title: Sequencing of candidate chromosome instability genes in endometrial cancers reveals somatic mutations in ESCO1, CHTF18, and MRE11A.
abstract: Most endometrial cancers can be classified histologically as endometrioid, serous, or clear cell. Non-endometrioid endometrial cancers (NEECs; serous and clear cell) are the most clinically aggressive of the three major histotypes and are characterized by aneuploidy, a feature of chromosome instability. The genetic alterations that underlie chromosome instability in endometrial cancer are poorly understood. In the present study, we used Sanger sequencing to search for nucleotide variants in the coding exons and splice junctions of 21 candidate chromosome instability genes, including 19 genes implicated in sister chromatid cohesion, from 24 primary, microsatellite-stable NEECs. Somatic mutations were verified by sequencing matched normal DNAs. We subsequently resequenced mutated genes from 41 additional NEECs as well as 42 endometrioid ECs (EECs). We uncovered nonsynonymous somatic mutations in ESCO1, CHTF18, and MRE11A in, respectively, 3.7% (4 of 107), 1.9% (2 of 107), and 1.9% (2 of 107) of endometrial tumors. Overall, 7.7% (5 of 65) of NEECs and 2.4% (1 of 42) of EECs had somatically mutated one or more of the three genes. A subset of mutations are predicted to impact protein function. The co-occurrence of somatic mutations in ESCO1 and CHTF18 was statistically significant (P = 0.0011, two-tailed Fisher's exact test). This is the first report of somatic mutations within ESCO1 and CHTF18 in endometrial tumors and of MRE11A mutations in microsatellite-stable endometrial tumors. Our findings warrant future studies to determine whether these mutations are driver events that contribute to the pathogenesis of endometrial cancer.
authors.affiliation: Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Price
authors.forename: Lana M
authors.initials: LM
authors.lastname: Pollock
authors.forename: Meghan L
authors.initials: ML
authors.lastname: Rudd
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Fogoros
authors.forename: Hassan
authors.initials: H
authors.lastname: Mohamed
authors.forename: Christin L
authors.initials: CL
authors.lastname: Hanigan
authors.forename: Matthieu
authors.initials: M
authors.lastname: Le Gallo
authors.forename: Suiyuan
authors.initials: S
authors.lastname: Zhang
authors.forename: Pedro
authors.initials: P
authors.lastname: Cruz
authors.forename: Praveen F
authors.initials: PF
authors.lastname: Cherukuri
authors.forename: Nancy F
authors.initials: NF
authors.lastname: Hansen
authors.forename: Kirk J
authors.initials: KJ
authors.lastname: McManus
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Sgroi
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Merino
authors.forename: Philip
authors.initials: P
authors.lastname: Hieter
authors.forename: Daphne W
authors.initials: DW
authors.lastname: Bell
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000123:Acetyltransferases / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D043171:Chromosomal Instability / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D000076228:MRE11 Homologue Protein; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*
chemical_list: C477290:CHTF18 protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D009687:Nuclear Proteins; D000123:Acetyltransferases; C479413:ESCO1 protein, human; D000076228:MRE11 Homologue Protein; D000074183:ATPases Associated with Diverse Cellular Activities