Nasal intestinal-type adenocarcinomas (ITAC) are strongly related to chronic wood dust exposure: The intestinal phenotype relies on CDX2 overexpression but underlying molecular mechanisms remain unknown. Our objectives were to investigate transcriptomic and methylation differences between healthy non-exposed and tumor olfactory cleft mucosae and to compare transcriptomic profiles between non-exposed, wood dust-exposed and ITAC mucosa cells. We conducted a prospective monocentric study (NCT0281823) including 16 woodworkers with ITAC, 16 healthy exposed woodworkers and 13 healthy, non-exposed, controls. We compared tumor samples with healthy non-exposed samples, both in transcriptome and in methylome analyses. We also investigated wood dust-induced transcriptome modifications of exposed (without tumor) male woodworkers’ samples and of contralateral sides of woodworkers with tumors. We conducted in parallel transcriptome and methylome analysis, and then, the transcriptome analysis was focused on the genes highlighted in methylome analysis. We replicated our results on dataset GSE17433. Several clusters of genes enabled the distinction between healthy and ITAC samples. Transcriptomic and IHC analysis confirmed a constant overexpression of CDX2 in ITAC samples, without any specific DNA methylation profile regarding the CDX2 locus. ITAC woodworkers also exhibited a specific transcriptomic profile in their contralateral (non-tumor) olfactory cleft, different from that of other exposed woodworkers, suggesting that they had a different exposure or a different susceptibility. Two top-loci (CACNA1C/CACNA1C-AS1 and SLC26A10) were identified with a hemimethylated profile, but only CACNA1C appeared to be overexpressed both in transcriptomic analysis and in immunohistochemistry. Several clusters of genes enable the distinction between healthy mucosa and ITAC samples even in contralateral nasal fossa thus paving the way for a simple diagnostic tool for ITAC in male woodworkers. CACNA1C might be considered as a master gene of ITAC and should be further investigated. Trial registration: NIH ClinicalTrials, NCT0281823, registered May 23d 2016, https://www.clinicaltrials.gov/NCT0281823 .

中文翻译：

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鼻肠型腺癌的综合基因组学分析证明了 CACNA1C 的主要作用，并为男性木工的简单诊断工具铺平了道路

鼻肠型腺癌 (ITAC) 与慢性木屑暴露密切相关：肠道表型依赖于 CDX2 过表达，但潜在的分子机制仍然未知。我们的目标是研究健康未暴露和肿瘤嗅裂黏膜之间的转录组和甲基化差异，并比较未暴露、木屑暴露和 ITAC 黏膜细胞之间的转录组学特征。我们进行了一项前瞻性单中心研究 (NCT0281823)，包括 16 名患有 ITAC 的木工、16 名健康的暴露木工和 13 名健康、未暴露的对照。我们在转录组和甲基化组分析中将肿瘤样本与健康的未暴露样本进行了比较。我们还研究了暴露（无肿瘤）男性木工样本和有肿瘤的木工对侧的木屑诱导的转录组修饰。我们进行了平行的转录组和甲基化组分析，然后，转录组分析的重点是甲基化组分析中突出显示的基因。我们在数据集 GSE17433 上复制了我们的结果。几个基因簇能够区分健康样本和 ITAC 样本。转录组学和 IHC 分析证实了 ITAC 样品中 CDX2 的持续过表达，没有关于 CDX2 基因座的任何特定 DNA 甲基化谱。ITAC 木工在其对侧（非肿瘤）嗅裂中也表现出特定的转录组学特征，与其他暴露在外的木工不同，表明他们有不同的暴露或不同的敏感性。两个顶级位点（CACNA1C/CACNA1C-AS1 和 SLC26A10）被鉴定为具有半甲基化谱，但在转录组分析和免疫组织化学中似乎只有 CACNA1C 过表达。即使在对侧鼻窝中，几个基因簇也能够区分健康粘膜和 ITAC 样本，从而为男性木工 ITAC 的简单诊断工具铺平了道路。CACNA1C可能被认为是ITAC的主基因，应进一步研究。试验注册：NIH ClinicalTrials，NCT0281823，2016 年 5 月 23 日注册，https://www.clinicaltrials.gov/NCT0281823。但在转录组分析和免疫组织化学中似乎只有 CACNA1C 过表达。即使在对侧鼻窝中，几个基因簇也能够区分健康粘膜和 ITAC 样本，从而为男性木工 ITAC 的简单诊断工具铺平了道路。CACNA1C可能被认为是ITAC的主基因，应进一步研究。试验注册：NIH ClinicalTrials，NCT0281823，2016 年 5 月 23 日注册，https://www.clinicaltrials.gov/NCT0281823。但在转录组分析和免疫组织化学中似乎只有 CACNA1C 过表达。即使在对侧鼻窝中，几个基因簇也能够区分健康粘膜和 ITAC 样本，从而为男性木工 ITAC 的简单诊断工具铺平了道路。CACNA1C可能被认为是ITAC的主基因，应进一步研究。试验注册：NIH ClinicalTrials，NCT0281823，2016 年 5 月 23 日注册，https://www.clinicaltrials.gov/NCT0281823。