Genomic insights into molecular profiling of thymic carcinoma: a narrative review
Review Article

Genomic insights into molecular profiling of thymic carcinoma: a narrative review

So Takata

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

Correspondence to: So Takata, MD, PhD. Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, 565-0871 Suita, Osaka, Japan. Email: sotakata@imed3.med.osaka-u.ac.jp.

Background and Objective: Thymic carcinoma is an exceptionally rare cancer, with an annual incidence of just 0.15–0.29 per 100,000 people. Owing to its rarity, only few proven treatments have been developed. Understanding its genetic profile is crucial for the development of targeted therapies. However, limited studies have exclusively examined thymic carcinoma mutations, with most investigation combining thymomas and thymic carcinomas. This paper reviews findings from genetic studies focusing on thymic carcinoma alone and compares them to those of thymoma.

Methods: We conducted a PubMed search for relevant English studies on thymic carcinoma genomics. Then, key papers utilizing target sequencing or whole-exome sequencing were analyzed.

Key Content and Findings: The most frequently mutated genes were TP53, CDKN2A, CDKN2B, CYLD, KIT, TET2, SETD2, BAP1, and ASXL1. TP53 and CDKN2A are correlated with poor prognosis. CYLD, which regulates signaling related with proliferation and interacts with AIRE expression and T cell development, might predict the immunotherapy response. KIT mutations might enable targeted therapy. TET2, SETD2, BAP1, and ASXL1 regulate epigenetics, suggesting disruption of these mechanisms. Higher tumor mutational burden (TMB) and 16q loss distinguish thymic carcinoma from thymoma. Although some copy number aberrations are shared, thymic carcinoma exhibits a mutational profile distinct from that of thymoma.

Conclusions: Thymic carcinoma demonstrates a unique genomic landscape, suggesting a molecular pathogenesis distinct from that of thymoma. Our findings revealed prognostic biomarkers such as TP53/CDKN2A and potential therapeutic targets such as KIT. Because thymic carcinoma is extremely rare, sharing molecular profiling data could provide valuable insights into the molecular mechanisms driving the development of these tumors.

Keywords: Thymic carcinoma; genomics; mutation; copy number aberration

Received: 10 January 2024; Accepted: 10 April 2024; Published online: 05 June 2024.

doi: 10.21037/med-24-5

Introduction

Background

Thymic carcinoma is a rare form of thymic epithelial tumor originating in the thymus. The overall incidence of thymic carcinoma in Japan is 0.15–0.29 per 100,000 person-years (1,2). Owing to its rarity, evidence-based treatments are limited. Notably, approximately around half of the patients with thymic carcinoma patients are unsuitable candidates for surgery (2,3), emphasizing the importance of exploring their genomic profile is crucial for an internal medicine approach.

Regarding treatment, multi-target tyrosine kinase inhibitors (TKIs) and immune checkpoint blockade (ICB) have been one of the treatment options. Sunitinib and lenvatinib showed response rates of 26% and 38% respectively in thymic carcinomas. ICB showed durable responses in 20–25% of patients with thymic carcinoma (4-6). Also, several trials of combination of TKI and chemotherapy or ICB are ongoing (4,7). The reports for genomic findings of thymic carcinoma aimed at elucidating novel therapeutic targets and biomarkers predictive of response are limited.

Rationale and knowledge gap

Although thymic carcinoma is typically classified as a thymic epithelial tumor, Radovich et al. proposed it as a distinct entity of thymic epithelial tumors (8). Numerous studies have examined genomic alterations in thymic tumors, including both thymomas and thymic carcinomas. However, only a few studies have specifically focused on thymic carcinoma, owing to its uncommon nature. Therefore, our search was focused on the genomic profiles of thymic carcinoma. Furthermore, genomic findings varied depending on whether targeted or whole-exome sequencing was used.

Objective

Our objective was to provide comprehensive summary of the genomic discoveries related to thymic carcinoma. I present this article in accordance with the Narrative Review reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-24-5/rc).

Methods

We systematically searched for relevant studies published on PubMed from 1982 to 2023, utilizing various combinations of the terms “thymic” and “thymus”. Articles related to genomics were selected by reviewing abstracts. Additional papers were identified by checking cited references and examining reference lists. Publications published in languages other than English were excluded. Data extraction was performed based on their relevance to the topic. Additional details of this method are presented in Table 1.

