Synapse - Understanding inherited risk in unselected newly diagnosed patients with endometrial cancer

Understanding inherited risk in unselected newly diagnosed patients with endometrial cancer Journal Article

Authors:	Cadoo, K. A.; Mandelker, D. L.; Mukherjee, S.; Stewart, C.; DeLair, D.; Ravichandran, V.; Srinivasan, P.; Hurley, D.; Kemel, Y.; Arnold, A. G.; Sheehan, M.; Pradhan, N.; Joseph, V.; Chi, D. S.; Gardner, G. J.; Jewell, E. L.; Leitao, M. M. Jr; Long Roche, K.; Mueller, J. J.; Sonoda, Y.; Zivanovic, O.; Walsh, M.; Carlo, M. I.; Berger, M. F.; Hyman, D. M.; Zhang, L.; Robson, M. E.; Offit, K.; Aghajanian, C.; Abu-Rustum, N. R.; Stadler, Z.
Article Title:	Understanding inherited risk in unselected newly diagnosed patients with endometrial cancer
Abstract:	PURPOSE Mutations in DNA mismatch repair genes and PTEN, diagnostic of Lynch and Cowden syndromes, respectively, represent the only established inherited predisposition genes in endometrial cancer to date. The prevalence of other cancer predisposition genes remains unclear. We determined the prevalence of pathogenic germline variants in unselected patients with endometrial cancer scheduled for surgical consultation. PATIENTS AND METHODS Patients prospectively consented (April 2016 to May 2017) to an institutional review board–approved protocol of tumor-normal sequencing via a custom next-generation sequencing panel—the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets—that yielded germline results for more than 75 cancer predisposition genes. Tumors were assessed for microsatellite instability. Per institutional standards, all tumors underwent Lynch syndrome screening via immunohistochemistry (IHC) for mismatch repair proteins. RESULTS Of 156 patients who consented to germline genetic testing, 118 (76%) had stage I disease. In 104 patients (67%), tumors were endometrioid, and 60 (58%) of those tumors were grade 1. Twenty-four pathogenic germline variants were identified in 22 patients (14%): seven (4.5%) had highly penetrant cancer syndromes and 15 (9.6%) had variants in low-penetrance, moderate-penetrance, or recessive genes. Of these, five (21%) were in Lynch syndrome genes (two MSH6, two PMS2, and one MLH1). All five tumors had concordant IHC staining; two (40%) were definitively microsatellite instability–high by next-generation sequencing. One patient had a known BRCA1 mutation, and one had an SMARCA4 deletion. The remaining 17 variants (71%) were incremental findings in low- and moderate-penetrance variants or genes associated with recessive disease. CONCLUSION In unselected patients with predominantly low-risk, early-stage endometrial cancer, germline multigene panel testing identified cancer predisposition gene variants in 14%. This finding may have implications for future cancer screening and risk-reduction recommendations. Universal IHC screening for Lynch syndrome successfully identifies the majority (71%) of high-penetrance germline mutations. © 2019 by American Society of Clinical Oncology
Keywords:	immunohistochemistry; adult; middle aged; gene mutation; major clinical study; promoter region; somatic mutation; exon; cancer patient; cancer staging; cancer diagnosis; endometrium cancer; prospective study; salpingooophorectomy; gene; cancer susceptibility; prevalence; genetic variability; obesity; risk factor; histology; tumor suppressor gene; body mass; mismatch repair; microsatellite instability; family history; atm protein; consultation; checkpoint kinase 2; genetic predisposition; genetic screening; protein msh6; apc protein; mismatch repair protein pms2; cowden syndrome; rhabdoid tumor; penetrance; hereditary nonpolyposis colorectal cancer; pten gene; dna glycosylase muty; germline mutation; brg1 protein; recql4 gene; next generation sequencing; ashkenazi jew; human; male; female; priority journal; article; mutl protein homolog 1; recessive gene; double strand break repair protein mre11
Journal Title:	JCO Precision Oncology
Volume:	3
ISSN:	2473-4284
Publisher:	American Society of Clinical Oncology
Date Published:	2019-01-01
Language:	English
DOI:	10.1200/PO.18.00338
PROVIDER:	scopus
PMCID:	PMC7409950
PUBMED:	32775946
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85077486338&doi=10.1200%2fPO.18.00338&partnerID=40&md5=4f3208cdd34ff1cecf5f4a855e017990
Notes:	Article -- Source: Scopus