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 copyneutral 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.

Characterization of a variant of t(14;18) negative nodal diffuse follicular lymphoma with CD23 expression, 1p36/TNFRSF14 abnormalities, and STAT6 mutations

“…Importantly, we show that the 1p36 deletion in these cases included TNFRSF14, a recurrently involved region in conventional follicular lymphoma. [20][21][22] Moreover, in the six cases lacking detectable 1p36 deletion in our series, another three demonstrated mutations in TNFRSF14, confirming that 1p36/TNFRSF14 abnormalities, whether by deletion or mutation, are strongly correlated with this variant. These data suggest that a combined approach assessing for chromosomal loss at 1p36 and TNFRSF14 mutation analysis may be necessary to identify these cases.…”

High rate of TNFRSF14 gene alterations related to 1p36 region in de novo follicular lymphoma and impact on prognosis

“…However, TNFRSF14 appears to be a serious candidate gene that might contribute to FL development, given the high frequency of alterations, in particular mutations, in de novo FL. Further studies are necessary to clarify their impact on prognosis, as our results are conflicting with published data, 8 and to better understand consequences of these mutations on protein functions.…”

“…Taken altogether, our study showed a higher frequency of TNFRSF14 mutations in FL, compared with recently published data; 44% versus 18%, respectively. 8 Moreover, we identified 19 exonic mutations not yet described and 10 mutations at exon-intron junction, whereas only one has been detected previously. The majority of these mutations were predicted to be inactivating events, as they led to the loss of the transmembrane domain and thus to a default of receptor anchoring at the cell surface.…”

Pathogenesis of follicular lymphoma

“…Recently, careful analysis of candidate genes within these regions has yielded insight into potential key players. For example, within the 1p36 region that is frequently targeted by heterozygous deletions and copy-neutral loss of heterozygosity, the TNFRSF14 gene was shown to be recurrently mutated (43,44). In two studies, mutations were found in 46 of 251 cases (18.3%) (43) and in 37 of 81 samples (46%) (44).…”

“…For example, within the 1p36 region that is frequently targeted by heterozygous deletions and copy-neutral loss of heterozygosity, the TNFRSF14 gene was shown to be recurrently mutated (43,44). In two studies, mutations were found in 46 of 251 cases (18.3%) (43) and in 37 of 81 samples (46%) (44). In both reports, 57% of TNFRSF14 mutations were predicted to result in a truncated protein devoid of its transmembrane domain, resulting in decreased surface expression.…”