CREBBP and STAT6 co-mutation and 16p13 and 1p36 loss define the t(14;18)-negative diffuse variant of follicular lymphoma

Abstract

The diffuse variant of follicular lymphoma (dFL) is a rare variant of FL lacking t(14;18) that was first described in 2009. In this study, we use a comprehensive approach to define unifying pathologic and genetic features through goldstandard pathologic review, FISH, SNP-microarray, and next-generation sequencing of 16 cases of dFL. We found unique morphologic features, including interstitial sclerosis, microfollicle formation, and rounded nuclear cytology, confirmed absence of t(14;18) and recurrent deletion of 1p36, and showed a novel association with deletion/CN-LOH of 16p13 (inclusive of CREBBP, CIITA, and SOCS1). Mutational profiling demonstrated near-uniform mutations in CREBBP and STAT6, with clonal dominance of CREBBP, among other mutations typical of germinal-center B-cell lymphomas. Frequent CREBBP and CIITA codeletion/mutation suggested a mechanism for immune evasion, while subclonal STAT6 activating mutations with concurrent SOCS1 loss suggested a mechanism of BCL-xL/BCL2L1 upregulation in the absence of BCL2 rearrangements. A review of the literature showed significant enrichment for 16p13 and 1p36 loss/ CN-LOH, STAT6 mutation, and CREBBP and STAT6 comutation in dFL, as compared with conventional FL. With this comprehensive approach, our study demonstrates confirmatory and novel genetic associations that can aid in the diagnosis and subclassification of this rare type of lymphoma.

Plasma Concentrations and Cancer-Associated Mutations in Cell-Free Circulating DNA of Treatment-Naive Follicular Lymphoma for Improved Non-Invasive Diagnosis and Prognosis

“…p.D419G, p.D419N, and p.D523V) were present in both cfDNA and tumor tissue DNA in FL patients. Moreover, all patients with STAT6 mutations were also carrying CREBBP mutations consistent with the observations in a previously reported study ( 41 ). In total 6 EZH2 variants were identified in four FL patients, of which two were present in both cfDNA and tumor tissue DNA.…”

Follicle Center Lymphoma (FCL) of the Lower Female Genital Tract (LFGT)

“…BCL2 -R negative, CD23-positive FCL typically presents with localized inguinal location, low-stage disease, predominant diffuse growth pattern, and is characterized by CD23 expression 29,30. Like our cases, BCL2-R negative, CD23-positive FCL has frequent alterations of the TNFRSF14 gene, but in contrast to our data, it is characterized by CREBBP and STAT6 co-mutation, alterations not encountered in our study 30,31. PTFL is another entity that, in addition to lack of BCL2-R , is of germinal center origin, has a predominance of large cells, and tendency to remain localized and not recur or progress 32.…”

“…29,30 Like our cases, BCL2-R negative, CD23-positive FCL has frequent alterations of the TNFRSF14 gene, but in contrast to our data, it is characterized by CREBBP and STAT6 co-mutation, alterations not encountered in our study. 30,31 PTFL is another entity that, in addition to lack of BCL2-R, is of germinal center origin, has a predominance of large cells, and tendency to remain localized and not recur or progress. 32 PTFL shares with FCL of the LFGT frequent mutations in TNFRSF14 without mutations in BCL2 and epigenetic modifiers, including CREBBP and KMT2D.…”

PARP14 is a novel target in STAT6 mutant follicular lymphoma

“…Specifically, up to a quarter of PMBL harbor gain-of-function mutations in the IL-4R alpha chain, which, of note, frequently co-occur with additional mutations in the JAK/STAT pathway, including STAT6 [ 40 ], further supporting the concept that STAT6 mutations function primarily as amplifiers of this signaling cascade. While we did not find IL-4R mutations in our previously reported cohort of patients with untreated FL ( N = 112, GLSG2000 cohort) [ 21 ], this may have to be re-addressed in larger cohorts including patients with variant histologies that indicate less dependence on the TME, such as diffuse FL or histologically transformed FL [ 18 – 20 , 41 , 42 ].…”