Table 1

The search strategy summary

Items Specification
Date of search 2023/6/1 to 2023/7/1
Databases and other sources searched PubMed and Web of Science
Search terms used Thymus and thymic
Timeframe 1982–2023
Inclusion criteria Original article and review article regarding the genomic features of thymic carcinoma published in English
Selection process S.T. did the search and selected the manuscript

Results

Recurrent mutations

The most frequently mutated genes depend on the panel list of target genes, and these recurrent mutations are detailed in Table 2.

Table 2

Genomic profiling of thymic carcinoma patients

Report No. Method Number* Histological subtype [number of patients] Genetic variations in each subtype Number of target genes Mutation [number of patients] Country Sample Authors Year
1 WES 10, 0 Sq [9], Undif [1] Accessible – TET2 [3], ARID1B [2], CYLD [2], SETD2 [2] Japan FF Saito et al. (9) 2017
2 WES 9, 1 Sq [4], Undif [4], LCNEC [1], unknown [1] Accessible – TP53 [1], NRAS [1] USA FF Radovich et al. (8) 2018
3 WES 19 (TC) – No – KMT2C [2], CYLD [2], NCOA1 [2], NOTCH1 [2],
NSD1 [2], WHSC1L1 [2]		 China FF Fang et al. (10) 2021
4 WES 9 (TC) – No – MYO16 [3] China FFPE Yang et al. (11) 2023
5 WES & TS 16 (TC) Sq [5], Undif [6], NEC [1], unknown [4] No 197 TP53 [4], CYLD [3], BAP1 [2], PBRM [2], CDKN2A [2] USA FF and FFPE Petrini et al. (12) 2014
6 WES & TS 11 (TC) – No – CYLD [3], TP53 [2] USA No information Ardeshir-Larijani et al. (13) 2023
7 TS 42, 5 – No 197 TP53 [12], BAP1 [6], CYLD [4], KIT [4], DNMT3A [4], SETD2 [4], TET3 [6.4%] USA FFPE Wang et al. (14) 2014
8 TS 12, 0 Sq [12] No 409 NF1 [2] Japan FF Shitara et al. (15) 2014
9 TS 15 (TC) Sq [14], Undif [1] No 275 TP53 [4], KDM6A [3], SMAD4 [2], CYLD [2], SETD2 [2], KMT2C [2], KMT2D [2] USA FF and FFPE Moreira et al. (16) 2015
10 TS 15 (TC) No 22 PIK3CA [2] China FFPE Song et al. (17) 2016
11 TS 52§ Sq [47], Ad [2], SCC [1], poorly differentiated carcinoma [7], NOS [7] No 50 TP53 [4], KRAS [2] Japan FF and FFPE Asao et al. (18) 2016
12 TS 34, 1 Sq [34], LEL [1] No 50 TP53 [9], CDKN2A [4], FGFR3 [2], KIT [2] Austria FFPE Enkner et al. (19) 2017
13 TS 5 (TC) – No 315 KMT2C [5], ARID1A [5], MAP3K1 [5] China No information Chen et al. (20) 2020
14 TS 15, 0 Sq [6], LEL [3], Ad [2], basaloid [4] Accessible 50 FGFR3 [5], CDKN2A [3], SMARCB1 [2] Italy FFPE Asselta et al. (21) 2021
15 TS 48, 6 Sq [44], Ad [4], carcinoid [5], LCNEC [1] Accessible 50 TP53 [12], KIT [4], PDGFRA [3], PIK3CA [3], EGFR [2], KRAS [2], FBXW [2], VHL [2] Japan FFPE Sakane et al. (22) 2021
16 TS 15, 4 Sq [10], LEL [1], Ad [1], unknown [3], carcinoid [2], SCC [1], undefined [1] Accessible 450 TC: CDKN2A [9], CYLD [6], CDKN2B [5], TP53 [4] China FFPE Wang et al. (23) 2021
TNET: MEN1 [2]
17 TS 28, 6 Sq [23], basaloid [1], Ad [1], Muco [1], NUT [1], LCNEC [6], NOS [1] No 15 TP53 [8], KIT [2], ERBB2 [2] Poland FFPE Szpechcinski et al. (24) 2022
18 TS 174 Sq [69], Undif [54], NEC [30], LEL [5], basaloid [5], Ad [7], sarcomatoid [4] Accessible 315 CDKN2A [65], CDKN2B [45], TP53 [44], CYLD [19], KIT [15], BAP1 [13] USA FFPE Girard et al. (25) 2022
19 TS 8, 0 Sq [5], Ad [3] No 315 KMT2C [5], NFKBIA [3], TET2 [3], TP53 [2], RPTOR [2], ASXL1 [2], BRCA2 [2] China FFPE Tan et al. (26) 2023
20 TS 414 (FMI), 52 (CCAT) – No 324 FMI: CDKN2A [165], TP53 [125], CDKN2B [102], BAP1 [34], TET2 [33], KIT [33], SETD2 [32], NFKBIA [32], ASXL1 [29], KMT2D [25] USA and Japan FFPE Kurokawa et al. (27) 2023
C-CAT: CDKN2A [20], TP53 [19], CDKN2B [16], KMT2D [12], MTAP [12], NFKBIA [11]
21 Other† 7, 0 Sq [7] No 12 KIT [2], KRAS [1] USA FF Girard et al. (28) 2009
22 Other‡ 48, 6 Sq [44], Ad [4], carcinoid [5], LCNEC [1] Accessible 6 KRAS [6], HRAS [3], TP53 [5] Japan FFPE Sakane et al. (29) 2019

