Skálová Alena, Bradová Martina, Agaimy Abbas, Laco Jan, Badual Cécile, Ihrler Stephan, Damjanov Ivan, Rupp Niels J, Bacchi Carlos E, Mueller Sarina, Ventelä Sami, Zhang Da, Comperat Eva, Martínek Petr, Šíma Radek, Vaněček Tomas, Grossmann Petr, Steiner Petr, Hájková Veronka, Kovářová Inka, Michal Michal, Leivo Ilmo
Department of Pathology, Charles University, Faculty of Medicine in Pilsen.
Bioptic Laboratory Ltd.
Am J Surg Pathol. 2025 Mar 1;49(3):227-242. doi: 10.1097/PAS.0000000000002349. Epub 2025 Jan 6.
Adenoid cystic carcinomas (AdCC) of salivary gland origin have long been categorized as fusion-defined carcinomas owing to the almost universal presence of the gene fusion MYB::NFIB , or less commonly MYBL1::NFIB. Sinonasal AdCC is an aggressive salivary gland malignancy with no effective systemic therapy. Therefore, it is urgent to search for potentially targetable genetic alterations associated with AdCC. We have searched the authors' registries and selected all AdCCs arising in the sinonasal tract. The tumors were examined histologically, immunohistochemically, by next generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH) looking for MYB/MYBL1 and/or NFIB gene fusions or any novel gene fusions and/or mutations. In addition, all tumors were tested for HPV by genotyping using (q)PCR. Our cohort comprised 88 cases of sinonasal AdCC, predominantly characterized by canonical MYB::NFIB (49 cases) and MYBL1::NFIB (9 cases) fusions. In addition, noncanonical fusions EWSR1::MYB ; ACTB::MYB; ESRRG::DNM3 , and ACTN4::MYB were identified by NGS, each of them in 1 case. Among nine fusion-negative AdCCs, FISH detected rearrangements in MYB (7 cases) , NFIB (1 case), and EWSR1 (1 case). Six AdCCs lacked fusions or gene rearrangements, while 11 cases were unanalyzable. Mutational analysis was performed by NGS in 31/88 (35%) AdCCs. Mutations in genes with established roles in oncogenesis were identified in 21/31 tumors (68%), including BCOR (4/21; 19%), NOTCH1 (3/21; 14%), EP300 (3/21; 14%), SMARCA4 (2/21; 9%), RUNX1 (2/21; 9%), KDM6A (2/21; 9%), SPEN (2/21; 9%), and RIT1, MGA, RB1, PHF6, PTEN, CREBBP, DDX41, CHD2, ROS1, TAF1, CCD1, NF1, PALB2, AVCR1B, ARID1A, PPM1D, LZTR1, GEN1 , PDGFRA , each in 1 case (1/21; 5%). Additional 24 cases exhibited a spectrum of gene mutations of uncertain pathogenetic significance. No morphologic differences were observed between AdCCs with MYBL1::NFIB and MYB::NFIB fusions. Interestingly, mutations in the NOTCH genes were seen in connection with both canonical and noncanonical fusions, and often associated with high-grade histology or metatypical phenotype, as well as with poorer clinical outcome. Noncanonical fusions were predominantly observed in metatypical AdCCs. These findings emphasize the value of comprehensive molecular profiling in correlating morphologic characteristics, genetic landscape, and clinical behavior in AdCC.
长期以来，涎腺来源的腺样囊性癌（AdCC）一直被归类为融合定义的癌，因为几乎普遍存在基因融合MYB::NFIB，或较少见的MYBL1::NFIB。鼻窦AdCC是一种侵袭性涎腺恶性肿瘤，尚无有效的全身治疗方法。因此，迫切需要寻找与AdCC相关的潜在可靶向基因改变。我们检索了作者的病例库，选择了所有起源于鼻窦的AdCC。对肿瘤进行了组织学、免疫组织化学检查，通过二代测序（NGS）和/或荧光原位杂交（FISH）寻找MYB/MYBL1和/或NFIB基因融合或任何新的基因融合和/或突变。此外，所有肿瘤均通过（q）PCR基因分型检测HPV。我们的队列包括88例鼻窦AdCC，主要特征为典型的MYB::NFIB（49例）和MYBL1::NFIB（9例）融合。此外，通过NGS鉴定出非典型融合EWSR1::MYB、ACTB::MYB、ESRRG::DNM3和ACTN4::MYB，各1例。在9例融合阴性的AdCC中，FISH检测到MYB重排（7例）、NFIB重排（1例）和EWSR1重排（1例）。6例AdCC缺乏融合或基因重排，11例无法分析。31/88（35%）例AdCC通过NGS进行了突变分析。在21/31（68%）例肿瘤中鉴定出在肿瘤发生中起既定作用的基因突变，包括BCOR（4/21；19%）、NOTCH1（3/21；14%）、EP300（3/21；14%）、SMARCA4（2/21；9%）、RUNX1（2/21；9%）、KDM6A（2/21；9%）、SPEN（2/21；9%）以及RIT1、MGA、RB1、PHF6、PTEN、CREBBP、DDX41、CHD2、ROS1、TAF1、CCD1、NF1、PALB2、AVCR1B、ARID1A、PPM1D、LZTR1、GEN1、PDGFRA，各1例（1/21；5%）。另外24例表现出一系列致病意义不确定的基因突变。MYBL1::NFIB和MYB::NFIB融合的AdCC之间未观察到形态学差异。有趣的是，NOTCH基因突变与典型和非典型融合均有关，且常与高级别组织学或化生型表型以及较差的临床结局相关。非典型融合主要见于化生型AdCC。这些发现强调了全面分子谱分析在关联AdCC形态学特征、基因图谱和临床行为方面的价值。
