Top

Hereditary Cancer in Clinical Practice

Published in:

Open Access 01-12-2021 | osteosarcoma | Case report

Unusual course of disease and genetic profile in Li-Fraumeni syndrome-associated osteosarcoma – a case report

Authors: Alexander Puzik, Markus Uhl, Juri Ruf, Tilmann Schumacher, Udo Kontny

Published in: Hereditary Cancer in Clinical Practice | Issue 1/2021

Abstract

Background

Osteosarcoma is a highly malignant tumour associated with numerous and complex genetic alterations like copy number alterations. Recent whole genome studies revealed distinct mutations in several candidate oncogenes.

While clinical parameters stratify osteosarcoma patients in risk groups, genetic profiles have not yet been used to tailor tumour treatment. However, specific copy number alterations seem to have a prognostic impact in osteosarcoma treatment.

Somatic TP53 gene mutation frequently occurs in sporadic osteosarcoma. When arising germline, TP53 mutation leads to Li-Fraumeni syndrome and may result in early life osteosarcoma. The effect of Li-Fraumeni syndrome on the genetic profile of osteosarcoma and the consideration of the syndrome during cancer treatment are topics of current research.

Case presentation

We report a 25-year-old female with pelvic osteosarcoma refusing continuation of therapy. She interrupted neo-adjuvant chemotherapy according to EURAMOS-1/COSS recommendations and declined local or further adjuvant therapy. Surprisingly, she remained in sustained remission for the osteosarcoma but eventually died from newly diagnosed breast cancer. After establishment of breast cancer, we detected TP53 germline mutation and investigated the osteosarcoma material with array-CGH.

Conclusion

Genetic examination of the tumour evidenced several copy number alterations with striking differences to previously reported data. We discuss possible influences of the genetic profile on the unusual clinical course and the significance of Li-Fraumeni syndrome for the genetic profile. Specific loss of (proto-) oncogenes might have contributed to the unusual case. Further large-scale genetics of Li-Fraumeni patients combined with detailed clinical data will help to identify specific genetic risk profiles and improve treatment.

Available only for authorised users

Rosenberg AE, Cleton-Jansen AM, de Pineux G, Deyrup AT, Hauben E, Squire J. Conventional Osteosarcoma. In: Fletcher CDM, Bridge JA, Hogendoorn PC, editors. WHO classification of tumours of soft tissue and bone. 4th ed. Lyon: IARC; 2013. p. 282–8.

Jaffé N, Carrasco H, Raymond K, Ayala A, Eftekhari F. Can cure in patients with osteosarcoma be achieved exclusively with chemotherapy and abrogation of surgery? Cancer. 2002;95(10):2202–10. https://doi.org/10.1002/cncr.10944.CrossRefPubMed

Smida J, Baumhoer D, Rosemann M, Walch A, Bielack S, Poremba C, et al. Genomic alterations and allelic imbalances are strong prognostic predictors in osteosarcoma. Clin Cancer Res. 2010;16(16):4256–67. https://doi.org/10.1158/1078-0432.CCR-10-0284.CrossRefPubMed

Yen CC, Chen WM, Chen TH, Chen WYK, Chen PCH, Chiou HJ, et al. Identification of chromosomal aberrations associated with disease progression and a novel 3q13.31 deletion involving LSAMP gene in osteosarcoma. Int J Oncol. 2009;35(4):775–88. https://doi.org/10.3892/ijo_00000390.CrossRefPubMed

Sadikovic B, Park PC, Selvarajah S, Zielenska M. Array comparative genomic hybridization in osteosarcoma. In: Banerjee D and Shah SP, editors. Array comparative genomic hybridization: protocols and applications. Methods Mol Biol 2013;973: 227–246.

Bousquet M, Noirot C, Accadbled F, Sales de gauzy J, Castex MP, Brousset P, et al. Whole-exome sequencing in osteosarcoma reveals important heterogeneity of genetic alterations. Ann Oncol. 2016;27(4):738–44. https://doi.org/10.1093/annonc/mdw009.CrossRefPubMed

Ognjanovic S, Olivier M, Bergemann TL, Hainaut P. Sarcomas in TP53 germline mutation carriers. Cancer. 2012;118:1387–96.CrossRef

Malkin D. Li-Fraumeni syndrome. In: Fletcher CDM, Bridge JA, Hogendoorn PC, editors. WHO classification of tumours of soft tissue and bone. 4th ed. Lyon: IARC; 2013. p. 379–81.

