognostic factors in breast sarcoma: a multicenter study from the rare cancer network. Radiother Oncol 85(3):355–361. CrossRefPubMedGoogle Scholar
  5. 5.
    Johnstone PA, Pierce LJ, Merino MJ, Yang JC, Epstein AH, DeLaney TF (1993) Primary soft tissue sarcomas of the breast: local-regional control with post-operative radiotherapy. Int J Radiat Oncol Biol Phys 27(3):671–675. CrossRefPubMedGoogle Scholar
  6. 6.
    Toesca A, Spitaleri G, De Pas T, Botteri E, Gentilini O, Bottiglieri L, Rotmentsz N, Sangalli C, Marrazzo E, Cassano E, Veronesi P, Rietjens M, Luini A (2012) Sarcoma of the breast: outcome and reconstructive options. Clin Breast Cancer 12(6):438–444. CrossRefPubMedGoogle Scholar
  7. 7.
    Adem C, Reynolds C, Ingle JN, Nascimento AG (2004) Primary breast sarcoma: clinicopathologic series from the Mayo Clinic and review of the literature. Br J Cancer 91(2):237–241. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Barnes L, Pietruszka M (1977) Sarcomas of the breast: a clinicopathologic analysis of ten cases. Cancer 40(4):1577–1585.;2-D CrossRefPubMedGoogle Scholar
  9. 9.
    Barrow BJ, Janjan NA, Gutman H, Benjamin RS, Allen P, Romsdahl MM, Ross MI, Pollock RE (1999) Role of radiotherapy in sarcoma of the breast–a retrospective review of the M.D. Anderson experience. Radiother Oncol 52(2):173–178. CrossRefPubMedGoogle Scholar
  10. 10.
    Fields RC, Aft RL, Gillanders WE, Eberlein TJ, Margenthaler JA (2008) Treatment and outcomes of patients with primary breast sarcoma. Am J Surg 196(4):559–561. CrossRefPubMedGoogle Scholar
  11. 11.
    North JH Jr, McPhee M, Arredondo M, Edge SB (1998) Sarcoma of the breast: implications of the extent of local therapy. Am Surg 64(11):1059–1061PubMedGoogle Scholar
  12. 12.
    Pandey M, Mathew A, Abraham EK, Rajan B (2004) Primary sarcoma of the breast. J Surg Oncol 87(3):121–125. CrossRefPubMedGoogle Scholar
  13. 13.
    Stanley MW, Tani EM, Horwitz CA, Tulman S, Skoog L (1988) Primary spindle-cell sarcomas of the breast: diagnosis by fine-needle aspiration. Diagn Cytopathol 4(3):244–249. CrossRefPubMedGoogle Scholar
  14. 14.
    Surov A, Holzhausen HJ, Ruschke K, Spielmann RP (2011) Primary breast sarcoma: prevalence, clinical signs, and radiological features. Acta Radiol 52(6):597–601. CrossRefPubMedGoogle Scholar
  15. 15.
    Lim SZ, Ong KW, Tan BK, Selvarajan S, Tan PH (2016) Sarcoma of the breast: an update on a rare entity. J Clin Pathol 69(5):373–381. CrossRefPubMedGoogle Scholar
  16. 16.
    Gao P, Seebacher NA, Hornicek F, Guo Z, Duan Z (2018) Advances in sarcoma gene mutations and therapeutic targets. Cancer Treat Rev 62:98–109. CrossRefPubMedGoogle Scholar
  17. 17.
    Tan PH, Tse GM, Lee A, Simpson J, Hanby A (2012) Fibroepithelial tumours. In: Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ (eds) WHO classification of tumours of the breast. IARC Press, Lyon, pp 142–147Google Scholar
  18. 18.
    Sawyer EJ, Poulsom R, Hunt FT, Jeffery R, Elia G, Ellis IO, Ellis P, Tomlinson IP, Hanby AM (2003) Malignant phyllodes tumours show stromal overexpression of c-myc and c-kit. J Pathol 200(1):59–64. CrossRefPubMedGoogle Scholar
  19. 19.
    Sawyer EJ, Hanby AM, Rowan AJ, Gillett CE, Thomas RE, Poulsom R, Lakhani SR, Ellis IO, Ellis P, Tomlinson IP (2002) The Wnt pathway, epithelial-stromal interactions, and malignant progression in phyllodes tumours. J Pathol 196(4):437–444. CrossRefPubMedGoogle Scholar
  20. 20.
