Sipilä Lauri J, Katainen Riku, Aavikko Mervi, Ravantti Janne, Donner Iikki, Lehtonen Rainer, Leivo Ilmo, Wolff Henrik, Holmila Reetta, Husgafvel-Pursiainen Kirsti, Aaltonen Lauri A
Department of Medical and Clinical Genetics, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8), PO Box 63, Helsinki, FI-00014, Finland.
Applied Tumor Genomics, Research Programs Unit, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8), PO Box 63, Helsinki, FI-00014, Finland.
Genes Environ. 2024 May 6;46(1):12. doi: 10.1186/s41021-024-00306-8.
Sinonasal adenocarcinoma is a rare cancer, encompassing two different entities, the intestinal-type sinonasal adenocarcinoma (ITAC) and the non-intestinal-type sinonasal adenocarcinoma (non-ITAC). Occurrence of ITAC is strongly associated with exposure to hardwood dusts. In countries with predominant exposure to softwood dust the occurrence of sinonasal adenocarcinomas is lower and the relative amount of non-ITACs to ITACs is higher. The molecular mechanisms behind the tumorigenic effects of wood dust remain largely unknown.
We carried out whole-genome sequencing of formalin-fixed paraffin-embedded (FFPE) samples of sinonasal adenocarcinomas from ten wood dust-exposed and six non-exposed individuals, with partial tobacco exposure data. Sequences were analyzed for the presence of mutational signatures matching COSMIC database signatures. Driver mutations and CN variant regions were characterized.
Mutation burden was higher in samples of wood dust-exposed patients (p = 0.016). Reactive oxygen species (ROS) damage-related mutational signatures were almost exclusively identified in ITAC subtype samples (p = 0.00055). Tobacco smoke mutational signatures were observed in samples of patients with tobacco exposure or missing information, but not in samples from non-exposed patients. A tetraploidy copy number (CN) signature was enriched in ITAC subtype (p = 0.042). CN variation included recurrent gains in COSMIC Cancer Gene Census genes TERT, SDHA, RAC1, ETV1, PCM1, and MYC. Pathogenic variants were observed most frequently in TP53, NF1, CHD2, BRAF, APC, and LRP1B. Driver mutations and copy number gains did not segregate by subtype.
Our analysis identified distinct mutational characteristics in ITAC and non-ITAC. Mutational signature analysis may eventually become useful for documentation of occupation-related cancer, while the exact mechanisms behind wood dust-driven carcinogenesis remain elusive. The presence of homologous recombination deficiency signatures implies a novel opportunity for treatment, but further studies are needed.
鼻窦腺癌是一种罕见的癌症，包括两种不同的类型，即肠型鼻窦腺癌（ITAC）和非肠型鼻窦腺癌（非ITAC）。ITAC的发生与接触硬木粉尘密切相关。在主要接触软木粉尘的国家，鼻窦腺癌的发生率较低，非ITAC与ITAC的相对比例较高。木粉尘致癌作用背后的分子机制在很大程度上仍不清楚。
我们对来自10名接触木粉尘和6名未接触木粉尘个体的鼻窦腺癌福尔马林固定石蜡包埋（FFPE）样本进行了全基因组测序，并获取了部分烟草暴露数据。分析序列中是否存在与COSMIC数据库特征匹配的突变特征。对驱动突变和拷贝数变异区域进行了表征。
接触木粉尘患者的样本中突变负担更高（p = 0.016）。活性氧（ROS）损伤相关的突变特征几乎仅在ITAC亚型样本中被识别（p = 0.00055）。在有烟草暴露或信息缺失的患者样本中观察到烟草烟雾突变特征，但在未接触患者的样本中未观察到。四倍体拷贝数（CN）特征在ITAC亚型中富集（p = 0.042）。CN变异包括COSMIC癌症基因普查基因TERT、SDHA、RAC1、ETV1、PCM1和MYC的反复扩增。在TP53、NF1、CHD2、BRAF、APC和LRP1B中最常观察到致病变体。驱动突变和拷贝数增加并未按亚型区分。
我们的分析确定了ITAC和非ITAC中不同的突变特征。突变特征分析最终可能有助于记录职业相关癌症，而木粉尘驱动致癌的确切机制仍然难以捉摸。同源重组缺陷特征的存在意味着一个新的治疗机会，但还需要进一步研究。
