Genomic and microenvironmental landscape of stage I follicular lymphoma, compared with stage III/IV

G. Tjitske Los-de Vries; Wendy B. C. Stevens; Erik van Dijk; Carole Langois-Jacques; Andrew J. Clear; Phylicia Stathi; Margaretha G. M. Roemer; Matias Mendeville; Nathalie J. Hijmering; Birgitta Sander; Andreas Rosenwald; Maria Calaminici; Eva Hoster; Wolfgang Hiddemann; Philippe Gaulard; Gilles Salles; Heike Horn; Wolfram Klapper; Luc Xerri; Catherine Burton; Reuben M. Tooze; Alexandra G. Smith; Christian Buske; David W. Scott; Yasodha Natkunam; Ranjana Advani; Laurie H. Sehn; John Raemaekers; John Gribben; Eva Kimby; Marie José Kersten; Delphine Maucort-Boulch; Bauke Ylstra; Daphne de Jong

doi:10.1182/bloodadvances.2022008355

Genomic and microenvironmental landscape of stage I follicular lymphoma, compared with stage III/IV

G. Tjitske Los-de Vries
, Wendy B. C. Stevens^*
, Erik van Dijk
, Carole Langois-Jacques
, Andrew J. Clear
, Phylicia Stathi
, Margaretha G. M. Roemer
, Matias Mendeville
, Nathalie J. Hijmering
, Birgitta Sander
, Andreas Rosenwald
, Maria Calaminici
, Eva Hoster
, Wolfgang Hiddemann
, Philippe Gaulard
, Gilles Salles
, Heike Horn
, Wolfram Klapper
, Luc Xerri
, Catherine Burton

Reuben M. Tooze, Alexandra G. Smith, Christian Buske, David W. Scott, Yasodha Natkunam, Ranjana Advani, Laurie H. Sehn, John Raemaekers, John Gribben, Eva Kimby, Marie José Kersten, Delphine Maucort-Boulch, Bauke Ylstra, Daphne de Jong

^*Corresponding author for this work

Amsterdam UMC
Radboud University Medical Center
Universite Claude Bernard Lyon 1
Department of Stroke Medicine, Lyon, France
Laboratoire de Biométrie et Biologie Évolutive
Queen Mary University of London
Karolinska Institutet
German National Reference Center for Meningococci and Haemophilus influenzae, Germany
Comprehensive Cancer Center Mainfranken
Ludwig Maximilian University of Munich
Hôpital Henri Mondor
Memorial Sloan-Kettering Cancer Center
Robert Bosch Foundation
Kiel University
Institut Paoli Calmettes
Leeds Teaching Hospitals NHS Trust
University of Leeds
University of York
Ulm University
University of British Columbia
Stanford University
Radboud University Nijmegen
Unité d’Hygiène, Epidémiologie, Infectiovigilance et Prévention, Hospices Civils de Lyon, Lyon, France
Karolinska University Hospital
University of Würzburg
University Hospital Munich
Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College
University Hospital Schleswig-Holstein Campus Kiel
St James’s University Hospital
University Hospital of Ulm
Centre for Mobility and Health

