Gnanasekar Aditi, Castaneda Grant, Iyangar Anjali, Magesh Shruti, Perez Daisy, Chakladar Jaideep, Li Wei Tse, Bouvet Michael, Chang Eric Y, Ongkeko Weg M
Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, UC San Diego School of Medicine, San Diego, CA 92093, USA.
Research Service, VA San Diego Healthcare System, San Diego, CA 92161, USA.
Comput Struct Biotechnol J. 2021 Apr 9;19:1986-1997. doi: 10.1016/j.csbj.2021.03.032. eCollection 2021.
While the intratumor microbiome has become increasingly implicated in cancer development, the microbial landscape of papillary thyroid carcinoma (PTC) is essentially uninvestigated. PTC is characterized by varied prognosis between gender and cancer subtype, but the cause for gender and subtype-based dissimilarities is unclear. Women are more frequently diagnosed with PTC, while men suffer more advanced-staged PTC. In addition, tall cell variants are more aggressive than classical and follicular variants of PTC. We hypothesized that intratumor microbiome composition distinctly alters the immune landscape and predicts clinical outcome between PTC subtypes and between patient genders. Raw whole-transcriptome RNA-sequencing, Level 3 normalized mRNA expression read counts, and DNA methylation 450 k sequencing data for untreated, nonirradiated tumor, and adjacent normal tissue were downloaded from the Genomic Data Commons (GDC) legacy archive for 563 thyroid carcinoma patients. Microbe counts were extracted using Pathoscope 2.0 software. We correlated microbe abundance to clinical variables and immune-associated gene expression. Gene-set enrichment, mutation, and methylation analyses were conducted to correlate microbe abundance to characterize microbes' roles. Overall, PTC tumor tissue significantly lacked microbes that are populated in adjacent normal tissue, which suggests presence of microbes may be critical in controlling immune cell expression and regulating immune and cancer pathways to mitigate cancer growth. In contrast, we also found that microbes distinctly abundant in tall cell and male patient cohorts were also correlated with higher mutation expression and methylation of tumor suppressors. Microbe dysbiosis in specific PTC types may explain observable differences in PTC progression and pathogenesis. These microbes provide a basis for developing specialized prebiotic and probiotic treatments for varied PTC tumors.
虽然肿瘤内微生物群越来越多地被认为与癌症发展有关，但甲状腺乳头状癌（PTC）的微生物情况基本上尚未得到研究。PTC的特点是性别和癌症亚型之间的预后各不相同，但基于性别和亚型的差异原因尚不清楚。女性更常被诊断出患有PTC，而男性患的PTC分期更晚。此外，高细胞变体比PTC的经典和滤泡变体更具侵袭性。我们假设肿瘤内微生物群的组成会明显改变免疫格局，并预测PTC亚型之间以及患者性别之间的临床结果。从基因组数据共享库（GDC）遗留档案中下载了563例甲状腺癌患者未经治疗、未受辐射的肿瘤及相邻正常组织的原始全转录组RNA测序数据、3级标准化mRNA表达读数计数和DNA甲基化450k测序数据。使用Pathoscope 2.0软件提取微生物计数。我们将微生物丰度与临床变量和免疫相关基因表达进行关联。进行基因集富集、突变和甲基化分析，以将微生物丰度与表征微生物作用相关联。总体而言，PTC肿瘤组织明显缺乏在相邻正常组织中存在的微生物，这表明微生物的存在可能对控制免疫细胞表达以及调节免疫和癌症途径以减轻癌症生长至关重要。相比之下，我们还发现，在高细胞和男性患者队列中明显丰富的微生物也与肿瘤抑制因子的较高突变表达和甲基化相关。特定PTC类型中的微生物失调可能解释了PTC进展和发病机制中可观察到的差异。这些微生物为开发针对不同PTC肿瘤的专门益生元和益生菌治疗提供了基础。
