Presentation: Patient with osteosarcoma

A 19-year-old male is diagnosed with an osteosarcoma. His mother was diagnosed with breast cancer at age 35 years and his maternal aunt had glioblastoma at age 38 years. You wish to undertake genomic testing and are considering what constitutional (germline) and somatic (tumour) genomic testing is available and appropriate for him.

Constitutional (germline) testing

• The majority of osteosarcomas are sporadic but a small proportion occur as part of an inherited cancer predisposition syndrome (for example, Li-Fraumeni syndrome, hereditary retinoblastoma, Rothmund-Thomson syndrome). There is also increasing evidence to suggest that osteosarcoma may be part of the Lynch syndrome phenotype.
• If the history is suggestive of Li-Fraumeni syndrome (LFS), as in the clinical scenario given above, the following criteria apply for TP53 gene testing in the context of a proband with osteosarcoma:
  • ≥2 LFS-related cancers* (both occurring ≤46 years; two breast cancers not eligible); or
  • ≥1 LFS-related cancer* with ≥1 first-/second-degree relative with ≥1 LFS-related cancer (one case ≤46 years, the other case ≤56 years; two breast cancers not eligible); or
  • cancer with ≥2 first-/second-degree relatives with cancer; across the family, there is:
    • one individual with sarcoma ≤45 years; and
    • one individual with any cancer ≤45 years; and
    • one individual with either a sarcoma or any cancer occurring ≤45 years.
  • jaw osteosarcoma <18 years.

*LFS-related cancers comprise: sarcoma of bone/soft tissue, breast cancer, brain cancer, adrenocortical cancer or any childhood cancer (occurring ≤18 years).

Somatic (tumour) testing

• All patients with sarcomas are now eligible for whole genome sequencing (WGS) if a fresh-frozen tumour sample is available.
• Parosteal osteosarcoma, dedifferentiated parosteal osteosarcoma and low-grade central (intramedullary) osteosarcomas are eligible for MDM2 copy number variant detection. MDM2 expression data can inform diagnostic decisions. MDM2 inhibitors are under investigation in clinical trials.
• Somatic testing for NTRK1, NTRK2 and NTRK3 fusion genes is available for osteosarcoma patients as a biomarker for treatment with an NTRK inhibitor when all other approved lines of treatment have been exhausted.
• Other somatic testing may be available within clinical trials.

• Consult the National Genomic Test Directory eligibility criteria to ensure your patient is eligible for testing. You can also refer to this spreadsheet of all available tests.
• For information on the genes that are included on different gene panels for constitutional (germline) testing, see the NHS Genomic Medicine Service signed-off panels resource.
• Decide which of the panels best suits the needs of your patient. For those affected with osteosarcoma, the constitutional options are:
  • R216: Li-Fraumeni syndrome
  • R219: Retinoblastoma
  • R359: Childhood solid tumours
• After appropriate pre-test counselling, a record of discussion (RoD) form is required. If you have not completed an RoD form before and/or do not have access to one, please review this Knowledge Hub article on how to complete an RoD form.
• Depending on the details you provide and the test that is chosen, a range of different genomic investigation techniques will be applied to your patient’s/their family’s (if appropriate) DNA. These tests include (but are not restricted to):
  • Single gene sequencing
  • Gene panel sequencing
  • MLPA
• For DNA-based tests (all the above listed tests), an EDTA blood sample is required. Please refer to your local Genomics Laboratory Hub for details of test request forms and where to send samples.
• WGS of a fresh-frozen tumour sample is requested as M70.2 (WGS germline and tumour) for all patients. A matched germline blood sample is also required. An RoD must be completed for this investigation.
• MDM2 copy number variant detection can be requested as M70.1 (MDM2 copy number FISH) or M70.4 (Multi-target NGS panel).
• NTRK fusion gene analysis can be requested as M70.3 (Multi-target NHS panel – structural variant (NTRK1, NTRK2, NTRK3)).
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• NHS England: National Genomic Test Directory and eligibility criteria (note that somatic (tumour) tests are listed in the directory for cancer, while constitutional (germline) tests are listed in the directory for rare and inherited disease)

References:

• Ballinger, ML, Goode DL, Ray-Coquard I and others. ‘Monogenic and polygenic determinants of sarcoma risk: an international genetic study‘. The Lancet Oncology 2016: volume 17, issue 9, pages 1,261–1,271. DOI: 10.1016/S1470-2045(16)30147-4
• Dominguez-Valentin M, Sampson JR, Møller P and others. ‘Analysis in the Prospective Lynch Syndrome Database identifies sarcoma as part of the Lynch syndrome tumor spectrum‘. International Journal of Cancer 2021: volume 148, issue 2, pages 512–513. DOI: 10.1002/ijc.33214
• Gerrand C, Athanasou N, Brennan B and others. ‘UK guidelines for the management of bone sarcomas‘. Clinical Sarcoma Research 2016: issue 6, article 7. DOI: 10.1186/s13569-016-0047-1
• Hameed M, Mandelker D. ‘Tumor Syndromes Predisposing to Osteosarcoma‘. Advances in Anatomic Pathology 2018: volume 25, issue 4, pages 217–222. DOI: 10.1097/PAP.0000000000000190
• Morrow J, Khanna C. ‘Osteosarcoma genetics and epigenetics: emerging biology and candidate therapies‘. Critical Reviews in Oncogenesis 2015: volume 20, issues 3-4, pages 173–197. DOI: 10.1615/CritRevOncog.2015013713

For patients

• Bone Cancer Research Trust: Osteosarcoma information
• Cancer.net: Osteosarcoma risk factors in childhood and adolescence
• Sarcoma UK: Osteosarcoma information