High-risk follicular lymphomas harbour more somatic mutations including those in the AID-motif

Taku Tsukamoto,Shinsuke Mizutani,Ryuichi Sato,Akio Yanagisawa,Nobuhiko Uoshima,Satoru Yasukawa,Tsutomu Kobayashi,Shigeo Horiike,Junya Kuroda,Yoshiaki Chinen,Miki Kiyota,Yuji Shimura,Eri Kawata,Hiroko Adachi,Kei Tashiro,Masafumi Taniwaki,Masakazu Nakano

doi:10.1038/s41598-017-14150-0

Abstract

We investigated clinical and genetic characteristics of high-risk follicular lymphoma (FL), that lacked evidence of large cell transformation at diagnosis, in the rituximab era. First, we retrospectively analysed the clinical features of 100 patients with non-transformed FL that were consecutively treated with rituximab-containing therapies in a discovery cohort. The presence of either peripheral blood and/or bone involvement was associated with short progression-free survival. This was confirmed in a validation cohort of 66 FL patients. Then, whole exome sequencing was performed on randomly selected 5 high- and 9 standard-risk FL tumours. The most common mutational signature was a CG > TG substitution-enriched signature associated with spontaneous deamination of 5-methylcytosine at CpG, but mutations in WA and WRC(Y) motifs (so-called activation-induced cytidine deaminase (AID) motifs) were also enriched throughout the whole exome. We found clustered mutations in target sequences of AID in the IG and BCL2 loci. Importantly, high-risk FLs harboured more somatic mutations (mean 190 vs. 138, P = 0.04), including mutations in WA (33 vs. 22, P = 0.038), WRC (34 vs. 22, P = 0.016) and WRCY motifs (17 vs. 11, P = 0.004). These results suggest that genomic instability that allows for emergence of distinct mutations through AID activity underlies development of the high-risk FL phenotype.

Highlights

We investigated clinical and genetic characteristics of high-risk follicular lymphoma (FL), that lacked evidence of large cell transformation at diagnosis, in the rituximab era
Univariate analysis revealed that the presence of at least one of three extranodal involvements, i.e., peripheral blood (PB) (N = 7), bone (N = 6), or lung (N = 1), significantly associated with poor progression-free survival (PFS) (Supplementary Table S3)
We evaluated the significance of PB and bone involvements as the variables adjusted for high risk of Follicular Lymphoma International Prognostic Index (FLIPI), while lung was excluded from the analysis because only 1 patient had lung involvement

Summary

Introduction

We investigated clinical and genetic characteristics of high-risk follicular lymphoma (FL), that lacked evidence of large cell transformation at diagnosis, in the rituximab era. A series of novel agents has improved the outcomes of relapsed patients, FL with a short PFS after the initial therapy requires more intensive and more types of salvage therapies, including autologous and allogeneic hematopoietic stem cell transplantation. To further improve the treatment outcome of FL patients, it is essential to identify the clinical features and the molecular basis for development of the high-risk disease phenotype in FL, excluding transformed FL. To this end, we first tried to identify the high-risk disease phenotype in FL, excluding FL cases showing evidence of transformation at diagnosis. We investigated the genetic features of the high-risk FLs defined by our criteria using whole exome sequencing (WES)

Methods

Results

Conclusion