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Sex- and Female Age-Dependent Differences in Gene Expression in Diffuse Large B-Cell Lymphoma—Possible Estrogen Effects

SIMPLE SUMMARY: Females show a favorable sex difference in incidence as well as in survival for many cancer types, so also in lymphoma. The reasons for this are unknown. We have therefore analyzed global gene expression in a large cohort of the most common lymphoma type, diffuse large B-cell lymphom...

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Autores principales: Huang, Dan, Berglund, Mattias, Damdimopoulos, Anastasios, Antonson, Per, Lindskog, Cecilia, Enblad, Gunilla, Amini, Rose-Marie, Okret, Sam
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9954534/
https://www.ncbi.nlm.nih.gov/pubmed/36831639
http://dx.doi.org/10.3390/cancers15041298
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author Huang, Dan
Berglund, Mattias
Damdimopoulos, Anastasios
Antonson, Per
Lindskog, Cecilia
Enblad, Gunilla
Amini, Rose-Marie
Okret, Sam
author_facet Huang, Dan
Berglund, Mattias
Damdimopoulos, Anastasios
Antonson, Per
Lindskog, Cecilia
Enblad, Gunilla
Amini, Rose-Marie
Okret, Sam
author_sort Huang, Dan
collection PubMed
description SIMPLE SUMMARY: Females show a favorable sex difference in incidence as well as in survival for many cancer types, so also in lymphoma. The reasons for this are unknown. We have therefore analyzed global gene expression in a large cohort of the most common lymphoma type, diffuse large B-cell lymphoma. We show that many genes are differentially expressed between males and females. Furthermore, the results demonstrate sex-dependent differences in gene expression between DLBCL subtypes. In addition, gene expression differs in pre- vs. postmenopausal women suggesting that estrogen regulation of genes is involved. Thus, estrogens may contribute to the sex and female age differences in incidence and prognosis observed. ABSTRACT: For most lymphomas, including diffuse large B-cell lymphoma (DLBCL), the male incidence is higher, and the prognosis is worse compared to females. The reasons are unclear; however, epidemiological and experimental data suggest that estrogens are involved. With this in mind, we analyzed gene expression data from a publicly available cohort (EGAD00001003600) of 746 DLBCL samples based on RNA sequencing. We found 1293 genes to be differentially expressed between males and females (adj. p-value < 0.05). Few autosomal genes and pathways showed common sex-regulated expression between germinal center B-cell (GCB) and activated B-cell lymphoma (ABC) DLBCL. Analysis of differentially expressed genes between pre- vs. postmenopausal females identified 208 GCB and 345 ABC genes, with only 5 being shared. When combining the differentially expressed genes between females vs. males and pre- vs. postmenopausal females, nine putative estrogen-regulated genes were identified in ABC DLBCL. Two of them, NR4A2 and MUC5B, showed induced and repressed expression, respectively. Interestingly, NR4A2 has been reported as a tumor suppressor in lymphoma. We show that ABC DLBCL females with a high NR4A2 expression showed better survival. Inversely, MUC5B expression causes a more malignant phenotype in several cancers. NR4A2 and MUC5B were confirmed to be estrogen-regulated when the ABC cell line U2932 was grafted to mice. The results demonstrate sex- and female reproductive age-dependent differences in gene expression between DLBCL subtypes, likely due to estrogens. This may contribute to the sex differences in incidence and prognosis.
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spelling pubmed-99545342023-02-25 Sex- and Female Age-Dependent Differences in Gene Expression in Diffuse Large B-Cell Lymphoma—Possible Estrogen Effects Huang, Dan Berglund, Mattias Damdimopoulos, Anastasios Antonson, Per Lindskog, Cecilia Enblad, Gunilla Amini, Rose-Marie Okret, Sam Cancers (Basel) Article SIMPLE SUMMARY: Females show a favorable sex difference in incidence as well as in survival for many cancer types, so also in lymphoma. The reasons for this are unknown. We have therefore analyzed global gene expression in a large cohort of the most common lymphoma type, diffuse large B-cell lymphoma. We show that many genes are differentially expressed between males and females. Furthermore, the results demonstrate sex-dependent differences in gene expression between DLBCL subtypes. In addition, gene expression differs in pre- vs. postmenopausal women suggesting that estrogen regulation of genes is involved. Thus, estrogens may contribute to the sex and female age differences in incidence and prognosis observed. ABSTRACT: For most lymphomas, including diffuse large B-cell lymphoma (DLBCL), the male incidence is higher, and the prognosis is worse compared to females. The reasons are unclear; however, epidemiological and experimental data suggest that estrogens are involved. With this in mind, we analyzed gene expression data from a publicly available cohort (EGAD00001003600) of 746 DLBCL samples based on RNA sequencing. We found 1293 genes to be differentially expressed between males and females (adj. p-value < 0.05). Few autosomal genes and pathways showed common sex-regulated expression between germinal center B-cell (GCB) and activated B-cell lymphoma (ABC) DLBCL. Analysis of differentially expressed genes between pre- vs. postmenopausal females identified 208 GCB and 345 ABC genes, with only 5 being shared. When combining the differentially expressed genes between females vs. males and pre- vs. postmenopausal females, nine putative estrogen-regulated genes were identified in ABC DLBCL. Two of them, NR4A2 and MUC5B, showed induced and repressed expression, respectively. Interestingly, NR4A2 has been reported as a tumor suppressor in lymphoma. We show that ABC DLBCL females with a high NR4A2 expression showed better survival. Inversely, MUC5B expression causes a more malignant phenotype in several cancers. NR4A2 and MUC5B were confirmed to be estrogen-regulated when the ABC cell line U2932 was grafted to mice. The results demonstrate sex- and female reproductive age-dependent differences in gene expression between DLBCL subtypes, likely due to estrogens. This may contribute to the sex differences in incidence and prognosis. MDPI 2023-02-17 /pmc/articles/PMC9954534/ /pubmed/36831639 http://dx.doi.org/10.3390/cancers15041298 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Huang, Dan
Berglund, Mattias
Damdimopoulos, Anastasios
Antonson, Per
Lindskog, Cecilia
Enblad, Gunilla
Amini, Rose-Marie
Okret, Sam
Sex- and Female Age-Dependent Differences in Gene Expression in Diffuse Large B-Cell Lymphoma—Possible Estrogen Effects
title Sex- and Female Age-Dependent Differences in Gene Expression in Diffuse Large B-Cell Lymphoma—Possible Estrogen Effects
title_full Sex- and Female Age-Dependent Differences in Gene Expression in Diffuse Large B-Cell Lymphoma—Possible Estrogen Effects
title_fullStr Sex- and Female Age-Dependent Differences in Gene Expression in Diffuse Large B-Cell Lymphoma—Possible Estrogen Effects
title_full_unstemmed Sex- and Female Age-Dependent Differences in Gene Expression in Diffuse Large B-Cell Lymphoma—Possible Estrogen Effects
title_short Sex- and Female Age-Dependent Differences in Gene Expression in Diffuse Large B-Cell Lymphoma—Possible Estrogen Effects
title_sort sex- and female age-dependent differences in gene expression in diffuse large b-cell lymphoma—possible estrogen effects
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9954534/
https://www.ncbi.nlm.nih.gov/pubmed/36831639
http://dx.doi.org/10.3390/cancers15041298
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