Differences and similarities of GTF2I mutated thymomas in different Eurasian ethnic groups

Abstract

Thymic malignancies are rare diseases. They consist mainly of thymomas, carcinomas and neuroendocrine neoplasms. While we commented on the latter entities recently (1,2), we here address the present article of Shimada et al. on thymomas (3). The vast majority of mutational burden in thymoma is related to the general transcription factor II-i (GTF2I) gene. In 2014, Petrini et al. (4) reported a missense mutation (chr7: 74146970 T>A) of GTF2I in 82% in World Health Organization (WHO) type A and in 74% in WHO type AB thymomas. This mutation is exclusively found in thymic epithelial tumors (TETs). Some confusion exists on the position of the thymine-to-adenine exchange (5): Commonly used labeling for the position is p.L383H (5), p.L404H (6-8), and p.L424H (3,9-12). This is explained by different isoforms of the gene, that comprise slight differences in length and sequence. The predominant isoforms are GTF2I β (NM_033000.2) and GTF2I δ (NM_001518.3), leading to the protein annotations p.Leu404His and p.Leu383His, respectively (4). However, when using the standard isoform (NM_032999.4) according to the “The Matched Annotation from the NCBI and EMBL-EBI” program (the National Center for Biotechnology Information and Europäisches Laboratorium für Molekularbiologie - European Bioinformatics Institute program) (MANE select, 11) the same mutation would be annotated as p.Leu424His. This issue highlights the importance of stating the isoform specific ID when annotating a mutation on protein or RNA level. Interestingly, other diseases related to this gene are the inherited Williams-Beuren syndrome, a heterozygous partial microdeletion of chromosome 7q11.23, which amongst many others is characterized by considerable strength in expressive language and a good sense of rhythm; and on the other hand the Somerville-van der Aa syndrome, caused by a chromosome 7q11.23 duplication, whose manifold symptoms include a severe delay in speech and language skills (13,14). Yet, both diseases are not related to thymic abnormalities. Shimada et al. (3) explored the genetic and clinical characteristics of TETs in a Japanese population. The study was conducted between 2013 and 2019. We would like to place the recent article in the current state of knowledge, setting a focus on thymomas and GTF2I mutations. Comparable retrospective publications exist from other Eurasian regions—China, India, and Germany (6,12). A summary of the interethnic results can be found in Table 1 . Table 1 Clinical and pathological characteristics in different ethnic groups of TETs (3,6,12) Characteristics German (n=77) Indian (n=37) Chinese (n=296) Japanese (n=31) Sex, n (%)    Female 33 (42.9) 19 (51.4) 133 (44.9) 21 (67.7)    Male 44 (57.1) 18 (48.6) 163 (55.1) 10 (32.3) Myasthenia gravis, n (%)*    No 13 (52.0) 3 (17.6) 279 (94.3) 22 (77.5)    Yes 12 (48.0) 14 (82.4) 17 (5.7) 7 (22.5) Masaoka-Koga stage, n (%)*    I 16 (20.8) 24 (64.9) 189 (63.9) 12 (38.7)    II 38 (49.4) 9 (24.3) 40 (13.5) 10 (32.3)    III/IV 23 (29.9) 4 (10.8) 67 (22.6) 9 (29.0) GTF2I status, n (%)*    Wildtype 28 (36.4) 12 (35.3) 172 (58.1) 19 (61.3)    p.L424H 9 (63.6) 22 (64.7) 124 (41.9) 12 (38.7) Histological type, n (%)    A 15 (19.5) 8 (21.6) 23 (7.8) 1 (3.2)    AB 31 (40.3) 21 (56.8) 89 (30.1) 11 (35.5)    Atypical A/AB 15 (19.5) 2 (5.4) Not mentioned Not mentioned    B 16 (20.8) 6 (16.2) 145 (49.0) 17 (54.8) Carcinoma, n (%) Excluded Excluded 39 (13.2) 2 (6.5) Median age, years 65 50 49 63 *, data in some patients missing, therefore n is lower than in the entire cohort. TETs, thymic epithelial tumors; GTF2I, general transcription factor II-i. The Japanese group is the smallest with 31 patients, but the only prospective. The female to male ratio of 2:1 is in contrast to the reported more or less equal sex distribution in other series. Shimada et al. report 38.7% of GTF2I mutated thymoma in their series, reflecting the lowest rate amongst the groups. This correlates with the lowest proportion of type A or AB thymoma (38.7%). The Chinese series reports comparable results, whereas in the Indian and German cohorts, a mutation was confirmed in 64%. It should be noted that thymic carcinomas were excluded in the German/Indian comparison group, but included in the Chinese and Japanese. Thymic carcinomas only rarely show GTF2I mutations. The incidence of myasthenia gravis, a condition commonly associated with TETs and found in 22% of the Japanese patients, varied grossly in the groups, ranging from 5.7% in the Chinese to 82.4% in the Indian data. So, concluding the Japanese cohort differed substantially by a higher female to male ratio. The Chinese and Japanese cases as east Asian groups had a lower incidence in myasthenia gravis, more wild type status in GTF2I and less type A or AB thymoma than their German and Indian counterparts. Nevertheless, considering the low overall number of patients and the differences in study design preclude a firm conclusion. The data, however, allow the generation of a working hypothesis. The therapeutic options in thymomas are limited (15). While many glandular tumors are attributable to targeted therapies (16,17), to date no GTF2I specific drug is available. Even so, detection of this mutation may help to establish a diagnosis in small samples that are otherwise difficult to assess (7). As GTF2I mutated thymomas are characterized by an indolent course of disease, from the clinician’s point of view the detection of this mutation is of prognostic value, but unfortunately has no therapeutic relevance so far. Supplementary The article’s supplementary files as 10.21037/tlcr-23-396