Identification of primary mediastinal B-cell lymphomas with higher clonal dominance and poorer outcome using 5' RACE
Vincent Camus
(1)
,
Mathieu Viennot
(1)
,
Pierre-Julien Viailly
(2)
,
Fanny Drieux
(1)
,
Elena-Liana Veresezan
(1)
,
Victor Bobée
(3)
,
Vinciane Rainville
(1, 2)
,
Elodie Bohers
(1, 2)
,
Pierre Sesques
(4)
,
Corinne Haioun
(5)
,
Eric Durot
(6)
,
Michael Bayaram
(6)
,
Cédric Rossi
(7)
,
Laurent Martin
(7)
,
Dominique Penther
(1)
,
Sophie Kaltenbach
(8)
,
Julie Bruneau
(8, 9)
,
Jérôme Paillassa
(10)
,
Olivier Tournilhac
(11, 12, 13)
,
Nicolas Gower
(14)
,
Alexandre Willaume
(15)
,
Chloe Antier
(16)
,
Loïc Renaud
(17)
,
Emilie Leveque
(1)
,
Pierre Decazes
(1)
,
Stéphanie Becker
(1)
,
David Tonnelet
(1)
,
Philippe Gaulard
(5)
,
Hervé Tilly
(1)
,
Thierry Molina
(8)
,
Alexandra Traverse-Glehen
(4)
,
Marie Donzel
(18)
,
Philippe Ruminy
(1)
,
Fabrice Jardin
(1)
1
CLCC Henri Becquerel -
Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen
2 CBG - Cancer and Brain Genomics
3 CHU Rouen
4 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
5 Hôpital Henri Mondor
6 Hôpital Robert Debré
7 CHU Dijon
8 Hôpital Necker - Enfants Malades [AP-HP]
9 UPD5 - Université Paris Descartes - Paris 5
10 CHU Angers - Centre Hospitalier Universitaire d'Angers
11 CHU Estaing [Clermont-Ferrand]
12 CHELTER - Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias
13 CIC 1405 - Centre d'Investigation Clinique [CHU Clermont-Ferrand]
14 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
15 Hôpital Saint Vincent de Paul de Lille
16 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
17 IGR - Institut Gustave Roussy
18 HCL - Hospices Civils de Lyon
2 CBG - Cancer and Brain Genomics
3 CHU Rouen
4 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
5 Hôpital Henri Mondor
6 Hôpital Robert Debré
7 CHU Dijon
8 Hôpital Necker - Enfants Malades [AP-HP]
9 UPD5 - Université Paris Descartes - Paris 5
10 CHU Angers - Centre Hospitalier Universitaire d'Angers
11 CHU Estaing [Clermont-Ferrand]
12 CHELTER - Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias
13 CIC 1405 - Centre d'Investigation Clinique [CHU Clermont-Ferrand]
14 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
15 Hôpital Saint Vincent de Paul de Lille
16 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
17 IGR - Institut Gustave Roussy
18 HCL - Hospices Civils de Lyon
Vincent Camus
- Fonction : Auteur
- PersonId : 766025
- ORCID : 0000-0002-1559-007X
Elodie Bohers
- Fonction : Auteur
- PersonId : 178431
- IdHAL : elodie-bohers
- ORCID : 0000-0001-9168-576X
Pierre Sesques
- Fonction : Auteur
- PersonId : 797365
- ORCID : 0000-0001-8264-822X
Julie Bruneau
- Fonction : Auteur
- PersonId : 1178707
- ORCID : 0000-0001-5519-8489
Pierre Decazes
- Fonction : Auteur
- PersonId : 1212009
- ORCID : 0000-0001-5323-9910
David Tonnelet
- Fonction : Auteur
- PersonId : 1308885
- ORCID : 0000-0002-8609-0611
Thierry Molina
- Fonction : Auteur
- PersonId : 1191416
- ORCID : 0000-0002-3929-9754
Marie Donzel
- Fonction : Auteur
- PersonId : 1430936
- ORCID : 0000-0002-5797-5744
Résumé
Few data exist regarding the tumor B-cell receptor (BCR) repertoire and lymphoid microenvironment in primary mediastinal B-cell lymphoma (PMBL). We applied 5' rapid amplification of cDNA ends (5'RACE) to tumor RNA samples from 137 PMBL patients with available gene expression profiling and next-generation sequencing data. We obtained 5'RACE results for 75/137 (54.7%) patients, with clinical characteristics as follows: median [min-max] age, 33 [18-64] years; female, 53.3%; ECOG score 0-1, 86.7%; stage I-II, 57.3%; 1st-line treatment with anti-CD20 plus ACVBP, 72%; CHOP14, 14.7%; CHOP21, 13.3%. Among the 60 biopsies that expressed a productive BCR, we highlighted a strong somatic hypermutation profile with 58 (96.7%) patients carrying mutated IgVH, defined as <98% identity to the germline sequence. We then identified a subgroup of 12/75 patients (16%) with a worse prognosis (progression-free survival (PFS): HR [95% CI]=17 [3.2-88]; overall survival (OS): HR=21 [2.1-210]) associated with the highest clonal dominance status (HCD), defined by the dominant clonotype representing >81.1% and >78.6% of all CDR3 sequences for IgVH and IgVL, respectively. Compared to other patients, this subgroup had similar clinical characteristics but a greater median allele frequency for all somatic variants, decreased BCR diversity, and greater expression of PDL1/PDL2 and MS4A1 genes, suggesting a greater tumoral infiltration. According to a multivariate model integrating AID expression and BCR diversity, only HCD status was associated with outcome (PFS: HR=14.6 [2.46-86.8]; OS: HR=11.4 [1-128.8]). We confirmed this poorer prognosis in an independent cohort, in which 6/37 (16%) patients exhibited HCD (PFS: HR=12 [3-46]; OS: HR=17 [1.8-170]).