Aim: To investigate the molecular aberrations of thymic epithelial tumors (TETs) which, currently, are largely unknown, hampering progress in diagnosis, prognostication and targeted therapy. Methods: Frozen tumor and normal blood were available for 28 TETs with a high proportion of cancer cell content (>80%). Exome capture was performed using Sure Select All Exon (Agilent) and TruSeq Exome Enrichment kit (Illumina) in 21 and 35 samples, respectively. Sequencing was performed using Genome Analyzer-II (Illumina) and HiSeq2000 (Illumina) in 21 and 35 samples, respectively. Reads were aligned using Novoalign (Novocraft) and somatic mutations were detected comparing exome sequencing of tumor and normal DNA of each patients using VarScan2. A single nucleotide missense mutation of GTF2I was the most common in TETs, and was confirmed in an independent cohort of 268 formalin fixed paraffin embedded TETs. Results: Thymic carcinomas had a higher number of mutations than thymomas with a mean of 43.5 and 17.4, respectively (p=0.001). In thymic carcinomas (11), genes with recurrent mutations included TP53 (4), CYLD (3), BAP1 (2), CDKN2A (2) and PBRM1 (2). A single nucleotide mutation of GTF2I (chr7:74146970T/A) was observed in 35% of thymomas (17). The mutation was missense (leucine to histidine), not previously described in cancer or as a polymorphism in dbSNP137 database. The mutation was predicted to alter the structure of the protein or its function according to Poliphen2 and SIFT algorithms. The presence of GTF2I mutation was confirmed in an extended cohort of 268 TETs: 82% of A (56), 74% of AB (54), 32% of B1 (28), 22% of B2 (32), 21% of B3 thymomas (62) and 8% of thymic carcinomas (36). The mutation was more frequent in stages I-II (57%) than in stages III-IV (19%; p<0.001). Patients with GTF2I mutation had a better disease related survival than those without (96% vs 70% 10-year survival, respectively; Log-Rank p<0.001). In a multivariate model only tumor stage but not GTF2I mutation or WHO histotypes were independent prognostic factors (p=0.008, p=0.209 and p=0.242, respectively). GTF2I mutation stimulated cell proliferation in in vitro models. Conclusions: GTF2I mutation is frequent in thymic epithelial tumors, especially in A-AB histotypes and is associated with a better outcome
GTF2I MUTATIONS ARE FREQUENT IN THYMIC EPITHELIAL TUMORS
PETRINI, IACOPO;LUCCHI, MARCO;FONTANINI, GABRIELLA;
2014-01-01
Abstract
Aim: To investigate the molecular aberrations of thymic epithelial tumors (TETs) which, currently, are largely unknown, hampering progress in diagnosis, prognostication and targeted therapy. Methods: Frozen tumor and normal blood were available for 28 TETs with a high proportion of cancer cell content (>80%). Exome capture was performed using Sure Select All Exon (Agilent) and TruSeq Exome Enrichment kit (Illumina) in 21 and 35 samples, respectively. Sequencing was performed using Genome Analyzer-II (Illumina) and HiSeq2000 (Illumina) in 21 and 35 samples, respectively. Reads were aligned using Novoalign (Novocraft) and somatic mutations were detected comparing exome sequencing of tumor and normal DNA of each patients using VarScan2. A single nucleotide missense mutation of GTF2I was the most common in TETs, and was confirmed in an independent cohort of 268 formalin fixed paraffin embedded TETs. Results: Thymic carcinomas had a higher number of mutations than thymomas with a mean of 43.5 and 17.4, respectively (p=0.001). In thymic carcinomas (11), genes with recurrent mutations included TP53 (4), CYLD (3), BAP1 (2), CDKN2A (2) and PBRM1 (2). A single nucleotide mutation of GTF2I (chr7:74146970T/A) was observed in 35% of thymomas (17). The mutation was missense (leucine to histidine), not previously described in cancer or as a polymorphism in dbSNP137 database. The mutation was predicted to alter the structure of the protein or its function according to Poliphen2 and SIFT algorithms. The presence of GTF2I mutation was confirmed in an extended cohort of 268 TETs: 82% of A (56), 74% of AB (54), 32% of B1 (28), 22% of B2 (32), 21% of B3 thymomas (62) and 8% of thymic carcinomas (36). The mutation was more frequent in stages I-II (57%) than in stages III-IV (19%; p<0.001). Patients with GTF2I mutation had a better disease related survival than those without (96% vs 70% 10-year survival, respectively; Log-Rank p<0.001). In a multivariate model only tumor stage but not GTF2I mutation or WHO histotypes were independent prognostic factors (p=0.008, p=0.209 and p=0.242, respectively). GTF2I mutation stimulated cell proliferation in in vitro models. Conclusions: GTF2I mutation is frequent in thymic epithelial tumors, especially in A-AB histotypes and is associated with a better outcomeI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
