University of North Carolina, Chapel Hill, NC, USA.
Duke Cancer Institute and Center for Genomic and Computational Biology, Durham, NC, USA.
Mod Pathol. 2020 Aug;33(8):1482-1491. doi: 10.1038/s41379-020-0506-3. Epub 2020 Feb 20.
Lymphoma incidence in sub-Saharan Africa (SSA) is increasing due to HIV and population aging. Diffuse Large B-cell lymphoma (DLBCL), the most common lymphoma in SSA and worldwide, is highly associated with HIV, but molecular studies of HIV-associated DLBCL are scarce globally. We describe profiling of DLBCL from Malawi, aiming to elucidate tumor biology and identify clinically meaningful biomarkers specifically for SSA. Between June 1, 2013 and June 1, 2016, 59 cases of DLBCL (32 HIV+/27 HIV-) enrolled in the Kamuzu Central Hospital Lymphoma Study were characterized, of which 54 (92%) were negative for Epstein-Barr virus. Gene expression profiling (GEP) by whole transcriptome sequencing was performed on the first 36 cases (22 HIV+/14 HIV-). Immunohistochemistry (IHC) and GEP results were compared with published data and correlated to clinical outcome and pathologic features. Unsupervised clustering strongly segregated DLBCL by HIV status (p = 0.0003, Chi-squared test), indicating a marked contribution of HIV to expression phenotype. Pathway analysis identified that HIV-associated tumors were enriched in hypoxia, oxidative stress, and metabolism related gene expression patterns. Cell-of-origin subtype, determined by sequencing and IHC, did not associate with differences in overall survival (OS), while Ki-67 proliferation index ≥80% was associated with inferior OS in HIV+ DLBCL only (p = 0.03) and cMYC/BCL2 co-expression by IHC was negatively prognostic across the entire cohort (p = 0.01). This study provides among the first molecular characterizations of DLBCL from SSA, demonstrates marked gene expression differences by HIV status, and identifies genomic and immunophenotypic characteristics that can inform future basic and clinical investigations.
由于 HIV 和人口老龄化，撒哈拉以南非洲（SSA）的淋巴瘤发病率正在上升。弥漫性大 B 细胞淋巴瘤（DLBCL）是 SSA 和全球最常见的淋巴瘤，与 HIV 高度相关，但全球 HIV 相关 DLBCL 的分子研究很少。我们描述了马拉维的 DLBCL 分析，旨在阐明肿瘤生物学并确定针对 SSA 的具有临床意义的生物标志物。2013 年 6 月 1 日至 2016 年 6 月 1 日，卡姆祖中央医院淋巴瘤研究纳入了 59 例 DLBCL 病例（32 例 HIV+/27 例 HIV-），其中 54 例（92%）EBV 阴性。对前 36 例（22 例 HIV+/14 例 HIV-）进行了全转录组测序的基因表达谱分析。免疫组织化学（IHC）和 GEP 结果与已发表的数据进行了比较，并与临床结果和病理特征相关联。无监督聚类根据 HIV 状态强烈分离了 DLBCL（p=0.0003，卡方检验），表明 HIV 对表达表型有明显贡献。途径分析表明，与 HIV 相关的肿瘤在缺氧、氧化应激和代谢相关基因表达模式中富集。通过测序和 IHC 确定的细胞起源亚型与总体生存率（OS）无差异相关，而仅在 HIV+ DLBCL 中，Ki-67 增殖指数≥80%与较差的 OS 相关（p=0.03），而 IHC 中 cMYC/BCL2 的共表达在整个队列中均具有负预后意义（p=0.01）。这项研究提供了 SSA 中 DLBCL 的首批分子特征之一，表明 HIV 状态存在明显的基因表达差异，并确定了可以为未来的基础和临床研究提供信息的基因组和免疫表型特征。
