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.
Highlights
Follicular lymphoma (FL) is characterized at the karyotype level by the t(14;18)(q32;q21) translocation, which leads to overexpression of the antiapoptotic gene BCL2 due to relocation in proximity to the IGH enhancer [1,2,3,4,5,6]
Based on microarray-based copy number and copy-neutral loss of heterozygosity (cnLOH) data analyses, we have identified a minimum region of deletion (MRD) at chromosome band 1p36 in FL that measures approximately 97 kb
The mutations detected in the 251 case study were not definitively confirmed to be somatic by parallel constitutional DNA sequencing, the lack of similar mutations in large public genomic databases and the significant correlation of these observed mutations with inferior clinical outcomes provide strong evidence that these mutations are somatic in nature and that TNFRSF14 is the target gene in the 1p36 MRD
Summary
Follicular lymphoma (FL) is characterized at the karyotype level by the t(14;18)(q32;q21) translocation, which leads to overexpression of the antiapoptotic gene BCL2 due to relocation in proximity to the IGH enhancer [1,2,3,4,5,6]. Forts have been hampered by relatively small sample cohorts, the inclusion of heterogeneous subtypes of lymphoma, and the low resolution of analytic tools available including standard cytogenetic analysis and chromosome-based comparative genomic hybridization (CGH). Most of these studies have reported 1p36 aberrations in the form of intrachromosomal deletions and unbalanced translocations [7,8,9,10]. O'Shea and colleagues [11], using a lowerresolution 10k SNP assay, found 8% of cases to show cnLOH but found no evidence of deletions, possibly because of the low-resolution capability of the array; correlation between 1p36 cnLOH and overall survival (OS) was significant These studies have highlighted the importance of alternate mechanisms of gene inactivation that may be operative in FL. The affected region of alteration identified in these studies was still relatively large at 8.5 Mb [5], a specific candidate gene was not identified
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