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Oncology

Presentation: Patient with endometrial cancer

Genomic testing in patients with endometrial cancer affects the clinical management of the patient’s current cancer as well as their relatives’ future cancer risk.

Example clinical scenario

A 52-year-old woman is diagnosed with metastatic endometrial cancer. There is no significant family history of cancer. You wish to undertake genomic testing and are considering what somatic (tumour) and/or constitutional (germline) genomic testing is available and appropriate for her.

When to consider genomic testing

Somatic (tumour) testing

  • As endometrial cancer can be the sentinel cancer in Lynch syndrome, current recommendations (HealthTech guidance HTG557, formerly DG42) from the National Institute for Health and Care Excellence (NICE) advise assessment of mismatch repair (MMR) and/or microsatellite instability (MSI) status of all endometrial tumours, irrespective of the patient’s age at diagnosis or their family history. Detection of MMR deficiency can help identify those patients requiring testing for Lynch syndrome, and can also help determine treatment options for metastatic disease.
  • NICE have recommended dostarlimab (an immune checkpoint inhibitor) with platinum-based chemotherapy as an option for treating primary advanced or recurrent endometrial cancer with high MSI or MMR deficiency in adults who are candidates for systemic therapy.
  • MMR status may be assessed by an immunohistochemistry (IHC) four‑panel test, checking for expression of MLH1, MSH2, MSH6 and PMS2 proteins (not a genomic test).
  • MSI may be assessed by polymerase chain reaction (PCR) (a genomic test).
  • If IHC is abnormal, demonstrating loss of expression of MLH1, or loss of both MLH1 and PMS2 protein expression, or the tumour is MSI-H and corresponding IHC is not available, MLH1 promotor hypermethylation testing of tumour DNA should be performed as the next step. If there is no evidence of hypermethylation of the MLH1 promoter, then constitutional (germline) testing for Lynch syndrome is indicated.
  • Somatic testing of MLH1, MSH2, MSH6, PMS2 may be considered, if appropriate, for all patients with a known endometrial cancer if constitutional (germline) genetic testing does not confirm Lynch syndrome (i.e. if mismatch repair deficiency remains unexplained). Indications for this testing should be discussed with clinical genetics.
  • Somatic testing of POLE is available for patients (M215.5) with endometrial cancer if molecular assessment will aid diagnosis or management. POLE-associated cancers tend to occur in younger women and are typically high-grade tumours with adverse histopathologic features. They have an excellent prognosis despite their aggressive appearance. Identification of POLE variants has the potential to reduce risks of overtreatment in relatively young patients. POLE-mutated endometrial cancers tend to show overexpression of the immune markers PD-1 and PD-L1.
  • Somatic testing for fusions involving NTRK1, NTRK2 and NTRK3 genes is available for patients with metastatic endometrial cancer, as a biomarker for treatment with an NTRK inhibitor, when all other approved lines of treatment have been exhausted.
  • If, during tumour testing, a pathogenic variant is identified in a gene known to be associated with cancer predisposition that is suspected to be of constitutional (germline) origin (for example, because of variant allele frequency, variant type or clinical factors), follow-up constitutional testing for the same variant may be appropriate (R240 Diagnostic testing for known mutation(s)), if constitutional testing has not already been undertaken. Such cases are best discussed through a genomic tumour advisory board (GTAB) or with clinical genetics.
    • A negative tumour-based genomic test does not replace the need for constitutional (germline) testing in those individuals fulfilling constitutional genomic testing criteria, as somatic testing is unlikely to detect large genomic rearrangements.
  • Whole genome sequencing of non-CNS solid tumours in adults (>25 years) is now only available if there is a clear clinical question and expected utility/impact.

