Follicular lymphoma t(14;18)-negative is genetically a heterogeneous disease
Dominik Nann
(1, 2)
,
Joan Enric Ramis-Zaldivar
(3, 4)
,
Inga Müller
(1, 2)
,
Blanca Gonzalez-Farre
(3, 4)
,
Janine Schmidt
(1, 2)
,
Caoimhe Egan
(5)
,
Julia Salmeron-Villalobos
(3, 4)
,
Guillem Clot
(3, 4)
,
Sven Mattern
(1, 2)
,
Franziska Otto
(1, 2)
,
Barbara Mankel
(1, 2)
,
Dolors Colomer
(3, 4)
,
Olga Balagué
(3, 4)
,
Vanessa Szablewski
(6, 7)
,
Carmen Lome-Maldonado
(8)
,
Lorenzo Leoncini
(9)
,
Stefan Dojcinov
(10)
,
Andreas Chott
(11)
,
Christiane Copie-Bergman
(12, 13)
,
Irina Bonzheim
(1, 2)
,
Falko Fend
(1, 2)
,
Elaine Jaffe
(5)
,
Elias Campo
(3, 4)
,
Itziar Salaverria
(3, 4)
,
Leticia Quintanilla-Martinez
(1, 2)
1
Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen
2 Universitätsklinikum Tübingen - University Hospital of Tübingen
3 Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
4 CIBERONC - Centro de Investigación Biomédica en Red de Cáncer
5 NCI-NIH - National Cancer Institute [Bethesda]
6 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
7 Pathogénèse et contrôle des infections chroniques (PCCI)
8 Instituto Nacional de Cancerología
9 UNISI - Università degli Studi di Siena = University of Siena
10 UHW - University Hospital of Wales
11 Wilhelminenspital Vienna = Wilhelminen Hospital
12 IMRB - Institut Mondor de Recherche Biomédicale
13 Hôpital Henri Mondor
2 Universitätsklinikum Tübingen - University Hospital of Tübingen
3 Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
4 CIBERONC - Centro de Investigación Biomédica en Red de Cáncer
5 NCI-NIH - National Cancer Institute [Bethesda]
6 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
7 Pathogénèse et contrôle des infections chroniques (PCCI)
8 Instituto Nacional de Cancerología
9 UNISI - Università degli Studi di Siena = University of Siena
10 UHW - University Hospital of Wales
11 Wilhelminenspital Vienna = Wilhelminen Hospital
12 IMRB - Institut Mondor de Recherche Biomédicale
13 Hôpital Henri Mondor
Résumé
Abstract Fifty-five cases of t(14;18)− follicular lymphoma (FL) were genetically characterized by targeted sequencing and copy number (CN) arrays. t(14;18)− FL predominated in women (M/F 1:2); patients often presented during early clinical stages (71%), and had excellent prognoses. Overall, t(14;18)− FL displayed CN alterations (CNAs) and gene mutations carried by conventional t(14;18)+ FL (cFL), but with different frequencies. The most frequently mutated gene was STAT6 (57%) followed by CREBBP (49%), TNFRSF14 (39%), and KMT2D (27%). t(14;18)− FL showed significantly more STAT6 mutations and lacked MYD88, NOTCH2, MEF2B, and MAP2K1 mutations compared with cFL, nodal marginal zone lymphoma (NMZL), and pediatric-type FL (PTFL). We identified 2 molecular clusters. Cluster A was characterized by TNFRSF14 mutations/1p36 alterations (96%) and frequent mutations in epigenetic regulators, with recurrent loss of 6q21-24 sharing many features with cFL. Cluster B showed few genetic alterations; however, a subgroup with STAT6 mutations concurrent with CREBBP mutations/16p alterations without TNFRSF14 and EZH2 mutations was noted (65%). These 2 molecular clusters did not distinguish cases by inguinal localization, growth pattern, or presence of STAT6 mutations. BCL6 rearrangements were demonstrated in 10 of 45 (22%) cases and did not cluster together. Cases with predominantly inguinal presentation (20 of 50; 40%) had a higher frequency of diffuse growth pattern, STAT6 mutations, CD23 expression, and a lower number of CNAs, in comparison with noninguinal cases (5.1 vs 9.1 alterations per case; P < .05). STAT6 mutations showed a positive correlation with CD23 expression (P < .001). In summary, t(14;18)− FL is genetically a heterogeneous disorder with features that differ from cFL, NMZL, and PTFL.