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Abstract

Although the genomic and immunemicroenvironmental landscape of follicular lymphoma (FL) has been extensively investigated, little is known about the potential biological differences between stage I and stage III/IV disease. Using next-generation sequencing and immunohistochemistry, 82 FL nodal stage I caseswere analyzed and comparedwith 139 FL stage III/IV nodal cases.Many similarities in mutations, chromosomal copy number aberrations, and microenvironmental cell populationswere detected. However, therewere also significant differences inmicroenvironmental and genomic features. CD8- T cells (P= .02) and STAT6 mutations (false discovery rate [FDR],0.001)weremore frequent in stage I FL. In contrast, programmed cell death protein 1-positive T cells, CD68-/CD163- macrophages (P<.001), BCL2 translocation (BCL2trl-) (P< .0001), and KMT2D (FDR= 0.003) and CREBBP (FDR= 0.04) mutationswere foundmore frequently in stage III/IV FL. Using clustering,we identified 3 clusters within stage I, and 2 clusterswithin stage III/IV. The BLC2trl- stage I clusterwas comparable to the BCL2trl- cluster in stage III/IV. The two BCL2trl- stage I clusters were unique for stage I. One was enriched for CREBBP (95%) andSTAT6 (64%)mutations,without BLC6 translocation (BCL6trl), whereas the BCL2trl- stage III/IV cluster contained BCL6trl (64%)with fewer CREBBP (45%) andSTAT6 (9%)mutations. The other BCL2trl- stage I clusterwas relatively heterogeneouswith more copy number aberrations and linker histonemutations. This exploratory study shows that stage I FL is genetically heterogeneouswith different underlying oncogenic pathways. Stage I FL BCL2trl- is likely STAT6 driven,whereas BCL2trl- stage III/IV appears to bemore BCL6trl driven.

Original language	English
Pages (from-to)	5482-5493
Number of pages	12
Journal	Blood advances
Volume	6
Issue number	18
DOIs	https://doi.org/10.1182/bloodadvances.2022008355
Publication status	Published - 27 Sept 2022

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Los-de Vries, G. T., Stevens, W. B. C., van Dijk, E., Langois-Jacques, C., Clear, A. J., Stathi, P., Roemer, M. G. M., Mendeville, M., Hijmering, N. J., Sander, B., Rosenwald, A., Calaminici, M., Hoster, E., Hiddemann, W., Gaulard, P., Salles, G., Horn, H., Klapper, W., Xerri, L., ... de Jong, D. (2022). Genomic and microenvironmental landscape of stage I follicular lymphoma, compared with stage III/IV. Blood advances, 6(18), 5482-5493. https://doi.org/10.1182/bloodadvances.2022008355

@article{9d6f2f8c1cc54057b9b9400f98a8824c,

title = "Genomic and microenvironmental landscape of stage I follicular lymphoma, compared with stage III/IV",

abstract = "Although the genomic and immunemicroenvironmental landscape of follicular lymphoma (FL) has been extensively investigated, little is known about the potential biological differences between stage I and stage III/IV disease. Using next-generation sequencing and immunohistochemistry, 82 FL nodal stage I caseswere analyzed and comparedwith 139 FL stage III/IV nodal cases.Many similarities in mutations, chromosomal copy number aberrations, and microenvironmental cell populationswere detected. However, therewere also significant differences inmicroenvironmental and genomic features. CD8- T cells (P= .02) and STAT6 mutations (false discovery rate [FDR],0.001)weremore frequent in stage I FL. In contrast, programmed cell death protein 1-positive T cells, CD68-/CD163- macrophages (P<.001), BCL2 translocation (BCL2trl-) (P< .0001), and KMT2D (FDR= 0.003) and CREBBP (FDR= 0.04) mutationswere foundmore frequently in stage III/IV FL. Using clustering,we identified 3 clusters within stage I, and 2 clusterswithin stage III/IV. The BLC2trl- stage I clusterwas comparable to the BCL2trl- cluster in stage III/IV. The two BCL2trl- stage I clusters were unique for stage I. One was enriched for CREBBP (95\%) andSTAT6 (64\%)mutations,without BLC6 translocation (BCL6trl), whereas the BCL2trl- stage III/IV cluster contained BCL6trl (64\%)with fewer CREBBP (45\%) andSTAT6 (9\%)mutations. The other BCL2trl- stage I clusterwas relatively heterogeneouswith more copy number aberrations and linker histonemutations. This exploratory study shows that stage I FL is genetically heterogeneouswith different underlying oncogenic pathways. Stage I FL BCL2trl- is likely STAT6 driven,whereas BCL2trl- stage III/IV appears to bemore BCL6trl driven.",

