Frequent Genetic Alterations and Their Clinical Significance in Patients With Thymic Epithelial Tumors

Abstract

PurposeThymic epithelial tumors (TETs) are relatively rare neoplasms, including thymomas (types A, AB, B1, B2, and B3) and thymic carcinomas (TCs). The current knowledge about the biological properties of TETs is limited due to their low incidence. This study aimed to detect genetic alterations in TETs using next-generation sequencing(NGS) and explore their clinical significance in survival.MethodsTumor tissues and clinical data were collected from 34 patients with resected TETs in the Tianjin Medical University General Hospital between January 2011 and January 2019, and 56 cancer-associated genes were analyzed. The data of 123 TETs were retrieved from TCGA, and the information on their clinical and somatic mutations was explored.ResultsThe cohort comprised 34 TETs including 17 thymomas and 17 TCs. The NGS results indicated that 73.08% of TCs+type B3 TETs and 37.50% of non-TCs+type B3 TETs each exhibited gene mutations. For patients with type B3/C, TP53 was the most frequent mutation (19.23%), followed by CDKN2A (11.54%). Similarly, in 123 TETs from the TCGA cohort, TP53 mutations were more frequent in patients with type B3/C than in patients with non-type B3/C (11.53% vs 3.09%). Further, patients with TET with TP53 mutations in the present cohort and the TCGA cohort had a worse prognosis compared with those without TP53 mutations.ConclusionsGene mutation profiles between TCs+type B3 TETs and non-TCs+type B3 TETs were significantly different. The presence of TP53 mutations was more frequent in TCs+type B3 TETs than in non-TCs+type B3 TETs, which was associated with a worse prognosis.

Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas

“…We did not evaluate p53 expression by immunohistochemistry (IHC) because the full coding sequence of TP53 was analysed for SNVs. Xu et al reported a significantly shorter DFS in patients with TP53 mutated compared to wild-type TP53 ( n = 34, p = 0.003) [ 44 ]. Mutations in TP53 are among the most frequent somatic aberrations in human cancers and are frequently reported as a negative prognostic factor for survival in many solid tumour types, including lung [ 45 ], colorectal [ 46 ], breast [ 47 ], and prostate carcinoma [ 48 ], irrespective of systemic therapy.…”

“…Alterations in FOXL2 have not previously been associated with TETs. However, FOXL2 was not analysed in most studies of genetic alterations in thymomas or thymic carcinomas by targeted sequencing because it is absent from NGS panels [ 31 , 44 , 49 , 50 , 60 ]. In our analysis, this variant was heterozygous and had an allele frequency of 6% (4905 total reads), suggesting a somatic origin.…”

“…Unlike other authors, we did not identify pathogenic variants of TP53 , KRAS , PIK3CA , AKT1 , EGFR , or RET in thymomas [ 30 , 35 , 38 , 49 , 50 , 67 ]. Significant enrichment of mutated genes of the RAS and PI3K-Akt signalling pathways was reported in thymomas ( AKT3 , ALK , CSF1R , FGFR4 , KRAS , NRAS , HRAS , PIK3CA ), and their role in thymoma development was suggested [ 30 , 31 , 35 , 38 , 44 , 49 ].…”

Clinical Significance of Tumor Markers for Advanced Thymic Carcinoma: A Retrospective Analysis from the NEJ023 Study

“…Recently, next-generation sequencing (NGS) for ATC has become a popular topic. In TC, TP53 was one of the most frequent mutation genes, and the mutation frequency ranged from 7.7% to 26.7%; on the other hand, TP53 mutations were rare in thymomas [ 55 ]. Several studies have suggested that TP53 mutations are a negative prognostic factor for ATC [ 55 , 56 ].…”

“…In TC, TP53 was one of the most frequent mutation genes, and the mutation frequency ranged from 7.7% to 26.7%; on the other hand, TP53 mutations were rare in thymomas [ 55 ]. Several studies have suggested that TP53 mutations are a negative prognostic factor for ATC [ 55 , 56 ]. TP53 mutation seems to be associated with a more aggressive behavior, as confirmed in an earlier report [ 57 ].…”