A sequential screening strategy for inherited susceptibility genes in endometrial cancer

Abstract Objective Current screening strategies for hereditary endometrial cancer (EC) have limitations. This single-center study aimed to evaluate a novel sequential screening strategy for identifying hereditary EC in an unselected cohort. Methods All patients newly diagnosed with EC between December 1, 2017 and October 1, 2019, at the study center were included. All participants underwent comprehensive evaluation, cincluding clinical criteria (Amsterdam II and revised Bethesda), microsatellite instability (MSI) testing, immunohistochemical (IHC) for mismatch repair (MMR) proteins, and germline sequencing of hereditary cancer genes. We assessed a new screening strategy, beginning with clinical criteria, followed by reflex IHC plus MSI testing for patients not meeting the clinical criteria. The diagnostic accuracy of this strategy was compared against existing methods, using germline sequencing results as the reference standard. Results Among 301 unselected newly diagnosed EC patients enrolled, 31 (10.30%) harbored a deleterious germline mutation, including 22 (7.31%) with Lynch syndrome (LS). The sequential screening strategy achieved sensitivity, specificity, positive and negative predictive values of 95.45%, 99.64%, 0.954 and 0.996 for LS-associated EC (LS-EC), respectively, and 57.89%, 100.00%, 1.000 and 0.930 for hereditary EC, respectively. In screening LS-EC or hereditary EC, the sequential screening strategy had sensitivity similar to those of IHC and/or MSI and higher than those of clinical criteria, but had significantly higher specificity than any of current methods ( p values < 0.05). Conclusion A new sequential screening strategy, initiated with clinical criteria followed by IHC or MSI testing, achieved favorable accuracy for hereditary EC, especially LS-EC in this single-center cohort.