Szpechcinski Adam, Szolkowska Malgorzata, Winiarski Sebastian, Lechowicz Urszula, Wisniewski Piotr, Knetki-Wroblewska Magdalena
Department of Genetics and Clinical Immunology, The Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland.
Department of Pathology, The Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland.
Cancers (Basel). 2022 Jul 12;14(14):3388. doi: 10.3390/cancers14143388.
A better understanding of the molecular pathogenesis of thymic epithelial tumours (TETs) could revolutionise their treatment. We evaluated thymomas and thymic carcinomas by next-generation sequencing (NGS) of somatic or germline single nucleotide variants (SNVs) in genes commonly mutated in solid tumours. In total, 19 thymomas and 34 thymic carcinomas were analysed for nonsynonymous SNVs in 15 genes by targeted NGS (reference genome: hg19/GRCh37). Ten SNVs in (G154V, R158P, L194H, R267fs, R273C, R306 *, Q317 *), (V773M), (L576P), and (Q61L) considered somatic and pathogenic/likely pathogenic were detected in 10 of 34 (29.4%) thymic carcinomas. No somatic SNVs confirmed as pathogenic/likely pathogenic were found in thymomas. Rare SNVs of uncertain or unknown functional and clinical significance, to our knowledge not reported previously in TETs, were found in (S703R), (I690V), and (P157S) in 3 of 19 (16%) thymomas. The most frequent germline SNVs were P72R (94% TETs), I655V (40% TETs), and M541L (9% TETs). No significant difference in median disease-free survival (DFS) was found between thymic carcinoma patients with and without pathogenic SNVs ( = 0.190); however, a trend toward a longer DFS was observed in the latter (16.0 vs. 30.0 months, respectively). In summary, NGS analysis of TETs revealed several SNVs in genes related to the p53, AKT, MAPK, and K-Ras signalling pathways. Thymic carcinomas showed greater genetic dysregulation than thymomas. The germline and rare SNVs of uncertain clinical significance reported in this study add to the number of known genetic alterations in TETs, thus extending our molecular understanding of these neoplasms. Druggable KIT alterations in thymic carcinomas have potential as therapeutic targets.
对胸腺上皮肿瘤（TETs）分子发病机制的更好理解可能会彻底改变其治疗方法。我们通过对实体瘤中常见突变基因的体细胞或种系单核苷酸变异（SNV）进行二代测序（NGS）来评估胸腺瘤和胸腺癌。总共对19例胸腺瘤和34例胸腺癌进行了靶向NGS分析（参考基因组：hg19/GRCh37），以检测15个基因中的非同义SNV。在34例（29.4%）胸腺癌中的10例中检测到 （G154V、R158P、L194H、R267fs、R273C、R306*、Q317*）、 （V773M）、 （L576P）和 （Q61L）中的10个SNV，这些SNV被认为是体细胞性的且具有致病性/可能致病性。在胸腺瘤中未发现被确认为致病性/可能致病性的体细胞SNV。在19例（16%）胸腺瘤中的3例中发现了功能和临床意义不确定或未知的罕见SNV，据我们所知，这些SNV此前在TETs中未被报道过，分别存在于 （S703R）、 （I690V）和 （P157S）中。最常见的种系SNV是 P72R（94%的TETs）、 I655V（40%的TETs）和 M541L（9%的TETs）。在有和没有致病性SNV的胸腺癌患者之间，无病生存期（DFS）的中位数没有显著差异（ = 0.190）；然而，在后者中观察到DFS有延长的趋势（分别为16.0个月和30.0个月）。总之，TETs的NGS分析揭示了与p53、AKT、MAPK和K-Ras信号通路相关的基因中的几个SNV。胸腺癌比胸腺瘤表现出更大的基因失调。本研究中报道的种系和临床意义不确定的罕见SNV增加了TETs中已知的基因改变数量，从而扩展了我们对这些肿瘤的分子认识。胸腺癌中可靶向治疗的KIT改变具有作为治疗靶点的潜力。