    Sawyer EJ, Hanby AM, Ellis P, Lakhani SR, Ellis IO, Boyle S, Tomlinson IP (2000) Molecular analysis of phyllodes tumors reveals distinct changes in the epithelial and stromal components. Am J Pathol 156(3):1093–1098. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Karim RZ, Gerega SK, Yang YH, Horvath L, Spillane A, Carmalt H, Scolyer RA, Lee CS (2009) Proteins from the Wnt pathway are involved in the pathogenesis and progression of mammary phyllodes tumours. J Clin Pathol 62(11):1016–1020. CrossRefPubMedGoogle Scholar
  22. 22.
    Karim RZ, Scolyer RA, Tse GM, Tan PH, Putti TC, Lee CS (2009) Pathogenic mechanisms in the initiation and progression of mammary phyllodes tumours. Pathology 41(2):105–117. CrossRefPubMedGoogle Scholar
  23. 23.
    Yoshida M, Ogawa R, Yoshida H, Maeshima A, Kanai Y, Kinoshita T, Hiraoka N, Sekine S (2015) TERT promoter mutations are frequent and show association with MED12 mutations in phyllodes tumors of the breast. Br J Cancer 113(8):1244–1248. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Tan J, Ong CK, Lim WK, Ng CC, Thike AA, Ng LM, Rajasegaran V, Myint SS, Nagarajan S, Thangaraju S, Dey S, Nasir ND, Wijaya GC, Lim JQ, Huang D, Li Z, Wong BH, Chan JY, McPherson JR, Cutcutache I, Poore G, Tay ST, Tan WJ, Putti TC, Ahmad BS, Iau P, Chan CW, Tang AP, Yong WS, Madhukumar P, Ho GH, Tan VK, Wong CY, Hartman M, Ong KW, Tan BK, Rozen SG, Tan P, Tan PH, Teh BT (2015) Genomic landscapes of breast fibroepithelial tumors. Nat Genet 47(11):1341–1345. CrossRefPubMedGoogle Scholar
  25. 25.
    Nozad S, Sheehan CE, Gay LM, Elvin JA, Vergilio JA, Suh J, Ramkissoon S, Schrock AB, Hirshfield KM, Ali N, Ganesan S, Ali SM, Miller VA, Stephens PJ, Ross JS, Chung JH (2017) Comprehensive genomic profiling of malignant phyllodes tumors of the breast. Breast Cancer Res Treat 162(3):597–602. CrossRefPubMedGoogle Scholar
  26. 26.
    McGowan TS, Cummings BJ, O’Sullivan B, Catton CN, Miller N, Panzarella T (2000) An analysis of 78 breast sarcoma patients without distant metastases at presentation. Int J Radiat Oncol Biol Phys 46(2):383–390. CrossRefPubMedGoogle Scholar
  27. 27.
    McGregor GI, Knowling MA, Este FA (1994) Sarcoma and Cystosarcoma phyllodes tumors of the breast–a retrospective review of 58 cases. Am J Surg 167(5):477–480. CrossRefPubMedGoogle Scholar
  28. 28.
    Confavreux C, Lurkin A, Mitton N, Blondet R, Saba C, Ranchère D, Sunyach MP, Thiesse P, Biron P, Blay JY, Ray-Coquard I (2006) Sarcomas and malignant phyllodes tumours of the breast–a retrospective study. Eur J Cancer 42(16):2715–2721. CrossRefPubMedGoogle Scholar
  29. 29.
    Wang F, Jia Y, Tong Z (2015) Comparison of the clinical and prognostic features of primary breast sarcomas and malignant phyllodes tumor. Jpn J Clin Oncol 45(2):146–152. CrossRefPubMedGoogle Scholar
  30. 30.
    1000 Genomes Project Consortium, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA, Abecasis GR (2015) A global reference for human genetic variation. Nature 526(7571):68–74. CrossRefGoogle Scholar
  31. 31.
    Li H, Durbin R (2010) Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 26(5):589–595. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R, 1000 Genome Project Data Processing Subgroup (2009) The Sequence Alignment/Map format and SAMtools. Bioinformatics 25(16):2078–2079. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Garrison E, Marth G (2012) Haplotype-based variant detection from short-read sequencing. Accessed 5 Sept 2018
  34. 34.
    Yang H, Wang K (2015) Genomic variant annotation and prioritization with ANNOVAR and wANNOVAR. Nat Protoc 10(10):1556–1566. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Thorvaldsdóttir H, Robinson JT, Mesirov JP (2013) Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform 14(2):178–192. CrossRefGoogle Scholar
  36. 36.
