Dr Gehrig on the Use of Genetic Testing in Endometrial Cancer

Paola Gehrig, MD, gynecologic oncologist, chair, Department of Obstetrics and Gynecology, University of Virginia Health, discusses the optimal use and timing of genetic testing in endometrial cancer.

Patients with endometrial cancer will initially undergo tumor testing to identify potential mismatch repair deficiency (dMMR) via immunohistochemistry (IHC) of the biopsy or surgical tissue, Gehrig begins. IHC testing will reveal the expression of key mismatch repair proteins, such as MLH1, MSH2, MSH6 and PMS2.

If patients are dMMR negative, no further testing is needed, Gehrig states. However, patients who are dMMR positive and have lost a MMR protein should be evaluated for epigenetic hypermethylation to identify whether MRR gene inactivation was caused by germline or somatic mutations vs epigenetic silencing, Gehrig states.

Mutations in MMR genes, especially MLH1 and MSH2, can be an indicator for Lynch syndrome, she continues. Lynch syndrome is caused by germline mutations in MMR genes and increases the risk of a patient developing various cancers, including endometrial cancer.

MHL1 hypermethylation is strongly associated with sporadic microsatellite instability–positive tumors, but is rarely seen in patients with Lynch syndrome, Gehrig adds. It can indicate whether dMMR positivity is likely caused by epigenetic changes or genetic predisposition, she explains.

Patients with dMMR-negative tumors who experience a loss of MHL1 expression that cannot be attributed to hypermethylation should undergo genetic testing for Lynch syndrome, Gehrig says. Identification of Lynch syndrome could help inform patients and their families of their hereditary risk for developing endometrial cancer and encourage family members to undergo cascade family testing, Gehrig details. However, this genetic predisposition does not factor heavily into treatment decisions for the majority of patients, she notes.

However, information could be useful to informing treatment decisions for young, fit patients with endometrial cancer, Gehrig qualifies. If these patients have a Lynch syndrome that does not increase the risk of developing ovarian cancer, or do not have Lynch syndrome, oophorectomy may not be a necessity, Gehrig concludes.