Background: Oncogenic fusions ofMAML2withCRTC1,CRTC3,YAP1, andNR1D1retain theMAML2transactivating domain (TAD) and are believed to drive aberrant gene transcription. While the oncogenic roles of these known fusions have been established, we aimed to identify novelMAML2fusions across a range of human malignancies. Methods: DNA and RNA sequencing were performed on tumor samples submitted to Caris Life Sciences.MAML2fusions were identified from RNA transcripts and filtered to include only known pathogenic fusions or recurrent, in-frame fusions containing a C-terminalMAML2TAD. Fusion burden was defined as the number of unique fusion isoforms per sample. Results: Among 180,124 tumor samples, 143 specimens harboredMAML2fusions with aMAML2TAD: >50% of specimens harbored known fusions, but novel fusions withMTMR2(31/143),SESN3(11/143),CCDC82(6/143),FAM76B(4/143), andATXN3(3/143) were also identified. Compared to the known fusions, the novel fusions generally had lower expressions (median: 8 vs. 13 junction reads/sample,p= 0.0064), higher fusion burdens (median: 6 vs. 2 unique fusion isoforms/sample,p< 0.0001), more frequentTP53co-mutations (80% vs. 11.5%,p< 0.0001), and no clear association with the tissue of origin. ExcludingATXN3::MAML2, the novel fusion partners were located nearMAML2in the genome, likely arose from duplications or deletions, and occurred in samples harboring concurrent mutations. In contrast,ATXN3::MAML2arose via interchromosomal translocation, occurred in samples with a low fusion burden, and was not associated with TP53 mutations. Conclusions: We identified novelMAML2fusion partners, most of which likely represent passenger alterations, possibly arising from genomic instability or impaired p53 function. However,ATXN3::MAML2fusions, previously reported in a pre-cancerous pancreatic disease case, may represent a pathogenic alteration warranting further investigation.
背景：MAML2基因与CRTC1、CRTC3、YAP1及NR1D1形成的致癌融合体保留了MAML2的转录激活结构域（TAD），被认为可驱动异常基因转录。尽管这些已知融合体的致癌作用已得到确认，本研究旨在探索人类多种恶性肿瘤中新型MAML2融合体的存在。方法：对提交至Caris生命科学公司的肿瘤样本进行DNA与RNA测序。通过RNA转录本识别MAML2融合体，并筛选仅包含已知致病性融合或重复出现的、含有C端MAML2 TAD的框内融合。融合负荷定义为每个样本中独特融合亚型的数量。结果：在180,124份肿瘤样本中，143例携带含MAML2 TAD的MAML2融合体：超过50%的样本携带已知融合体，但也发现了与MTMR2（31/143）、SESN3（11/143）、CCDC82（6/143）、FAM76B（4/143）及ATXN3（3/143）的新型融合。与已知融合体相比，新型融合体普遍表达水平较低（中位数：8 vs. 13 连接读段/样本，p=0.0064）、融合负荷较高（中位数：6 vs. 2 独特融合亚型/样本，p<0.0001）、TP53共突变频率更高（80% vs. 11.5%，p<0.0001），且与起源组织无明确关联。除ATXN3::MAML2外，新型融合伴侣在基因组中均位于MAML2附近，可能由基因复制或缺失引起，并出现在伴有并发突变的样本中。相比之下，ATXN3::MAML2通过染色体间易位形成，出现在融合负荷较低的样本中，且与TP53突变无关。结论：我们发现了新型MAML2融合伴侣，其中多数可能代表伴随性改变，可能源于基因组不稳定性或p53功能受损。然而，先前在癌前胰腺疾病病例中报道的ATXN3::MAML2融合体可能具有致病性改变，值得进一步研究。
肿瘤(癌症)患者之家