Huang Dan, Berglund Mattias, Damdimopoulos Anastasios, Antonson Per, Lindskog Cecilia, Enblad Gunilla, Amini Rose-Marie, Okret Sam
Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 Huddinge, Sweden.
Bioinformatics and Expression Core Facility, Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 Huddinge, Sweden.
Cancers (Basel). 2023 Feb 17;15(4):1298. doi: 10.3390/cancers15041298.
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. -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, and , 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 expression showed better survival. Inversely, MUC5B expression causes a more malignant phenotype in several cancers. and 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.
对于大多数淋巴瘤，包括弥漫性大B细胞淋巴瘤（DLBCL），男性发病率较高，与女性相比预后更差。原因尚不清楚；然而，流行病学和实验数据表明雌激素与之有关。考虑到这一点，我们基于RNA测序分析了来自一个公开可用队列（EGAD00001003600）的746个DLBCL样本的基因表达数据。我们发现1293个基因在男性和女性之间存在差异表达（校正P值<0.05）。在生发中心B细胞（GCB）和活化B细胞淋巴瘤（ABC）DLBCL之间，很少有常染色体基因和通路表现出共同的性别调节表达。对绝经前与绝经后女性之间差异表达基因的分析确定了208个GCB基因和345个ABC基因，其中只有5个是共有的。当将女性与男性之间以及绝经前与绝经后女性之间的差异表达基因相结合时，在ABC DLBCL中鉴定出9个假定的雌激素调节基因。其中两个基因，分别表现出诱导表达和抑制表达。有趣的是，NR4A2在淋巴瘤中被报道为一种肿瘤抑制因子。我们表明，高表达的ABC DLBCL女性显示出更好的生存率。相反，MUC5B表达在几种癌症中导致更恶性的表型。当将ABC细胞系U2932移植到小鼠体内时，和被证实受雌激素调节。结果表明，DLBCL亚型之间在基因表达上存在性别和女性生殖年龄依赖性差异，可能是由于雌激素所致。这可能导致发病率和预后的性别差异。
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