Constitutional (germline) testing

  • Although most cases of endometrial cancer are sporadic, approximately 3% cases are due to Lynch syndrome. Identification of the underlying Lynch syndrome means that cancer prevention strategies and/or surveillance can be adopted to facilitate early diagnosis of any other Lynch syndrome-associated cancers, or to reduce cancer risk (where possible). Constitutional (germline) testing for Lynch syndrome under the R210 indication is recommended in patients with endometrial tumours that demonstrate one of the following:
    • loss of MSH2 and/or MSH6;
    • isolated loss of PMS2; or
    • loss of MLH1 with/without corresponding loss of PMS2, and/or MSI where a MLH1 promoter hypermethylation test is negative.
  • A rare cause of endometrial cancer is PTEN hamartoma tumour syndrome, caused by pathogenic constitutional (germline) variants in PTEN. A referral to clinical genetics for consideration of PTEN testing should be offered to patients with endometrial cancer and other suggestive features of this condition, such as macrocephaly (occipito-frontal circumference ≥97th percentile), or PTEN-associated mucocutaneous lesion (facial papules, oral mucosal papillomatosis, acral keratoses, palmoplantar keratoses), or a personal/family history of other PTEN-associated cancers (such as breast, thyroid, kidney or bowel cancers, among others).
  • Constitutional (germline) pathogenic variants in a number of other genes have also been reported to increase endometrial cancer risk as part of broader syndromes that also predispose the patient to a risk of colorectal polyposis or cancer. Such genes include POLE, POLD1 (polymerase proofreading-associated polyposis) and NTHL1 (NTHL1 tumour predisposition syndrome).
  • All patients diagnosed with endometrial cancer before age 40 are eligible for constitutional (germline) genetic testing of a wide panel of relevant cancer susceptibility genes including those mentioned above, under the R211 indication. Patients diagnosed between the ages of 40 and 50 may also be eligible for testing under this indication if they have a strong family history of endometrial or related cancers.

What do you need to do?

  • Consult the National Genomic Test Directory. From this resource you can access:
    • the rare and inherited disease eligibility criteria, which gives information about constitutional (germline) tests and their associated eligibility criteria;
    • the test directory for rare and inherited disease, which is a spreadsheet of all available constitutional (germline) tests; and
    • the test directory for cancer, which is a spreadsheet of all available somatic tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
  • For information on the genes that are included on different gene panels for constitutional (germline) testing, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
  • Decide which of the panels best suits the needs of your patient. For patients affected with endometrial cancer and indication codes are:
    • R210 Inherited MMR deficiency (Lynch syndrome), including sequencing and MLPA of MLH1, MSH2, MSH6, PMS2 and CNV analysis of 3′ end of EPCAM. If your patient has isolated loss of PMS2, please include this detail on the request, as specialised assessment of PMS2 is required in such cases.
    • R211 Inherited polyposis and early onset colorectal cancer – germline test. This is a multigene panel including genes associated with bowel cancer and polyposis predisposition, many of which are also associated with endometrial cancer predisposition. This test can be requested by clinicians working in clinical genetics, gastroenterology, gynaecology and surgery. Search ‘R211’ in the Signed Off Panels Resource for an up-to-date list of the genes in this panel.
    • R213 PTEN Hamartoma tumour syndrome: This test can currently only be requested by specialists in clinical genetics, neurology and dermatology. This is a single gene test (of PTEN) including sequencing and MLPA.
  • Germline (constitutional) testing for variants found in somatic testing, to determine if they are of germline origin, is requested as R240 Diagnostic testing for known mutation(s).
  • A record of discussion form (RoD) is required before any constitutional genomic testing. If you have not completed this form before and/or do not have access to one, please review this Knowledge Hub article on how to complete an RoD form.
  • For DNA-based tests (all the above listed tests), an EDTA sample is required. Please refer to your local Genomic Laboratory Hub (GLH) for details of the test request forms and where to send the samples.
  • Somatic genomic tests on endometrial tumours are requested using the following codes:
    • M215.1 Multi-target NGS panel – structural variant (NTRK1, NTRK2, NTRK3): Testing for NTRK1, NTRK2 and NTRK3 fusion genes is available for metastatic endometrial cancer patients, as a biomarker for treatment with an NTRK inhibitor, when all other approved lines of treatment have been exhausted.
    • M215.2 MLH1 promoter hypermethylation: MLH1 promotor hypermethylation testing of tumour DNA where either immunohistochemistry testing indicates loss of MLH1/PMS2, or where MSI testing indicates microsatellite instability. This is as per the NICE guidelines algorithm for molecular testing for Lynch syndrome.
    • M215.4 Multi-target NGS panel – small variant (MLH1, MSH2, MSH6, PMS2): A multi-target massively parallel sequencing – also called next generation sequencing (NGS) – panel for MLH1, MSH2, MSH6 and PMS2 genes).
    • M215.5 Multi-target NGS panel-small variant detection POLE: A multi-target massively parallel sequencing panel to detection small variant in POLE.
  • WGS of non-CNS solid tumours in adults must be discussed with the cancer clinical lead of your GLH before submitting any samples. If WGS is authorised you will require:
    • access to a fresh tumour sample and a matched blood (EDTA) sample (WGS requires paired somatic (tumour) and constitutional (germline) DNA analysis);
    • a completed RoD form.
  • If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
  • 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: 22/07/2026
  • Next review due: 22/07/2028
  • Authors: Dr Nicola Campbell
  • Reviewers: Professor Ellen Copson, Dr Clare Green, Dr David McMahon, Dr Terri McVeigh