Listed with a frequency more than 5% in each cohort. *, the number of patients with thymic carcinoma and thymic neuroendocrine tumor were described respectively; †, array-based comparative genomic hybridization; ‡, single-base extension multiplex assay; §, total patients number was 64, of which 52 patients were analyzed for genetic testing. WES, whole exome sequencing; TS, target sequencing; FMI, Foundation Medicine Inc.; CCAT, Center for Cancer Genomics and Advanced Therapeutics; Sq, squamous; Undif, undifferentiated carcinoma; LCNEC, large cell neuroendocrine carcinoma; NEC, neuroendocrine carcinoma; Ad, adenocarcinoma; SCC, small cell carcinoma; Muco, mucoepidermoid carcinoma; NOS, not otherwise specified; LEL, lympho-epithelial carcinoma; NUT, NUT carcinoma; C-CAT, Center for Cancer Genomics and Advanced Therapeutics; FF, fresh frozen; FFPE, formalin-fixed paraffin-embedded; TC, thymic carcinoma; TNET, thymic neuroendocrine tumor.

The results of whole-exome sequencing vary across different reports. Subsequently, recurrently reported mutations were focused. The most frequently reported genes were TP53, CDKN2A, CDKN2B, CYLD, KIT, TET2, SETD2, BAP1, ASXL1 and FGFR3 (Table 2). The pathological finding of immunohistochemical staining for TP53 was strongly correlated with TP53 mutations in patients with thymic carcinoma, similar to observations in other cancer types (30), and TP53 mutations were associated with poor prognosis (16). Cyclin dependent factor such as CDKN2A and CDKN2B were also frequently reported genes. Particularly, loss of p16INK4A (encoded by CDKN2A) expression due to a homozygous CDKN2A deletion was confirmed to be correlated with a worse prognosis, including earlier recurrence and shorter overall survival (31). Both TP53 and CDKN2A are recurrently mutated and have been confirmed to be associated with poor prognosis. CYLD is a deubiquitinating enzyme, that regulates cell signaling pathways (32). COSMIC, the Catalogue of Somatic Mutations in Cancer, explain that CYLD gene role as tumor suppressor gene according to its multiple role such as regulator of multiple pathway involving EGFR pathway. CYLD is related with angiogenesis (33), which is one of central pathways of thymic carcinoma (7). In addition, its position locates in chromosome 16q, of which copy number loss is characteristic to thymic carcinoma (8). Additionally, it is related with differentiation and maturation of medullary thymic epithelial cells and the regulation of AIRE expression, essential for T cell development (34). The reported frequency of truncating mutations in CYLD in patients with thymic carcinoma through whole exome sequencing suggesting that loss of function of CYLD can influence tumorigenesis. Moreover, CYLD mutations can serve as candidate biomarkers for the response to ICB. In a small phase 2 study using pembrolizumab in thymic carcinoma patients, the responder group had a higher ratio of CYLD mutations than the non-responder group (35). This result may be related to the upregulation of PD-L1 expression via interferon gamma, resulting in the down-regulation of CYLD in vitro (36). In contrast, target sequencing did not reveal many CYLD mutations, as shown in Table 2. This is because CYLD is not included in the many of the panel lists of mutations. Further, KIT mutations are one of the druggable mutations. Buti et al. reported a patient with thymic carcinoma harboring KIT mutation showed an impressive response to imatinib treatment (37). Although two related small phase 