Rickel K, Fang F, Tao J. Molecular genetics of osteosarcoma. Bone. 2017;102:69–79.CrossRef

10.

Sorrell AD, Espenschied CR, Culver JO, Weitzel JN. TP53 testing and li-Fraumeni syndrome: current status of clinical applications and future directions. Mol Diagn Ther. 2013;17(1):31–47.CrossRef

11.

Silva AG, Krepischi AC, Pearson PL, Hainaut P, Rosenberg C, Achatz MI. The profile and contribution of rare germline copy number variants to cancer risk in li-Fraumeni patients negative for TP53 mutations. Orphanet J Rare Dis. 2014;9:63.CrossRef

12.

Meazza C, Luksch R, Daolio P, Podda M, Luzzati A, Gronchi A, et al. Axial skeletal osteosarcoma: a 25-year monoinstitutional experience in children and adolescents. Med Oncol. 2014;31(4):875.CrossRef

13.

Overholtzer M, Rao PH, Favis R, Lu XY, Elowitz MB, Barany F, et al. The presence of p53 mutations in human osteosarcomas correlates with high levels of genomic instability. PNAS. 2003;100(20):11547–52.CrossRef

14.

Man TK, Lu XY, Jaeweon K, Perlaky L, Harris CP, Shah S, et al. Genome-wide array comparative genomic hybridization analysis reveals distinct amplifications in osteosarcoma. BMC Cancer. 2004;4:45. https://doi.org/10.1186/1471-2407-4-45.CrossRefPubMedPubMedCentral

15.

Sadikovic B, Yoshimoto M, Chilton-MacNeill S, Thorner P, Squire JA, Zielenska M. Identification of interactive networks of gene expression associated with osteosarcoma oncogenesis by integrated molecular profiling. Hum Mol Genet. 2009;18(11):1962–75.CrossRef

16.

Atlas of Genetics and Cytogenetics in Oncology and Hematology. http://atlasgeneticsoncology.org. Last accessed 30 October 2020.

17.

Oda Y, Sakamoto A, Shinohara N, Ohga T, Uchiumi T, Kohno K, et al. Nuclear expression of YB-1 protein correlates with P-glycoprotein expression in human osteosarcoma. Clin Cancer Res. 1998;4(9):2273–7.PubMed

18.

Su HC, Zhao YH, Fan DG, Fan QY, Zhang P, Wen YH, et al. Relationship between expression of BLCAP protein and malignancy of osteosarcoma. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2003;19(5):465–6.PubMed

19.

Carter JM, Inwards CY, Jin L, Evers B, Wenger DE, Oliveira AM, et al. Activating GNAS mutations in parosteal osteosarcoma. Am J Surg Pathol. 2014;38(3):402–9.CrossRef

20.

Li-Fraumeni-Syndrome-Cancer-Predisposition-Syndrome Registry 01 (Version 2017-12-29) https://www.kinderkrebsinfo.de/fachinformationen/studienportal/pohkinderkrebsinfotherapiestudien/krebspraedispositionsregister/index_ger.html Last accessed 30 October 2019.

Title: Unusual course of disease and genetic profile in Li-Fraumeni syndrome-associated osteosarcoma – a case report
Authors: Alexander Puzik
Markus Uhl
Juri Ruf
Tilmann Schumacher
Udo Kontny
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: osteosarcoma
Osteosarcoma
Published in: Hereditary Cancer in Clinical Practice / Issue 1/2021
Electronic ISSN: 1897-4287
DOI: https://doi.org/10.1186/s13053-021-00202-0

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Case presentation

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2021

“Left in limbo”: Exploring how patients with colorectal cancer interpret and respond to a suspected Lynch syndrome diagnosis

Neoadjuvant therapy of BRCA1-driven ovarian cancer by combination of cisplatin, mitomycin C and doxorubicin

Evaluation and comparison of hereditary Cancer guidelines in the population

Ultrasound guided needle biopsy of axilla to evaluate nodal metastasis after preoperative systemic therapy in cohort of 106 breast cancers enriched with BRCA1/2 pathogenic variant carriers

Assessment of genetic referrals and outcomes for women with triple negative breast cancer in regional cancer centres in Australia

Impact of national guidelines on use of BRCA1/2 germline testing, risk management advice given to women with pathogenic BRCA1/2 variants and uptake of advice

Keynote webinar | Spotlight on antibody–drug conjugates in cancer