title: Apoptotic and growth regulatory genes as mutational targets in mismatch repair deficient endometrioid adenocarcinomas of young patients.
abstract: Among multiple genetic pathways involved in endometrial cancer (EC), the mutator pathway is characterized by defective mismatch repair (MMR) causing microsatellite instability (MSI+). Inactivation of MMR genes allows elevation of mutation rates in key target genes involved in important cellular pathways, providing a selective growth advantage. Our aim was to investigate apoptotic and growth regulatory target genes in young endometrioid adenocarcinoma patients and their association with stepwise neoplastic progression through distinct stages of hyperplasia and cancer. Screening of 184 ECs revealed 38 microsatellite high (MSI-H), 10 microsatellite low (MSI-L) and 136 microsatellite stable (MSS) tumors. We observed somatic frameshift mutations in the coding region repeats of the target genes in 12/38 MSI-H tumors (T) and in 3/8 of available associated hyperplasias (HY). Mutations were detected in FAS (T=1, HY=1), BAX (T=6, HY=1), CASP5 (T=2) and IGFIIR (T=3, HY=1) genes. None of the MSI-L or MSS tumors showed alterations in these coding repeats. Increased mutation frequency in apoptotic and growth regulatory genes demonstrated a significant relationship with advancing tumor grade (p=0.02) by Fisher's exact test. Furthermore, a significant trend was found by Bartholomew's test (P<0.05) for the apoptotic pathway and close to significant (p approximately 0.06) for the overall mutation status for both pathways combined. Our results suggest that genes implicated in apoptosis may serve as targets in the progression of MSI+ EC in young patients.
authors.affiliation: Samuel Lunenfeld Research Institute, Toronto, Canada.
authors.forename: Vessela
authors.initials: V
authors.lastname: Vassileva
authors.forename: Anna
authors.initials: A
authors.lastname: Millar
authors.forename: Laurent
authors.initials: L
authors.lastname: Briollais
authors.forename: William
authors.initials: W
authors.lastname: Chapman
authors.forename: Bharati
authors.initials: B
authors.lastname: Bapat
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D000328:Adult; D017209:Apoptosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics; D016889:Endometrial Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D005260:Female; D018390:Gene Targeting; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D017978:Receptors, Growth Factor / Q000235:genetics*
chemical_list: D017978:Receptors, Growth Factor