author = "\{Los-de Vries\}, \{G. Tjitske\} and Stevens, \{Wendy B. C.\} and \{van Dijk\}, Erik and Carole Langois-Jacques and Clear, \{Andrew J.\} and Phylicia Stathi and Roemer, \{Margaretha G. M.\} and Matias Mendeville and Hijmering, \{Nathalie J.\} and Birgitta Sander and Andreas Rosenwald and Maria Calaminici and Eva Hoster and Wolfgang Hiddemann and Philippe Gaulard and Gilles Salles and Heike Horn and Wolfram Klapper and Luc Xerri and Catherine Burton and Tooze, \{Reuben M.\} and Smith, \{Alexandra G.\} and Christian Buske and Scott, \{David W.\} and Yasodha Natkunam and Ranjana Advani and Sehn, \{Laurie H.\} and John Raemaekers and John Gribben and Eva Kimby and Kersten, \{Marie Jos{\'e}\} and Delphine Maucort-Boulch and Bauke Ylstra and \{de Jong\}, Daphne",

note = "Funding Information: This study was supported by the Dutch Cancer Society (grant KWF 2015-7925) and by unrestricted grants from van Vlissingen Lymfoom Fonds, Genentech/Roche, GlaxoSmithKline, Pfizer Pharma, Teva Pharmaceuticals/Cephalon, Millenium Pharmaceuticals Inc., and Celgene. The HMRN is funded by Cancer Research UK (grant 29685) and Blood Cancer UK (grant 1503). Funding Information: The LLBC is a collaboration of 9 international lymphoma research groups, each represented by a clinical investigator and one or more hematopathologists and supported by a team of statisticians. Foundation of the LLBC was made possible with a grant from the Van Vlissingen Lymphoma Foundation. EORTC Lymphoma group represented by: Daphne de Jong and John Raemaekers. HOVON Lymphoma group represented by: Daphne de Jong and Marie-Jos{\'e} Kersten. Lymphoma Study Association represented by: Philippe Gaulard, Gilles Salles, Luc Xerri, Delphine Maucort-Boulch, and Carole Langois-Jacques. British Columbia Cancer Agency represented by: Laurie H. Sehn and David W. Scott. GLSG represented by: Andreas Rosenwald, Wolfram Klapper, Christian Buske, Wolfgang Hiddemann, Eva Hoster, and Heike Horn. Nordic lymphoma group represented by: Birgitta Sander and Eva Kimby. Barts Cancer Institute represented by: Maria Calaminici, John Gribben, and Andrew J. Clear. HMRN represented by: Catherine Burton, Reuben M. Tooze, Funding Information: G.T.L.-d.V., D.d.J., B.Y., and M.J.K. received funding from the Dutch Cancer Society (grant KWF 2015-7925). W.B.C.S., E.v.D., C.L.-J., and D.M.-J. were funded by unrestricted grants from Vlissingen Lymfoom Fonds, Genentech/Roche, GlaxoS-mithKline, Pfizer Pharma, Teva Pharmaceuticals/Cephalon, Millenium Pharmaceuticals Inc., and Celgene. A.G.S. was funded by Malignancy Research Network is funded by Cancer Research UK, grant numbers 29685; and Blood Cancer UK, grant number 1503. Publisher Copyright: {\textcopyright} 2022 American Society of Hematology. All rights reserved.",

year = "2022",

month = sep,

day = "27",

doi = "10.1182/bloodadvances.2022008355",

language = "English",

volume = "6",

pages = "5482--5493",

journal = "Blood advances",

issn = "2473-9529",

publisher = "American Society of Hematology",

number = "18",

}

Los-de Vries, GT, Stevens, WBC, van Dijk, E, Langois-Jacques, C, Clear, AJ, Stathi, P, Roemer, MGM, Mendeville, M, Hijmering, NJ, Sander, B, Rosenwald, A, Calaminici, M, Hoster, E, Hiddemann, W, Gaulard, P, Salles, G, Horn, H, Klapper, W, Xerri, L, Burton, C, Tooze, RM, Smith, AG, Buske, C, Scott, DW, Natkunam, Y, Advani, R, Sehn, LH, Raemaekers, J, Gribben, J, Kimby, E, Kersten, MJ, Maucort-Boulch, D, Ylstra, B & de Jong, D 2022, 'Genomic and microenvironmental landscape of stage I follicular lymphoma, compared with stage III/IV', Blood advances, vol. 6, no. 18, pp. 5482-5493. https://doi.org/10.1182/bloodadvances.2022008355

TY - JOUR

T1 - Genomic and microenvironmental landscape of stage I follicular lymphoma, compared with stage III/IV

AU - Los-de Vries, G. Tjitske

AU - Stevens, Wendy B. C.