2 studies using imatinib reported no response in patients with unselected thymic epithelial tumors (and possibly wild-type cKIT) (38), targeted therapy can be one of the treatment options for patients with thymic carcinoma who have KIT mutations. TET2 mutation is mainly reported by Saito et al. (9). They identified three mutations in ten Japanese patients with thymic carcinoma. TET2 affects DNA demethylation by converting 5methylcytosine to 5-hydroxymethylcytosine, resulting in abnormal genomic hypermethylation and reduced repression of hypermethylated genes in acute myeloid leukemia (39). The author further analyzed the methylation status using the bead array method and emphasized the difference in the methylation status of TET2 mutation-positive and TET2 mutation-negative patients. Another group identified recurrent mutations in histone modification-related genes, such as SETD2, BAP1, and ASXL1. The authors suggested that a possible disruption of epigenetic regulation in thymic carcinoma, which is a characteristic of genome that differs from that of thymoma. Additionally, several epigenomic alteration of thymic carcinoma has been found, for example, abnormal methylation of KSR1, ELF3, IL1RN, and RAG1 (40). FGFR3 mutations were found (26.6%) in four patients with thymic carcinoma in the report of Asselta et al. Also, the patients with FGFR3 mutations conferred a statistically significant survival advantage in addition to the lower proliferation fraction using Ki-67 estimation. Dysregulation of the FGFR signaling pathway through genetic alterations in FGFR2/3 is implicated in driving carcinogenesis across various solid tumor types (21).

Because most of thymic carcinoma is squamous cell carcinoma, these recurrent genomic finding could be regarded as the characteristics of squamous cell carcinoma of thymus. Its rarity of other subtypes led disability of finding recurrent mutations in another subtypes. Thereafter focusing on unique mutation even if found in a few patients, two basaloid and one lymphoepithelioma-like carcinoma harbored FGFR3 mutations, and a patient with adenocarcinoma intriguingly uniquely had APC out of frame deletion (21).

Mutations in thymic carcinoma compared to thymoma

The largest cohort study on target sequencing of thymic epithelial tumors suggested that CDKN2A, CDKN2B and TP53 were more frequently altered in patients with thymic carcinoma than in those with thymoma (27). Additionally, SETD2 mutations were common in both groups, which is consistent with another cohort study findings (14). Notably, CYLD mutation was specific to thymic carcinoma (12,14). Although this finding is intriguing, validation is required because the gene panel lists used in many other studies do not include the CYLD gene. Therefore, further analysis of large-scale cohorts is necessary. Regarding KIT mutations, a few thymic carcinoma patients had that, and one patient harbor pathogenic KIT p.(Leu576Pro) variant. Although a few thymoma patients had KIT mutations, they were considered variants of unknown significance, different from those observed in patients with thymic carcinoma (24). TET2 mutations, emphasized by Saito et al. (9), were also unique to patients with thymic carcinoma in a study by Tan et al. (thymic carcinoma 3/8; thymoma 0/39) (26). BAP1 mutations were slightly more common in patients with thymic carcinoma; however, they were also observed in some thymoma patients (12,14). ASXL1 mutations were recurrent but not frequently enough to be evaluated.

