Multigene Panel Testing Identifies Actionable Germline Mutations in Newly Diagnosed Endometrial Cancer

Investigators identified potentially actionable germline variants in 10% of unselected women with newly diagnosed endometrial cancer, supporting the use of upfront multigene panel testing for all in the population.

Investigators identified potentially actionable germline variants in 10% of unselected women with newly diagnosed endometrial cancer, supporting the use of upfront multigene panel testing for all in the population. Furthermore, findings from prospective, multicenter study (NCT03460483) published in JCO® Precision Oncology showed that BRCA1 or BRCA2 heterozygotes frequently had type II cancers, which suggests that there may be therapeutic opportunities for patients with aggressive histologic endometrial cancer subtypes.1

Results from the study showed that pathologic variants were identified in 10.1% of patients examined (n = 97/961). Lynch syndrome was diagnosed in 3% (95% CI, 2.1%-4.3%) of patients (n = 29/961), and most frequently in those with pathologic variants in PMS2. Additionally, multigene panel testing identified 9 patients with Lynch syndrome in addition to the 20 identified through routine tumor-based screening. BRCA1 and BRCA2 pathologic variants were found in 1% (95% CI, 0.6%-1.9%) of patients and that group was significantly enriched for type II endometrial cancers (n = 10/961).

“Our data support the up-front use of multigene panel testing for all patients with endometrial cancer to improve Lynch syndrome detection and to better understand the role genetic risk plays in this common malignancy,” study authors wrote.

Lynch syndrome, present in 2% to 5% of all endometrial cancers, is caused by pathologic variants in the mismatch repair (MMR) genes MLH1, MSH2 (EPCAM), MSH6, and PMS2. Additionally, there is variability in the penetrance and expressivity of the different Lynch syndrome genes, and the identification of patients with endometrial cancer who have this condition offers prevention opportunities for both index cases and their family members. However, although universal tumor screening for these patients, using immunohistochemistry and reflex MLH1 promoter hypermethylation testing, has helped identify those at risk for Lynch syndrome, not all centers have adopted universal tumor testing.

“Furthermore, even with a positive tumor screen result, confirming the diagnosis of Lynch syndrome depends on successful referral for genetic counseling and that patients follow through with germline testing,” study authors wrote. “There is evidence of significant drop-off between finding an abnormal immunohistochemistry result and completion of genetic testing. A recent countrywide initiative in Canada found that despite universal tumor testing, Lynch syndrome was underdiagnosed.”

There is increasing evidence that findings associated with multigene panel testing are clinically relevant and can be used to guide both treatment and prevention strategies for patients with cancer. In this study, investigators sought to prospectively determine the frequency and spectrum of pathologic variants that cause Lynch syndrome, as well as pathologic variants in other cancer susceptibility genes, by using up-front, germline multigene panel testing in a large and unselected series of patients with endometrial cancer.

Investigators enrolled 963 Ohio women who had newly diagnosed endometrial cancer confirmed by hysterectomy or diagnostic biopsy from October 2017 to December 2020; 961 underwent germline multigene panel testing. Additionally, clinical and family history data, pathology reports, tumor block, and blood or saliva samples were collected, and relevant demographic and clinicopathologic data were examined for each patient.

Investigators performed germline testing using the 47-gene Common Hereditary Cancers Panel, and patients with likely or confirmed pathogenic variants received genetic counseling as part of the study. Any identified pathologic variants in cancer susceptibility genes other than Lynch syndrome-related genes were classified as high, moderate, or low penetrance, or autosomal recessive, based on National Comprehensive Cancer Network (NCCN) designations.

The median age among the 961 patients examined on the study was 62 (range, 26-96), and a majority were treated at non-NCI Comprehensive Cancer Center–affiliated facilities (56%). Nearly all patients were White (94%). The median BMI was 36.04 (range, 17.76-67.73), and most were classified as obese (71%). Additionally, a majority of patients had stage I disease (82%) and endometroid histology (85%). Furthermore, most patients underwent universal immunohistochemistry testing.

Further results showed that, in addition to the 97 patients with identified pathologic variants, 3 patients carried 2 pathologic variants and 321 others were found to have germline variants of uncertain significance. The most common gene defects observed were in PMS2 (11 patients) and MSH6 (10 patients), followed by MSH2 (6 patients) and MLH1 (2 patients). Of the 29 Lynch syndrome variants, 24 were classified as pathologic variants and 5 as likely pathologic variants.

Most patients with identified Lynch syndrome had early-stage endometrioid tumors, and cases were more prevalent in younger patients with lower BMIs.

On this study, multigene panel testing identified 10 patients with Lynch syndrome (34.5%) that would not otherwise have been recognized, 6 of whom had not undergone MMR immunohistochemistry testing, and 4 of whom had universal tumor screening that would not have triggered germline testing.

Immunohistochemistry testing was performed for patients with Lynch syndrome who did not have prior testing. The findings were largely consistent with the expected patterns of MMR expression for those with likely pathologic variants or pathologic variants involving MSH2, MLH1, and MSH6. Moreover, immunohistochemistry findings for those with germline PMS2 pathologic variants were variable, and highlight the challenges associated with using immunohistochemistry to identify PMS2-associated Lynch syndrome.

“Multigene panel testing identified 24 high- or moderate-penetrance variants in Lynch syndrome and/or hereditary breast and ovarian cancer genes in women who would not have been recommended for multigene panel testing on the basis of NCCN family history and MMR immunohistochemistry criteria,” study authors wrote. “This represents an approximately 2.5% increase in yield with up-front germline testing.”


  1. Levine MD, Pearlman R, Hampel H, et al. Up-front multigene panel testing for cancer susceptibility in patients with newly diagnosed endometrial cancer: a multicenter prospective study. JCO Precision Oncology. 2021;5:1588-1602. doi:10.1200/PO.21.00249