Concomitant 1p36 deletion and TNFRSF14 mutations in primary cutaneous follicle center lymphoma frequently expressing high levels of EZH2 protein

Abstract

Primary cutaneous follicle center lymphoma (PCFCL) is an indolent variant of follicular lymphoma (FL) with limited information available on the genetic background of the disease. The genetic hallmark of nodal FL, the t(14;18) translocation, affecting the BCL2 gene, is rare in PCFCL. Loss of 1p36, the most common secondary chromosomal abnormality in nodal FL, has been recently reported in 16.7% of PCFCL cases. In order to further characterize PCFCL, 21 cases were analyzed using interphase fluorescence in situ hybridization with BCL2 break apart and 1p36/1q25 dual color probes. Sanger sequencing was used to investigate TNFRSF14 and EZH2 mutations and immunohistochemistry to assess BCL2, EZH2 protein expressions.1p36 deletion occurred in 22% (5/21), BCL2 gene break in 10% (2/20) of the PCFCL cases. Mutations of the candidate tumor suppressor gene of the 1p36 region, TNFRSF14 mutations were detected in 4/17 (23.5%) cases with 2 cases presenting with concurrent 1p36 deletion. EZH2 hotspot mutations at Y641, A682, and A692 were not found. High EZH2 protein expression associated with a BCL2 negative phenotype was observed in 43% (9/21) of the cases. BCL2 gene break or 1p36 deletion did not impact the prognosis; however, they showed association with advanced stages at diagnosis (p = 0.016) and a tendency with shorter event free survival (p = 0.052).In conclusion, 1p36 deletion co-occurs with acquired TNFRSF14 mutations, suggesting a role of this tumor suppressor gene in the development of a subgroup of PCFCL. High EZH2 protein expression associated with BCL2 negative phenotype is common and might represent an ideal therapeutic target.

Genomic landscape of cutaneous follicular lymphomas reveals 2 subgroups with clinically predictive molecular features

“…Prior studies assessing BCL2 gene rearrangements and BCL2 expression in cutaneous FL (.300 cases of PCFCL and 50 of SCFL, combined). 3,4,[6][7][8][9]44,[48][49][50][51] have shown that, although BCL2 gene rearrangements are much more commonly associated with SCFL than PCFCL, a subset of cases of PCFCL (up to 30% of cases) also have this genetic alteration. Almost all cases of SCFL and 20% to 86% of those of PCFCL in prior studies have been shown to have BCL2 expression, including nearly all cases of SCFL and PCFCL that have BCL2 gene rearrangements.…”

“…Interestingly, 2 of the 3 PCFCL samples with 1p36 deletions (PS01, PS02, PR08) also had concomitant damaging TNFRSF14 mutations, which is consistent with a recent report on PCFCL. 44 Other validated cancerpromoting mutations included single gain-of-function mutations in JAK3, KRAS, FOXO1, CARD11, and RHOA and loss-of-function mutations in TET2, SOCS1, and B2M (Figures 2 and 3; supplemental Tables 2-7). Two cases had loss-of-function FAS mutations.…”

“…*Systemic disease below detection threshold at diagnosis a few studies. 9,44 The 30% threshold has been established as a cutoff for "high-PI" for FL in several studies. 25,46 Finally, given our current discovery that chromatin-modifying gene mutations are not as prominent a feature of PCFCL as they are of SCFL, we chose to include in the criteria the 4 most commonly mutated chromatinmodifying genes in FL.…”

Indolent clinical behaviour of primary cutaneous diffuse large B‐cell lymphoma, leg type, with double MYC and BCL6 gene rearrangement

“…BCL2‐positive cases with CD10 expression and BCL2 gene translocation makes it advisable to rule out a systemic origin. Only mutations in the TNFRSF14 gene have been reported in PCFCL, usually in combination with 1p36 deletion 10 . All these facts together allowed us to exclude the diagnosis of PCFCL with a diffuse pattern.…”

Recent advances in cutaneous lymphoma—implications for current and future classifications

“…As in nFL, PCFCL also frequently show deletions of 1p36/ TNFRSF14 [24,27]. In PCFCL, loss of 1p36 and BCL2R appear to be mutually exclusive, whereas they are often concurrent in nFL [32]. Mutations of TNFRSF14 are similarly frequent in both entities (30-40%) but the mutational profile of PCFCL differs from that of nFL harbouring BCL2R in having lower frequencies of mutations in chromatin modifiers (CREBBP, KMT2D, EZH2) and BCL2, and a higher incidence of mutations in TNFAIP3 (Table 2) [24].…”