    Jung H-S, Lefferts JA, Gregory J, Tsongalis (2017) Utilization of the oncoscan microarray assay in cancer diagnostics. Appl Cancer Res 37(1):1. CrossRefGoogle Scholar
  37. 37.
    Schmidt J, Liu B, Ghent M, Bolstad B, Siddiqui F, Abdueva D, Marjanovic M, Saplosky R, Shukla A, Venkatapathy S, Chen C, Bruckner C, Huynh V, Liu L, Suyenaga K, Weaver P, Greenfield L, Fung E (2014) A new method for high fidelity copy number analysis in solid tumor samples and its implementation in the OncoScan ™ FFPE assay kit. American Society of Human Genetics. Accessed 6 May 2018
  38. 38.
    Zelek L, Llombart-Cussac A, Terrier P, Pivot X, Guinebretiere JM, Le Pechoux C, Tursz T, Rochard F, Spielmann M, Le Cesne A (2003) Prognostic factors in primary breast sarcomas: a series of patients with long-term follow-up. J Clin Oncol 21(13):2583–2588. CrossRefPubMedGoogle Scholar
  39. 39.
    Fraga-Guedes C, André S, Mastropasqua MG, Botteri E, Toesca A, Rocha RM, Peradze N, Rotmensz N, Viale G, Veronesi P, Gobbi H (2015) Angiosarcoma and atypical vascular lesions of the breast: diagnostic and prognostic role of MYC gene amplification and protein expression. Breast Cancer Res Treat 151(1):131–140. CrossRefPubMedGoogle Scholar
  40. 40.
    Manner J, Radlwimmer B, Hohenberger P, Mössinger K, Küffer S, Sauer C, Belharazem D, Zettl A, Coindre JM, Hallermann C, Hartmann JT, Katenkamp D, Katenkamp K, Schöffski P, Sciot R, Wozniak A, Lichter P, Marx A, Ströbel P (2010) MYC high level gene amplification is a distinctive feature of angiosarcomas after irradiation or chronic lymphedema. Am J Pathol 176(1):34–39. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Italiano A, Thomas R, Breen M, Zhang L, Crago AM, Singer S, Khanin R, Maki RG, Mihailovic A, Hafner M, Tuschl T, Antonescu CR (2012) The miR-17-92 cluster and its target THBS1 are differentially expressed in angiosarcomas dependent on MYC amplification. Genes Chromosomes Cancer 51(6):569–578. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Guo T, Zhang L, Chang NE, Singer S, Maki RG, Antonescu CR (2011) Consistent MYC and FLT4 gene amplification in radiation-induced angiosarcoma but not in other radiation-associated atypical vascular lesions. Genes Chromosomes Cancer 50(1):25–33. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Thibodeau BJ, Lavergne V, Dekhne N, Benitez P, Amin M, Ahmed S, Nakamura JL, Davidson PR, Nakamura AO, Grills IS, Chen PY, Wobb J, Wilson GD (2018) Mutational landscape of radiation-associated angiosarcoma of the breast. Oncotarget 9(11):10042–10053. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Sue Zann Lim
    • 1
  • Cedric Chuan Young Ng
    • 2
    • 3
  • Vikneswari Rajasegaran
    • 2
    • 3
  • Peiyong Guan
    • 4
  • Sathiyamoorthy Selvarajan
    • 5
  • Aye Aye Thike
    • 5
  • Nur Diyana Binte Md Nasir
    • 5
  • Valerie Cui Yun Koh
    • 5
  • Benita Kiat Tee Tan
    • 1
  • Kong Wee Ong
    • 1
  • Bin Tean Teh
    • 2
    • 3
    • 6
    • 7
  • Puay Hoon Tan
    • 8
  1. 1.SingHealth Duke-National University of Singapore Breast CentreSingaporeSingapore
  2. 2.Laboratory of Cancer EpigenomeNational Cancer Centre SingaporeSingaporeSingapore
  3. 3.Division of Cancer and Stem Cell BiologyDuke-National University of Singapore Medical SchoolSingaporeSingapore
  4. 4.Integrated Biostatistics and Bioinformatics ProgrammeDuke-National University of Singapore Medical SchoolSingaporeSingapore
  5. 5.Department of Anatomical PathologySingapore General HospitalSingaporeSingapore
  6. 6.Cancer Science Institute of SingaporeNational University of SingaporeSingaporeSingapore
  7. 7.Institute of Molecular and Cellular BiologySingaporeSingapore
  8. 8.Division of PathologySingapore General HospitalSingaporeSingapore

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