OP-JNCI190245 330..334

Multigene panel testing (MGPT) has become a critical component of cancer risk assessment in clinical practice. As technology and access improve and costs decrease, more individuals than ever are undergoing MGPT for genetic evaluation. One gene that deserves special consideration when included on MGPT is CDH1, which codes for the cell-cell adhesion protein E-cadherin. Pathogenic and likely pathogenic germline variants in CDH1 have been associated with hereditary diffuse gastric cancer syndrome, and in highly penetrant families, testing for these variants is critical for proper risk management. However, recent data demonstrated that gastric cancer penetrance in unselected CDH1 carriers may be lower than expected. Further complicating matters are the lack of effective screening strategies for gastric cancer and recommendation for risk-reducing total gastrectomy in CDH1 carriers. Therefore, the discovery of an unexpected pathogenic or likely pathogenic CDH1 variant on multigene panel testing, when testing for CDH1 would not normally be considered based on personal or family history alone, creates dilemmas for both patients and providers. In this commentary, we highlight the potential for unexpected CDH1 variants on MGPT, outline the uncertainties associated with these variants, and emphasize the importance of pretest counseling regarding the potential for an unexpected CDH1 variant. Although CDH1 testing is often important for clinical decision-making, individuals and providers need to be aware of the potential for an unexpected CDH1 variant when CDH1 is included on MGPT for cancer risk assessment. With the advent of next-generation sequencing technologies, multigene panel testing (MGPT) is used increasingly for cancer risk assessment. MGPT allows for timely sequencing of multiple cancer susceptibility genes, is cost effective (1,2), and leads to incremental genetic findings (3–5). However, challenges remain to using MGPT for cancer risk assessment, including the incidental discovery of pathogenic or likely pathogenic germline variants in unexpected cancer risk genes, especially when testing for these genes would not otherwise be considered based on personal or family history. Given the increasing size of multigene panels, finding variants in these unexpected genes is inevitable and will continue to increase in frequency as MGPT is broadly used clinically and through direct-to-consumer marketing and testing. Managing cancer risk in individuals with unexpected genetic variants can prove extremely challenging for both clinicians and patients, especially when there is no personal or family history consistent with the cancer risk gene’s expected phenotype. These difficulties are compounded when patients do not receive appropriate genetic counseling about the potential for unexpected genetic findings before testing is performed. In our experience, this situation can lead to surprise and dissatisfaction on the patient’s part about the risks, uncertainties, recommended riskreduction strategies, and familial implications of the newly identified unexpected gene variant. Illustrating these challenges is the CDH1 gene, which codes for the protein E-cadherin. Pathogenic and likely pathogenic germline variants in CDH1 have been classically associated with hereditary diffuse gastric cancer (HDGC) syndrome, which carries a gastric cancer risk of up to approximately 70% in men and approximately 56% in women by age 80 years (6). Guidelines published by the International Gastric Cancer Linkage Consortium provide criteria to identify individuals who are candidates for CDH1 testing (7). However, given the association of CDH1 with lobular breast cancer (8) (but not invasive ductal cancer) as well as potentially with colon cancer (9), CDH1 is now included on many commonly ordered, cancer-focused multigene panels. Of note though, lobular breast cancer accounts for only 10% of breast cancer cases, and CDH1 mutations are uncommon C O M M EN T A R Y Received: September 18, 2019; Revised: October 18, 2019; Accepted: December 10, 2019 © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com 330 JNCI J Natl Cancer Inst (2020) 112(4): djz229 doi: 10.1093/jnci/djz229 First published online December 16, 2019