Molecular pathology/genetics of thymic tumors: extended abstract

Genetics of thymic epithelial tumors (TETs)

Comprehensive profiling of genetic or chromosomal abnormalities and gene expression has significantly advanced our molecular understanding of TETs. The most valuable discovery in TET genetics was made by Petrini et al. (1), who found that TETs can harbor the general transcription factor IIi (GTF2I) L424H variant: GTF2I(NM_032999.4):c.1271T>A p.(Leu424His). The significance of this finding is highlighted by two observations. First, this variant is common to TETs. The original study reported that the frequency in type A, AB, B1, B2, and B3 thymomas, and thymic carcinoma is 82%, 74%, 32%, 22%, 21%, and 8%, respectively (1). This high frequency contrasts with the fact that TETs have the fewest variants among cancers in humans (2-4). The study conducted as part of The Cancer Genome Atlas (TCGA) project confirmed the subtype dependency because the variant was observed in 100% and 72% of type A and type AB thymomas, respectively, but in 0% to 10% of type B thymomas and thymic carcinomas (2). Second, GTF2I L424H is virtually specific to TETs. Among 10,844 tumors from 31 TCGA studies for non-TETs, only 2 tumors harbored GTF2I L424H (3,4). These findings suggest that GTF2I L424H is biologically relevant in a thymus-specific manner.

Two recent in vivo mouse studies successfully addressed this hypothesis. Giorgetti et al. induced Gtf2i L384H with the Foxn1 promoter into thymic epithelial cells (TECs) and demonstrated that this caused developmental abnormalities of the thymus, such that the border between the cortex and medulla became obscured (5). He et al., the group that first reported GTF2I variant in TETs, established a Foxn1-dependent GTF2I L424H knock-in model and demonstrated that this caused tumor-like expansion of the thymus through proliferation of keratin-positive epithelial cells (6). These in vivo studies have demonstrated the biological significance of the GTF2I variant, and future studies may address the possibility that this variant could be a treatment target. Alternatively, these models could be improved by inducing the transgenes not congenitally but conditionally in adult mice.

Radovich et al. conducted the most comprehensive genomic profiling of TETs to date, as part of the TCGA study cited above (2). According to the study, HRAS, NRAS, and TP53 can be recurrently mutated in TETs, although in minor proportions. One drawback of the TCGA study is that the number of cases may not be sufficient, especially for minor thymoma subtypes and thymic carcinoma. On the other hand, some recent studies enrolled many cases for genetic studies by utilizing gene panel testing, a method that is gaining popularity. Girard et al. genetically analyzed 274 advanced-stage TETs (7). As found with the TCGA dataset, they reported few genomic alterations in thymomas. That study included many thymic carcinomas (n=144) with detailed histological subtypes and noted that even thymic carcinoma generally harbors few variants. A new finding was that CDKN2A and CDKN2B were relatively frequently mutated. A recent study from Japan enrolled the largest number of cases (n=794) (8) and reported results that overlapped substantially with that of Girard et al. (7). Collectively, we can summarize representative TET genetics as follows: (I) GTF2I L424H occurs often in type A and AB thymomas; (II) HRAS variants might be expected in type A thymoma, but the frequency is unconvincing; (III) TP53, CDKN2A, and CDKN2B variants are seen in about 30% of thymic carcinomas; (IV) druggable KIT variants can be detected in around 10% of thymic carcinomas (9); and (V) tumor mutation burden-high and microsatellite instability-high statuses are observed in less than 10% of thymic carcinomas, and these may be useful biomarkers for applying immune checkpoint inhibitors. Thus, it is true that TETs generally lack druggable variants; however, because TETs are rare and establishing treatment strategies based on big data is challenging, each case can be treated based on its unique features, which can be identified through genomic profiling. One example is a thymic carcinoma case that harbored a PI3KCA variant and substantially responded to everolimus (7). Another important finding about TET genetics is that thymomas rarely harbor gene fusions relevant to prognosis or diagnosis. KMT2A-MAML2 fusion in rare type B2 and B3 thymomas and YAP1-MAML2 fusion in metaplastic thymoma should be mentioned here (10,11).

Molecular pathology of TETs

The TCGA project (2) has played a fundamental role in this topic. By combining five omics platforms, it showed that TETs can be divided into four molecular subtypes: A (type A thymoma)-like, AB-like, B-like, and C (thymic carcinoma)-like, which are correlated with histotypes. Of note, the B-like and C-like clusters are entirely separate. A recent review indicated almost no histogenetic link between type B3 thymoma and thymic carcinoma (12). In contrast, recent studies, with the help of the TCGA dataset, have suggested that thymic carcinoma may have a phenotype related to medullary TECs. Our group proposed that thymic carcinoma often exhibits an expression profile similar to that of tuft cells, a unique subset of mTECs (13,14), and another group showed that thymic carcinoma can express AIRE, the representative mTEC gene (15). The functional and therapeutic relevance of this medullary characteristic has not been addressed, and future studies should answer these questions to advance our understanding of TET histogenesis.

Potential role of epigenetics linking genetics and molecular pathology in TETs: closing remarks

The relevance of epigenetic signatures in cancer has been appreciated (16). Indeed, the TCGA study of TETs demonstrated that methylation status alone is highly correlated with histological subtype (2,17). In addition, studies by Wang et al. (18) have indicated that epigenetic regulatory genes, such as BAP1, SETD2, and ASXL1, are recurrently mutated in thymic carcinomas, which was confirmed by a large Japanese study (8). Therefore, future in-depth epigenetic studies might contribute to a more comprehensive understanding of TETs. Accordingly, the significance of loss of 16q, the most common chromosomal abnormality in thymic carcinoma, should be investigated not only because the locus may contain functionally relevant genes for carcinogenesis, but because chromosomal abnormalities can cause global epigenetic alterations (19).

Acknowledgments

Funding: This work was supported by JSPS KAKENHI (Grant Number: JP 21K06902).

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Malgorzata Szolkowska, Chul Kim, Mohammad Ashraghi, and Claudio Silva) for “The Series Dedicated to the 13th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2023)” published in Mediastinum. The article has undergone external peer review.

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-23-55/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-23-55/coif). “The Series Dedicated to the 13th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2023)” was commissioned by the editorial office without any funding or sponsorship. Y.Y. reports funding from JSPS KAKENHI (Grant Number: JP 21K06902). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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