AU - van Dijk, Erik

AU - Langois-Jacques, Carole

AU - Clear, Andrew J.

AU - Stathi, Phylicia

AU - Roemer, Margaretha G. M.

AU - Mendeville, Matias

AU - Hijmering, Nathalie J.

AU - Sander, Birgitta

AU - Rosenwald, Andreas

AU - Calaminici, Maria

AU - Hoster, Eva

AU - Hiddemann, Wolfgang

AU - Gaulard, Philippe

AU - Salles, Gilles

AU - Horn, Heike

AU - Klapper, Wolfram

AU - Xerri, Luc

AU - Burton, Catherine

AU - Tooze, Reuben M.

AU - Smith, Alexandra G.

AU - Buske, Christian

AU - Scott, David W.

AU - Natkunam, Yasodha

AU - Advani, Ranjana

AU - Sehn, Laurie H.

AU - Raemaekers, John

AU - Gribben, John

AU - Kimby, Eva

AU - Kersten, Marie José

AU - Maucort-Boulch, Delphine

AU - Ylstra, Bauke

AU - de Jong, Daphne

N1 - Funding Information: This study was supported by the Dutch Cancer Society (grant KWF 2015-7925) and by unrestricted grants from van Vlissingen Lymfoom Fonds, Genentech/Roche, GlaxoSmithKline, Pfizer Pharma, Teva Pharmaceuticals/Cephalon, Millenium Pharmaceuticals Inc., and Celgene. The HMRN is funded by Cancer Research UK (grant 29685) and Blood Cancer UK (grant 1503). Funding Information: The LLBC is a collaboration of 9 international lymphoma research groups, each represented by a clinical investigator and one or more hematopathologists and supported by a team of statisticians. Foundation of the LLBC was made possible with a grant from the Van Vlissingen Lymphoma Foundation. EORTC Lymphoma group represented by: Daphne de Jong and John Raemaekers. HOVON Lymphoma group represented by: Daphne de Jong and Marie-José Kersten. Lymphoma Study Association represented by: Philippe Gaulard, Gilles Salles, Luc Xerri, Delphine Maucort-Boulch, and Carole Langois-Jacques. British Columbia Cancer Agency represented by: Laurie H. Sehn and David W. Scott. GLSG represented by: Andreas Rosenwald, Wolfram Klapper, Christian Buske, Wolfgang Hiddemann, Eva Hoster, and Heike Horn. Nordic lymphoma group represented by: Birgitta Sander and Eva Kimby. Barts Cancer Institute represented by: Maria Calaminici, John Gribben, and Andrew J. Clear. HMRN represented by: Catherine Burton, Reuben M. Tooze, Funding Information: G.T.L.-d.V., D.d.J., B.Y., and M.J.K. received funding from the Dutch Cancer Society (grant KWF 2015-7925). W.B.C.S., E.v.D., C.L.-J., and D.M.-J. were funded by unrestricted grants from Vlissingen Lymfoom Fonds, Genentech/Roche, GlaxoS-mithKline, Pfizer Pharma, Teva Pharmaceuticals/Cephalon, Millenium Pharmaceuticals Inc., and Celgene. A.G.S. was funded by Malignancy Research Network is funded by Cancer Research UK, grant numbers 29685; and Blood Cancer UK, grant number 1503. Publisher Copyright: © 2022 American Society of Hematology. All rights reserved.

