Abstract
There is limited understanding of the molecular pathogenesis of thymic epithelial tumors challenging the development of targeted therapies. These tumors exhibit chromosomal copy number alterations that increase in frequency and complexity with increasing aggressiveness of the histological subtype. They show low somatic mutation loads and recurrent mutations have been identified in a very limited number of genes, most commonly GTF2I. High-throughput studies have identified significant genomic and epigenomic differences among the different histological subtypes of thymomas, paving the way for a better understanding of tumorigenesis and progression. This chapter provides a concise overview of molecular genetic alterations of potential clinical significance.
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12.1 Introduction
Integrated genomic analyses of thymic epithelial tumors (TETs) demonstrate significant genetic and molecular heterogeneity among the different histological subtypes [1]. Type A, type AB thymomas, type B thymomas, and thymic carcinomas segregate into distinct genetic/molecular entities on multiplatform omics studies with differences in the loci and frequency of their chromosomal copy number alterations, recurrent gene mutations, miRNA profiles, and, more recently, DNA methylation patterns. Gene fusions and expression of viral/bacterial antigens have not been identified in these tumors [1]. Overall, there is limited understanding of the molecular pathogenesis of thymic epithelial tumors and successful targeted therapies are yet to be discovered. In this chapter, we highlight select molecular genetic features of diagnostic, prognostic, or potential therapeutic significance in TETs.
12.2 Recurrent Gene Mutations in Thymic Epithelial Tumors
Thymic epithelial tumors harbor one of the lowest rates of somatic mutations among adulthood onset cancers with estimated tumor mutation burden of approximately 0.48 mutations per mega base [1]. Whole genome sequencing studies have identified recurrent mutations in a very limited number of genes (Fig. 12.1), the most frequent being the General Transcription Factor 2I (GTF2I) gene, point mutations of which occur in ~39% of all TETs [1]. Recurrent mutations of genes involved in the EGFR signaling pathway such as RAS family, PIK3CA, AKT, EGFR, and TP53, also occur, albeit at much lower frequencies [1].
12.2.1 GTF2I (General Transcription Factor 2I) Mutations
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GTF2I is localized on chromosomal region 7q11.23 and encodes for members of the transcription factor IIi, a group of ubiquitously expressed proteins involved in diverse signaling pathways.
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Mutations are most frequent in type A (82–100%) and type AB (70–74%) thymomas, less common in type B thymomas (20–30%) and thymic carcinoma (7–8%) [1, 2].
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Characterized by a missense mutation in exon 15 at a single codon (L424H) resulting from T>A nucleotide substitution (Fig. 12.2) [3].
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Highly specific for thymic epithelial tumors; rare GTF2I mutations described in tumors other than thymomas involve other codons [1].
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GTF2I mutant tumors show higher expression of genes involved in cell morphogenesis, receptor tyrosine kinases, retinoic acid receptors, neuronal processes, and WNT and SHH signaling pathways [1].
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GTF2I mutation status not associated with myasthenia gravis [1].
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Within individual histological subtypes, GTF2I mutant tumors show better outcomes as compared to those wild type [4].
12.2.2 RAS Mutations
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Activating mutations in HRAS (codon 12, 13, 117), NRAS (codon 61), or KRAS are the second most prevalent gene mutations in TETs [1].
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HRAS mutations reported predominantly in type A thymomas [1, 5, 6].
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KRAS and NRAS mutations described in type B2 thymomas and thymic carcinomas [2].
12.2.3 TP53 Mutations
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Rare, mainly reported in thymic carcinomas and some type B thymomas [1, 2, 5].
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All mutations are pathogenic loss of function mutations.
12.2.4 KIT Mutations
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Very rare, detected exclusively in thymic carcinomas (~7% incidence).
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Reported KIT mutations include V560 deletion in exon 11, H697Y mutation in exon 14, L576P mutation in exon 11, and D820E mutation in exon 17, of which all except the last predict sensitivity to tyrosine kinase inhibition [7].
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KIT mutations do not correlate with KIT protein overexpression which is seen in more than 75% of thymic carcinomas [8].
12.2.5 Others
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EGFR mutations are consistently absent in thymomas and very rarely described in thymic carcinomas [5] despite frequent EGFR protein overexpression and EGFR gene amplification [8]; thymic epithelial tumors generally do not respond to EGFR tyrosine kinase inhibitors [8].
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Mutations in other genes involved in EGFR signaling, namely, AKT1 and PIK3CA, have been reported in type B3 thymomas and thymic carcinomas [5].
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Rare example of a thymic carcinoma with microsatellite instability due to MLH1 somatic mutation and high tumor mutation burden has been reported [1].
12.3 Chromosome Copy Number Alterations
Copy number gains and losses of multiple chromosomal regions are well described in thymic epithelial tumors with the frequency and complexity of the alterations increasing with the aggressiveness of the histological type (Fig. 12.1). The biological significance of a majority of these alterations is, however, yet to be determined.
12.3.1 6q25.2-25.3 Loss of Heterozygosity
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Observed in most types of thymomas including thymic carcinomas.
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FOXC1, a gene encoding for a transcription factor involved in normal thymus development, is located at this locus and is implicated as a tumor suppressor in the development of thymic epithelial tumors.
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Tumors with reduced m-RNA and protein expression levels of FOXC1 associate with poor prognosis [9].
12.3.2 CDKN2A/B Alterations
12.4 Epigenomic Alterations
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Many miRNAs have been found to be differentially expressed in various histological subtypes of thymic epithelial tumors [11].
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A large microRNA cluster on chr19q13.42 activating the PI3K pathway has been identified as the transcriptional hallmark of type A and AB thymomas and is a potential actionable target [12].
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Altered expression levels of specific miRNAs have been correlated with tumor pathogenesis and prognosis in TETs [8, 13, 14].
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Recent studies have identified significant differences in the DNA methylation patterns among normal thymus, type A thymoma, type B thymoma, and thymic carcinoma with diagnostic and prognostic connotations [15, 16].
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Nambirajan, A., Singh, V., Jain, D. (2020). Molecular Pathology of Thymic Epithelial Tumors. In: Jain, D., Bishop, J.A., Wick, M.R. (eds) Atlas of Thymic Pathology. Springer, Singapore. https://doi.org/10.1007/978-981-15-3164-4_12
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