TNFRSF14 Is Mutated in a Subset of Follicular Lymphoma and Correlated with Inferior Prognosis.

Abstract 1919

Poster Board I-942

The secondary genetic events associated with follicular lymphoma (FL) development are obscure as to the identification of critical driver genes. Clinical correlative studies have implicated chromosome band 1p36 deletions and linked them to a propensity for transformation and poor outcome. This region also showed a high frequency of copy-neutral loss of heterozygosity as demonstrated by SNP array analysis. In this study, we applied BAC array comparative genomic hybridization (array CGH) to 141 FL specimens and detected deletion of 1p36 in 20% of the cases with a minimum region of deletion (MRD) of ∼100 kb within the band 1p36.32. The majority of cases displayed heterozygous deletion, while two cases showed homozygous deletion. The MRD encompassed five genes: HES5, LOC115110, TNFRSF14, C1orf93 and MMEL1. Methylation status of CpG in the promoter region of genes in the MRD revealed no difference among samples differing in 1p36 status. However, exonic sequencing of the MRD genes identified somatic base mutations only in the TNFRSF14 gene in four of five selected cases with 1p36 deletion. Lower expression of TNFRSF14 was also found in 1p36 deleted cases. Validation of TNFRSF14 mutations was undertaken in an expanded cohort of 251 FL patients which showed that 45 cases (18%) displayed a total of 50 mutations and that inferior prognosis was significantly associated with TNFRSF14 mutation status. We propose that TNFRSF14, a gene previously implicated in growth inhibition and Fas-induced apoptosis, is a candidate tumor suppressor gene in FL.