Tumor mutational burden (TMB) and microsatellite instability (MSI) status

TMB is higher in thymic carcinomas than in thymic tumors, as indicated in several reports (8,25,27). However, thymic carcinomas exhibit elevated TMB compared to thymomas (8), accounting for 6–7% of cases (15,20). In addition, although few reports on MSI status are limited, the two largest studies utilizing target-sequencing indicate that high MSI cases are rare, ranging from 0–2.3% (25,27). Because of its rarity, it remains unclear whether the incidence of immune-related adverse events (irAEs) from ICB treatment is higher among thymic carcinoma patients compared to those with other solid tumors. Meanwhile, irAEs by using ICB for thymoma patients has reported clearly more frequently than individuals with other solid tumors (21). ICB can be a treatment option for patients with thymic carcinoma, although careful judgment is essential as a problem specific to immune organ (41).

Shared and divergent of copy number variations of thymic carcinoma and thymoma

The Cancer Genome Atlas (TCGA) project revealed that chromosome 16q loss is more common in thymic carcinoma than in thymoma (8). They estimated arm and focal-level copy number aberrations in 117 thymic epithelial tumor samples (107 thymomas and 10 thymic carcinomas). Also, chromosome 1q amplification and chromosome 6p and 6q loss were common in both thymic carcinomas and thymomas. This observation, consistent with prior report (42), has led to the hypothesis that thymomas (especially type B3 thymomas) and thymic carcinomas may represent sequential pathologies. However, the validity of this hypothesis remains unclear. The TCGA study revealed thymic carcinoma as distinct group with respect to molecular pathogenesis, based on multiomics analysis involving whole-exome sequencing. The assertion is further supported by the detection of only two cases of combined thymic carcinoma and B3 thymomas among a substantial cohort of more than 600 thymomas, inclusive of type B2 and B3 thymomas (43). However, this concept does not entirely exclude the possibility of malignant transformation from thymoma to thymic carcinoma. Thymic carcinoma typically develops de novo, the copy number aberrations observed in thymic squamous tumors differ from those in squamous cells of other organs such as lung cancer (28), Despite these characteristics, given that thymoma and thymic carcinoma share chromosome 1q amplification and chromosome 6 loss, the possibility of thymoma rarely transforming in thymic carcinoma persists. Unlike the mixed types, there are reports of two cases that were diagnosed as thymoma at the time of initial diagnosis and were diagnosed as thymic carcinoma after a period of time (15 and 40 years later) (44,45). The transformation is challenging to study because of its rarity, however, it can be revealed by genomic profiling of heterochronic samples from the same patient who showed transformation from thymoma to thymic carcinoma.

Mutational signature

Saito et al. (9) reported mutational signatures in all analyzed patients with thymic carcinoma. The majority group, consisted of 8 out of 10 instances, exhibited primarily COSMIC signature 1 (clock-like, http://cancer.sanger.ac.uk/cosmic/signatures), associated with the spontaneous deamination of 5-methylcytosine. However, two cases stood out in the minority group, displaying COSMIC signatures 5 (clock-like) and 6 (DNA mismatch repair deficit). Additionally, a patient with TCGA referral demonstrated an unusually high TMB, showcasing a mutational pattern similar to COSMIC signature 6. This patient presented a pathogenic nonsense mutation of MLH1, accompanied by a lack of its expression.

Conclusions

Thymic carcinomas have unique genomic profiles compared to thymomas, however, they share certain copy number aberrations. These mutations may present novel targets for therapeutic approaches.

Acknowledgments

We would like to thank Editage (www.editage.jp) for English language editing.

Funding: This work was supported by the Japan Society for the Promotion of Science KAKENHI (23K19534) and the Osaka Medical Research Foundation for Intractable Diseases (29-1-23).

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Masatsugu Hamaji) for the series “Locally Advanced Thymic Epithelial Tumors” published in Mediastinum. The article has undergone external peer review.

Reporting Checklist: The author has completed the Narrative Review reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-24-5/rc

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-24-5/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-24-5/coif). The series “Locally Advanced Thymic Epithelial Tumors” was commissioned by the editorial office without any funding or sponsorship. The author has no other conflicts of interest to declare.

Ethical Statement: The author is 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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doi: 10.21037/med-24-5
Cite this article as: Takata S. Genomic insights into molecular profiling of thymic carcinoma: a narrative review. Mediastinum 2024;8:39.

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