title: Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort.
abstract: Hereditary endometrial carcinoma is associated with germline mutations in Lynch syndrome genes. The role of other cancer predisposition genes is unclear. We aimed to determine the prevalence of cancer predisposition gene mutations in an unselected endometrial carcinoma patient cohort. Mutations in 25 genes were identified using a next-generation sequencing-based panel applied in 381 endometrial carcinoma patients who had undergone tumor testing to screen for Lynch syndrome. Thirty-five patients (9.2%) had a deleterious mutation: 22 (5.8%) in Lynch syndrome genes (three MLH1, five MSH2, two EPCAM-MSH2, six MSH6, and six PMS2) and 13 (3.4%) in 10 non-Lynch syndrome genes (four CHEK2, one each in APC, ATM, BARD1, BRCA1, BRCA2, BRIP1, NBN, PTEN, and RAD51C). Of 21 patients with deleterious mutations in Lynch syndrome genes with tumor testing, 2 (9.5%) had tumor testing results suggestive of sporadic cancer. Of 12 patients with deleterious mutations in MSH6 and PMS2, 10 were diagnosed at age >50 and 8 did not have a family history of Lynch syndrome-associated cancers. Patients with deleterious mutations in non-Lynch syndrome genes were more likely to have serous tumor histology (23.1 vs 6.4%, P=0.02). The three patients with non-Lynch syndrome deleterious mutations and serous histology had mutations in BRCA2, BRIP1, and RAD51C. Current clinical criteria fail to identify a portion of actionable mutations in Lynch syndrome and other hereditary cancer syndromes. Performance characteristics of tumor testing are sufficiently robust to implement universal tumor testing to identify patients with Lynch syndrome. Germline multi-gene panel testing is feasible and informative, leading to the identification of additional actionable mutations.
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Kari L
authors.initials: KL
authors.lastname: Ring
authors.affiliation: Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Amanda S
authors.initials: AS
authors.lastname: Bruegl
authors.affiliation: Myriad Genetics, Inc., Salt Lake City, UT, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Allen
authors.affiliation: Myriad Genetics, Inc., Salt Lake City, UT, USA.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Elkin
authors.affiliation: Myriad Genetics, Inc., Salt Lake City, UT, USA.
authors.forename: Nanda
authors.initials: N
authors.lastname: Singh
authors.affiliation: Myriad Genetics, Inc., Salt Lake City, UT, USA.
authors.forename: Anne-Renee
authors.initials: AR
authors.lastname: Hartman
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Molly S
authors.initials: MS
authors.lastname: Daniels
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
mesh_terms: D000368:Aged; D004252:DNA Mutational Analysis; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods*; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008875:Middle Aged