Heather Hampel

Instability in the Penta-C and Penta-D Loci in Microsatellite-Unstable Endometrial Cancer

Endometrial cancer (EC) is the most common gynecologic cancer. Early detection is one of the most important predictors of survival. The cancer is curable if detected early but the five-year survival rate in advanced cases can be as low as 22%. Microsatellite instability (MSI) testing is used to screen populations for Lynch Syndrome (LS), the most common cause of inherited EC, and to classify EC into distinct groups with unique histological, prognostic, and molecular features. Accurate sample identification is crucial for successful MSI testing because instability is assessed by comparing amplification patterns in markers in the normal and tumor samples that must be taken from the same individual. Penta-C and Penta-D pentanucleotide markers are used widely for sample identification in not only MSI testing but also parentage verification, forensic science, and population genetics studies. The objective of this study was to test 324 pairs of tumor and matched normal DNAs from EC patients for instability in these markers using the Promega MSI Analysis SystemTM considered the “gold standard” in MSI testing. Both markers were unstable, and therefore not reliable for MSI testing, in 8.2% of the EC patients with MSI. Instability in both mono- and pentanucleotide markers suggest that the tumors with MSI likely suffer from a “generalized” form of instability also affecting other short tandem repeats. Results from many studies using these markers for various purposes may not be accurate if samples with MSI are involved.

Up-Front Multigene Panel Testing for Cancer Susceptibility in Patients With Newly Diagnosed Endometrial Cancer: A Multicenter Prospective Study

PURPOSE Clinical utility of up-front multigene panel testing (MGPT) is directly related to the frequency of pathogenic variants (PVs) in the population screened and how genetic findings can be used to guide treatment decision making and cancer prevention efforts. The benefit of MGPT for many common malignancies remains to be determined. In this study, we evaluated up-front MGPT in unselected patients with endometrial cancer (EC) to determine the frequency of PVs in cancer susceptibility genes. METHODS Patients with EC were prospectively enrolled at nine Ohio institutions from October 1, 2017, to December 31, 2020. Nine hundred and sixty-one patients with newly diagnosed EC underwent clinical germline MGPT for 47 cancer susceptibility genes. In addition to estimating the prevalence of germline PVs, the number of individuals identified with Lynch syndrome (LS) was compared between MGPT and tumor-based screening. RESULTS Likely pathogenic variants or PVs were identified in 97 of 961 women (10.1%). LS was diagnosed in 29 of 961 patients (3%; 95% CI, 2.1 to 4.3), with PVs in PMS2 most frequent. MGPT revealed nine patients with LS in addition to the 20 identified through routine tumor-based screening. BRCA1 and BRCA2 PVs were found in 1% (10 of 961; 95% CI, 0.6 to 1.9) of patients and that group was significantly enriched for type II ECs. CONCLUSION This prospective, multicenter study revealed potentially actionable germline variants in 10% of unselected women with newly diagnosed EC, supporting the use of up-front MGPT for all EC patients. The discovery that BRCA1 or BRCA2 heterozygotes frequently had type II cancers points to therapeutic opportunities for women with aggressive histologic EC subtypes.

Point/Counterpoint: Is It Time for Universal Germline Genetic Testing for All GI Cancers?

Use of germline genetic testing among patients with cancer is increasing because of (1) the availability of multigene panel tests that include multiple cancer susceptibility genes in a single test, (2) decreased costs of these tests and improvements in insurance coverage, and (3) US Food and Drug Administration–approval of genotype-directed therapies such as poly(ADP-ribose) polymerase inhibitors for individuals with certain cancers and pathogenic germline variants in BRCA1 and BRCA2 (with possible benefits with other genes in the homologous repair deficiency pathway). In addition, National Comprehensive Cancer Network guidelines have already endorsed germline genetic testing for all patients with certain cancer types (epithelial ovarian cancer, exocrine pancreatic cancer, and high-grade/metastatic prostate cancer), regardless of age or personal/family history of cancer. Herein, we debate the pros and cons of offering germline multigene panel testing to all patients diagnosed with any GI cancer. The authors agree that it may just be a matter of time before germline multigene panel testing is offered to all patients with cancer; however, this article will highlight some of the benefits, risks, and limitations of this approach so that research can help fill some of the gaps to ensure that genetic medicine continues to be implemented in ways that improve real-world patient care and outcomes.