PURPOSE: Mutations in DNA mismatch repair (MMR) 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 sought the prevalence of pathogenic germline variants in unselected patients with endometrial cancer attending for surgical consultation. PATIENTS AND METHODS: Patients were prospectively consented (4/2016-5/2017) to an IRB-approved protocol of tumor-normal sequencing via a custom next-generation sequencing panel (MSK-IMPACT) with return of germline results for >75 cancer predisposition genes. Tumors were assessed for microsatellite instability (MSI). Per institutional standards, all tumors underwent Lynch syndrome screening via IHC for MMR proteins. RESULTS: Of 156 patients who consented to germline genetic testing, 118 (76%) had stage I disease. Tumors were endometrioid in 104 (67%), of which 60 (58%) were grade 1. Twenty-four pathogenic germline variants were identified in 22 patients (14%)-7 (4.5%) with highly penetrant cancer syndromes and 15 (9.6%) with variants in moderate-, low-penetrance, or recessive genes. Of these, 5 (21%) were in Lynch syndrome genes (2 MSH6, 2 PMS2, and 1 MLH1). All 5 tumors had concordant IHC staining; 2 (40%) were definitively MSI-high by next-generation sequencing. One patient had a known BRCA1 mutation; 1 had SMARCA4 deletion. The remaining 17 variants (71%) were incremental findings in moderate- and low-penetrance variants or genes associated with recessive disease. CONCLUSION: In unselected patients with predominantly low-risk, early-stage endometrial cancer, germline multi-gene panel testing identifies 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.
PURPOSE: Mutations in DNA mismatch repair (MMR) 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 sought the prevalence of pathogenic germline variants in unselected patients with endometrial cancer attending for surgical consultation. PATIENTS AND METHODS: Patients were prospectively consented (4/2016-5/2017) to an IRB-approved protocol of tumor-normal sequencing via a custom next-generation sequencing panel (MSK-IMPACT) with return of germline results for >75 cancer predisposition genes. Tumors were assessed for microsatellite instability (MSI). Per institutional standards, all tumors underwent Lynch syndrome screening via IHC for MMR proteins. RESULTS: Of 156 patients who consented to germline genetic testing, 118 (76%) had stage I disease. Tumors were endometrioid in 104 (67%), of which 60 (58%) were grade 1. Twenty-four pathogenic germline variants were identified in 22 patients (14%)-7 (4.5%) with highly penetrant cancer syndromes and 15 (9.6%) with variants in moderate-, low-penetrance, or recessive genes. Of these, 5 (21%) were in Lynch syndrome genes (2 MSH6, 2 PMS2, and 1 MLH1). All 5 tumors had concordant IHC staining; 2 (40%) were definitively MSI-high by next-generation sequencing. One patient had a known BRCA1 mutation; 1 had SMARCA4 deletion. The remaining 17 variants (71%) were incremental findings in moderate- and low-penetrance variants or genes associated with recessive disease. CONCLUSION: In unselected patients with predominantly low-risk, early-stage endometrial cancer, germline multi-gene panel testing identifies 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.
Authors: Christopher P Childers; Kimberly K Childers; Melinda Maggard-Gibbons; James Macinko Journal: J Clin Oncol Date: 2017-08-18 Impact factor: 44.544
Authors: Samir Gupta; Dawn Provenzale; Scott E Regenbogen; Heather Hampel; Thomas P Slavin; Michael J Hall; Xavier Llor; Daniel C Chung; Dennis J Ahnen; Travis Bray; Gregory Cooper; Dayna S Early; James M Ford; Francis M Giardiello; William Grady; Amy L Halverson; Stanley R Hamilton; Jason B Klapman; David W Larson; Audrey J Lazenby; Patrick M Lynch; Arnold J Markowitz; Robert J Mayer; Reid M Ness; Niloy Jewel Samadder; Moshe Shike; Shajanpeter Sugandha; Jennifer M Weiss; Mary A Dwyer; Ndiya Ogba Journal: J Natl Compr Canc Netw Date: 2017-12 Impact factor: 11.908
Authors: Elena M Stoffel; Pamela B Mangu; Stephen B Gruber; Stanley R Hamilton; Matthew F Kalady; Michelle Wan Yee Lau; Karen H Lu; Nancy Roach; Paul J Limburg Journal: J Clin Oncol Date: 2014-12-01 Impact factor: 44.544
Authors: Jeffrey N Weitzel; Kathleen R Blazer; Deborah J MacDonald; Julie O Culver; Kenneth Offit Journal: CA Cancer J Clin Date: 2011-08-19 Impact factor: 508.702
Authors: Daniel D Buchanan; Yen Y Tan; Michael D Walsh; Mark Clendenning; Alexander M Metcalf; Kaltin Ferguson; Sven T Arnold; Bryony A Thompson; Felicity A Lose; Michael T Parsons; Rhiannon J Walters; Sally-Ann Pearson; Margaret Cummings; Martin K Oehler; Penelope B Blomfield; Michael A Quinn; Judy A Kirk; Colin J Stewart; Andreas Obermair; Joanne P Young; Penelope M Webb; Amanda B Spurdle Journal: J Clin Oncol Date: 2013-12-09 Impact factor: 44.544
Authors: Amanda S Bruegl; Bojana Djordjevic; Brittany Batte; Molly Daniels; Bryan Fellman; Diana Urbauer; Rajyalakshmi Luthra; Charlotte Sun; Karen H Lu; Russell R Broaddus Journal: Cancer Prev Res (Phila) Date: 2014-04-25
Authors: Yanhong Liu; Jun Xia; James McKay; Spiridon Tsavachidis; Xiangjun Xiao; Margaret R Spitz; Chao Cheng; Jinyoung Byun; Wei Hong; Yafang Li; Dakai Zhu; Zhuoyi Song; Susan M Rosenberg; Michael E Scheurer; Farrah Kheradmand; Claudio W Pikielny; Christine M Lusk; Ann G Schwartz; Ignacio I Wistuba; Michael H Cho; Edwin K Silverman; Joan Bailey-Wilson; Susan M Pinney; Marshall Anderson; Elena Kupert; Colette Gaba; Diptasri Mandal; Ming You; Mariza de Andrade; Ping Yang; Triantafillos Liloglou; Michael P A Davies; Jolanta Lissowska; Beata Swiatkowska; David Zaridze; Anush Mukeria; Vladimir Janout; Ivana Holcatova; Dana Mates; Jelena Stojsic; Ghislaine Scelo; Paul Brennan; Geoffrey Liu; John K Field; Rayjean J Hung; David C Christiani; Christopher I Amos Journal: NPJ Precis Oncol Date: 2021-02-16