Pan-Cancer Landscape Analysis Reveals Recurrent KMT2A-MAML2 Gene Fusion in Aggressive Histologic Subtypes of Thymoma

Abstract

PURPOSE Thymomas are epithelial neoplasms that represent the most common thymic tumors in adults. These tumors have been shown to harbor a relatively low mutational burden. As a result, there is a lack of genetic alterations that may be used prognostically or targeted therapeutically for this disease. Here, we describe a recurrent gene rearrangement in type B2 + B3 thymomas. PATIENTS AND METHODS A single index case of thymoma was evaluated by an RNA-based solid fusion assay. Separately, tissues from 255,008 unique advanced cancers, including 242 thymomas, were sequenced by hybrid capture–based next-generation DNA sequencing/comprehensive genomic profiling of 186 to 406 genes, including lysine methyltransferase 2A ( KMT2A) rearrangements, and a portion were evaluated for RNA of 265 genes. We characterized molecular and clinicopathologic features of the pertinent fusion-positive patient cases. RESULTS We identified 11 patients with thymomas harboring a gene fusion of KMT2A and mastermind-like transcriptional coactivator 2 ( MAML2). Fusion breakpoints were identified between exon 8, 9, 10, or 11 of KMT2A and exon 2 of MAML2. Fifty-five percent were men, with a median age of 48 years at surgery (range, 29-69 years). Concurrent genomic alterations were infrequent. The 11 thymomas were of B2 or B3 type histology, with 1 case showing foci of thymic carcinoma. The frequency of KMT2A- MAML2 fusion was 4% of all thymomas (10 of 242) and 6% of thymomas of B2 or B3 histology (10 of 169). CONCLUSION KMT2A- MAML2 represents the first recurrent fusion described in type B thymoma. The fusion seems to be specific to type B2 and B3 thymomas, the most aggressive histologic subtypes. The identification of this fusion offers insights into the biology of thymoma and may have clinical relevance for patients with disease refractory to conventional therapeutic modalities.

Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1–KMT2A–YAP1 and VIM–KMT2A fusions

“…A fraction of sarcomas remain unclassified or difficult to classify based on histologic and immunohistochemical profile, with no putative driver mutation identified [ 2 ]. Recently, oncogenic rearrangements involving Lysine methyltransferase 2A ( KMT2A ), a frequent fusion partner in some acute leukemias, have been reported in solid tumors, including types B2 and B3 thymomas and soft tissue sarcomas [ 3 – 7 ]. Yoshida et al first described two soft tissue sarcomas with KMT2A rearrangements, one each to the partners yes-associated protein 1 ( YAP1) and vimentin ( VIM ) [ 3 ].…”

Molecular pathology of thymomas: implications for diagnosis and therapy

“…Overcoming the unacceptable frequency and severity of immune checkpoint inhibitor (ICI)induced autoimmune side effects and simultaneously maintaining ICI therapeutic efficiency is another perspective [20]. The recently described translocations, YAP1-MAML2 and KMT2A-MAML2 in rare metaplastic and type B2 and B3 thymomas, respectively, are currently not specifically targetable either [45,46]. However, it will be important to investigate, whether the respective fusion proteins depend in a similar way on unmutated EGFR signaling for their tumorigenic function as does the CRTC1-MAML2 fusion protein in EGFR inhibitor-sensitive mucoepidermoid carcinomas [72].…”

“…Recurrent KMT2A-MAML2 translocations were recently identified in 6% of clinically aggressive type B2 and B3 thymomas and a single case of combined TC (B3 thymoma with small TC component) [ 46 ]. The translocations variably involved exons 8, 9, 10, or 11 of KMT2A and exon 2 of MAML2 , and are highly characteristic of type B2 and B3 thymomas, because they were previously found only in very rare leukemias, myelodysplastic syndromes, and one plasmacytoma but not in any other tumor among over 250.000 cases sequenced by Foundation Medicine, including 266 thymic carcinomas [ 46 ].…”

“…Recurrent KMT2A-MAML2 translocations were recently identified in 6% of clinically aggressive type B2 and B3 thymomas and a single case of combined TC (B3 thymoma with small TC component) [ 46 ]. The translocations variably involved exons 8, 9, 10, or 11 of KMT2A and exon 2 of MAML2 , and are highly characteristic of type B2 and B3 thymomas, because they were previously found only in very rare leukemias, myelodysplastic syndromes, and one plasmacytoma but not in any other tumor among over 250.000 cases sequenced by Foundation Medicine, including 266 thymic carcinomas [ 46 ]. The function of the respective fusion proteins in thymomas is currently unclear, but might be oncogenic drivers, since 7 of the 11 cases did not harbor any concurrent mutations, while the four others showed only single additional mutations/variants in TP53 , ARID1A, SFB1 , and the TERT promoter [ 46 ].…”

“…Recurrent molecular alterations with potential differential diagnostic relevance in TETs. Radovich et al 2018[10]; Feng et al 2017[39]; Petrini et al 2015[12]; Viviero et al 2020[45]; Massoth et al 2020[46] …”