Molecular defects in BRAF wild-type ameloblastomas and craniopharyngiomas—differences in mutation profiles in epithelial-derived oropharyngeal neoplasms

Abstract

The aim of this study was to evaluate the mutation profile of BRAF wild-type craniopharyngiomas and ameloblastomas. Pre-screening by immunohistochemistry and pyrosequencing for identifying BRAF wild-type tumors was performed on archived specimens of ameloblastic tumors (n = 20) and craniopharyngiomas (n = 62). Subsequently, 19 BRAF wild-type tumors (nine ameloblastic tumors and ten craniopharyngiomas) were analyzed further using next-generation sequencing (NGS) targeting hot spot mutations of 22 cancer-related genes. Thereby, we found craniopharyngiomas mainly CTNNB1 mutated (8/10), including two FGFR3/CTNNB1-double mutated tumors. Ameloblastic tumors were often FGFR2 mutated (4/9; including one FGFR2/TP53/PTEN-triple mutated case) and rarely CTNNB1/TP53-double mutated (1/9) and KRAS-mutated (1/9). In the remaining samples, no mutation could be detected in the 22 genes under investigation. In conclusion, mutation profiles of BRAF wild-type craniopharyngiomas and ameloblastomas share mutations of FGFR genes and have additional mutations with potential for targeted therapy.

<p>Adamantinomatous Craniopharyngioma in an Adult: A Case Report with NGS Analysis</p>

“…In a previous study, two cases with CTNNB1 mutations tested positive by NGS analysis were reported to have FGFR3 mutations p. (Ile378Thr) and p. (Ala719Thr), respective, but not FGFR1 or FGFR2 mutations. 32 In the present case only, a synonymous mutation was found in FGFR3. Very rarely, other mutations also reported in ACP tumors having CTNNB1 mutations, in one case with CTNNB1 mutation, a mutation in the NF2 gene, and a frameshift mutation in the SETD2 gene was shown previously.…”

“…33 In the WES panel, and the customized primer panels used in two other studies, PIK3CA primers were present, but no mutation was found in this gene in ACP tumors. 13,30,32,34 Our NGS profiling showed that the PIK3CA gene, which is involved in cellular proliferation and inhibition of apoptosis, was mutated in exon 7 (C2 domain) and in exon 21 (kinase domain) and in an intronic site also. This exon 7 variant p. (Ile391Met) was reported in grade III anaplastic ependymoma.…”

“…29 In the present tumor, not many actionable mutations were detected in cancer driver genes, this is in agreement with several studies previously published by NGS analysis of ACP tumors. 21,[30][31][32][33][34] Marucci et al (2015) have reported only CTNNB1 mutation using NGS method in 12 out of 15 cases (80.0%) of BRAF negative ACP tumors. 21 Besides the CTNNB1 mutations in ACP and BRAF V600E mutations in PCP, no further mutations were detectable by NGS in both tumor subtypes in their studies.…”

“…As shown in Table 5, within the last 5 years, nine studies were published on the mutation profiling in ACP tumors using NGS methods. 13,21,[30][31][32][33][34][35][36] So far one hundred ACP tumor samples were sequenced by NGS, and 85 tumors (85%) had CTNNB1 mutations. In these studies, the majority of ACPs tumors have somatic activating mutations in the degradation-targeting box present between amino acids 32 to 45 in the exon 3 of CTNNB1 gene where casein kinase 1 (CK1 α) first phosphorylates on Ser-45.…”

Genetic Profile of Adenomatoid Odontogenic Tumor and Ameloblastoma. A Systematic Review

“…The prevalence of BRAF V600E in ameloblastoma ranges from 46 [6] to 90% [11], with a mean value of 68%. Other somatic mutations have been reported, either in MAPK or non-MAPK pathways [6,8,10,[12][13][14][15][16]. Some of these, such as mutations in PTEN, SMARCB1, EGFR, TP53, CTNNB1, and PIK3CA [6,[8][9][10], can occur in the background of the classical BRAF V600E mutation.…”