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Oncology

Presentation: Patient with osteosarcoma

Genomic testing in osteosarcoma affects clinical management of the current cancer and may affect management of the patient’s future cancer risk and that of their relatives.

Example clinical scenario

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.

When to consider genomic testing

Constitutional (germline) testing

  • The majority of osteosarcomas are sporadic but a small proportion occur as part of an inherited cancer predisposition syndrome (for example, heritable TP53-related cancer syndromes (Li-Fraumeni syndrome), hereditary retinoblastoma, or Rothmund-Thomson syndrome or other disorders of DNA repair). There is also some evidence to suggest that osteosarcoma may be part of the Lynch syndrome phenotype.
  • 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.

Note: POT1 testing is now routinely undertaken alongside TP53 testing under indication R216, but osteosarcoma risk is not known to be significantly increased in carriers of POT1 variants

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

  • Patients diagnosed with cancer before age 25 are eligible for testing of a broad panel of genes under indication R359 (Childhood solid tumours) if WGS has not been undertaken and/or other more targeted testing is uninformative. This panel includes TP53, as well as RB1, RECQL4, WRN and other genes associated with DNA repair disorders. Please refer to PanelApp for an up-to-date list of genes included on the panel.
  • Consider referral to clinical genetics where syndromic cancer predisposition is suspected; for example in patients with osteosarcoma demonstrating other features such as short stature or photosensitivity. A high index of suspicion for recessive cancer predisposition should exist where consanguinity exists in a family (e.g. first cousin marriage). Such conditions may be evident from childhood but milder phenotypes may not be evident until later in adolescence.

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.

What do you need to do?

  • Consult the National Genomic Test Directory to ensure your patient is eligible for testing. You can also access a spreadsheet containing details 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):
  • 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.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 01/09/2024
  • Next review due: 01/09/2025
  • Authors: Dr Georgina Wood
  • Reviewers: Dr Ellen Copson, Dr Amy Frost, Dr Terri McVeigh

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