PY - 2022/9/27

Y1 - 2022/9/27

N2 - Although the genomic and immunemicroenvironmental landscape of follicular lymphoma (FL) has been extensively investigated, little is known about the potential biological differences between stage I and stage III/IV disease. Using next-generation sequencing and immunohistochemistry, 82 FL nodal stage I caseswere analyzed and comparedwith 139 FL stage III/IV nodal cases.Many similarities in mutations, chromosomal copy number aberrations, and microenvironmental cell populationswere detected. However, therewere also significant differences inmicroenvironmental and genomic features. CD8- T cells (P= .02) and STAT6 mutations (false discovery rate [FDR],0.001)weremore frequent in stage I FL. In contrast, programmed cell death protein 1-positive T cells, CD68-/CD163- macrophages (P<.001), BCL2 translocation (BCL2trl-) (P< .0001), and KMT2D (FDR= 0.003) and CREBBP (FDR= 0.04) mutationswere foundmore frequently in stage III/IV FL. Using clustering,we identified 3 clusters within stage I, and 2 clusterswithin stage III/IV. The BLC2trl- stage I clusterwas comparable to the BCL2trl- cluster in stage III/IV. The two BCL2trl- stage I clusters were unique for stage I. One was enriched for CREBBP (95%) andSTAT6 (64%)mutations,without BLC6 translocation (BCL6trl), whereas the BCL2trl- stage III/IV cluster contained BCL6trl (64%)with fewer CREBBP (45%) andSTAT6 (9%)mutations. The other BCL2trl- stage I clusterwas relatively heterogeneouswith more copy number aberrations and linker histonemutations. This exploratory study shows that stage I FL is genetically heterogeneouswith different underlying oncogenic pathways. Stage I FL BCL2trl- is likely STAT6 driven,whereas BCL2trl- stage III/IV appears to bemore BCL6trl driven.

AB - Although the genomic and immunemicroenvironmental landscape of follicular lymphoma (FL) has been extensively investigated, little is known about the potential biological differences between stage I and stage III/IV disease. Using next-generation sequencing and immunohistochemistry, 82 FL nodal stage I caseswere analyzed and comparedwith 139 FL stage III/IV nodal cases.Many similarities in mutations, chromosomal copy number aberrations, and microenvironmental cell populationswere detected. However, therewere also significant differences inmicroenvironmental and genomic features. CD8- T cells (P= .02) and STAT6 mutations (false discovery rate [FDR],0.001)weremore frequent in stage I FL. In contrast, programmed cell death protein 1-positive T cells, CD68-/CD163- macrophages (P<.001), BCL2 translocation (BCL2trl-) (P< .0001), and KMT2D (FDR= 0.003) and CREBBP (FDR= 0.04) mutationswere foundmore frequently in stage III/IV FL. Using clustering,we identified 3 clusters within stage I, and 2 clusterswithin stage III/IV. The BLC2trl- stage I clusterwas comparable to the BCL2trl- cluster in stage III/IV. The two BCL2trl- stage I clusters were unique for stage I. One was enriched for CREBBP (95%) andSTAT6 (64%)mutations,without BLC6 translocation (BCL6trl), whereas the BCL2trl- stage III/IV cluster contained BCL6trl (64%)with fewer CREBBP (45%) andSTAT6 (9%)mutations. The other BCL2trl- stage I clusterwas relatively heterogeneouswith more copy number aberrations and linker histonemutations. This exploratory study shows that stage I FL is genetically heterogeneouswith different underlying oncogenic pathways. Stage I FL BCL2trl- is likely STAT6 driven,whereas BCL2trl- stage III/IV appears to bemore BCL6trl driven.

UR - https://www.scopus.com/pages/publications/85139389244

U2 - 10.1182/bloodadvances.2022008355

DO - 10.1182/bloodadvances.2022008355

M3 - Article

C2 - 35816682

SN - 2473-9529

VL - 6

SP - 5482

EP - 5493

JO - Blood advances

JF - Blood advances

IS - 18

ER -

Genomic and microenvironmental landscape of stage I follicular lymphoma, compared with stage III/IV

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