title: Acquired TNFRSF14 mutations in follicular lymphoma are associated with worse prognosis.
abstract: Clinical correlative studies have linked 1p36 deletions with worse prognosis in follicular lymphoma (FL). In this study, we sought to identify the critical gene(s) in this region that is responsible for conferring inferior prognosis. BAC array technology applied to 141 FL specimens detected a minimum region of deletion (MRD) of ∼97 kb within 1p36.32 in 20% of these cases. Frequent single-nucleotide polymorphism-detected copy-neutral loss of heterozygosity was also found in this region. Analysis of promoter CpGs in the MRD did not reveal differential patterns of DNA methylation in samples that differed in 1p36 status. Exon sequencing of MRD genes identified somatic alterations in the TNFRSF14 gene in 3 of 11 selected cases with matching normal DNA. An expanded cohort consisting of 251 specimens identified 46 cases (18.3%) with nonsynonymous mutations affecting TNFRSF14. Overall survival (OS) and disease-specific survival (DSS) were associated with the presence of TNFRSF14 mutation in patients whose overall treatment included rituximab. We further showed that inferior OS and DSS were most pronounced in patients whose lymphomas contained both TNFRSF14 mutations and 1p36 deletions after adjustment for the International Prognostic Index [hazard ratios of 3.65 (95% confidence interval, 1.35-9.878, P=0.011) and 3.19 (95% confidence interval, 1.06-9.57, P=0.039), respectively]. Our findings identify TNFRSF14 as a candidate gene associated with a subset of FL, based on frequent occurrence of acquired mutations and their correlation with inferior clinical outcomes.
authors.affiliation: Center for Lymphoid Cancer, British Columbia Cancer Agency, Canada. kjcheungjr@bccancer.bc.ca
authors.forename: K-John J
authors.initials: KJ
authors.lastname: Cheung
authors.forename: Nathalie A
authors.initials: NA
authors.lastname: Johnson
authors.forename: Joslynn G
authors.initials: JG
authors.lastname: Affleck
authors.forename: Tesa
authors.initials: T
authors.lastname: Severson
authors.forename: Christian
authors.initials: C
authors.lastname: Steidl
authors.forename: Susana
authors.initials: S
authors.lastname: Ben-Neriah
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Schein
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morin
authors.forename: Richard
authors.initials: R
authors.lastname: Moore
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
authors.forename: Hong
authors.initials: H
authors.lastname: Qian
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Paul
authors.forename: Adele
authors.initials: A
authors.lastname: Telenius
authors.forename: Thomas
authors.initials: T
authors.lastname: Relander
authors.forename: Wan
authors.initials: W
authors.lastname: Lam
authors.forename: Kerry
authors.initials: K
authors.lastname: Savage
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Connors
authors.forename: Carolyn
authors.initials: C
authors.lastname: Brown
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Horsman
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002872:Chromosome Deletion; D022202:Chromosomes, Artificial, Bacterial; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D055028:Comparative Genomic Hybridization / Q000379:methods; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008224:Lymphoma, Follicular / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D011379:Prognosis; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000235:genetics*; D000069283:Rituximab
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D053240:Receptors, Tumor Necrosis Factor, Member 14; C506028:TNFRSF14 protein, human; D000069283:Rituximab