Letícia Martins Guimarães

Oxidative stress plays an important role in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). The 8-Hydroxydeoxyguanosine (8-OHdG) is a major oxidative DNA adduct, and its levels have been noted as a triggering factor for inflammation-related carcinogenesis, but have not been assessed in CRSwNP. The MAPK/ERK pathway importance in the pathogenesis of CRSwNP has previously been reported. Mutations in RAS family genes occur in neoplastic and non-neoplastic proliferative lesions, and it has been previously demonstrated that KRAS mutations do not occur in CRSwNP. To assess the levels of 8-OHdG in nasal polyps occurring in CRSwNP, to associate these levels with clinicopathological parameters, and to investigate HRAS and NRAS hotspot mutations in the same samples. Both the HRAS (codons 49 and 61) and NRAS (codon 61) mutations were investigated through Sanger sequencing, and the levels of 8-OHdG were determined using ELISA in 14 freshly collected snap-frozen samples of nasal polyps occurring in CRSwNP. The associations between the levels of 8-OHdG and patients' age, presence of asthma, and eosinophil counts in nasal polyps were tested. No mutations were detected. The association between higher levels of 8-OHdG and higher eosinophil counts was observed, whereas there was no association between it and age or the presence of asthma. Based on the results in the present cohort, higher levels of 8-OHdG, indicative of oxidative stress, are associated with higher eosinophil counts in CRSwNP. Additionally, HRAS and NRAS mutations do not occur in nasal polyps or occur at a very low frequency.

Soft tissue tumours (STT) are a heterogeneous group of benign, malignant, and intermediate/borderline mesenchymal tumours. In the oral and maxillofacial region, less than 3% of all lesions correspond to benign STT and <1% are sarcomas. Overlapping microscopic features may lead to quite challenging diagnostic processes. Translocations and fusion genes are frequent, and type‐specific genetic alterations are detected in these tumours. The detection of such alterations by classic cytogenetic, FISH, RT‐PCR or NGS can help to define the diagnosis. This narrative review aims to review fusion genes reported for STT that affect the oral cavity and their use in diagnostic molecular pathology. Basic concepts regarding mechanisms of fusion genes formation are presented to clarify this information for surgical pathologists. The chromosomal rearrangements and fusion genes of adipocytic, fibroblastic and myofibroblastic, vascular, pericytic, smooth muscle, skeletal muscle, chondro‐osseous, and uncertain origin STT are summarised. The advance in molecular pathology techniques has led not only to a better understanding of the molecular pathogenesis of STT, but also to the development of helpful diagnostic tools. Therefore, it is important for the oral and head and neck pathologists to familiarise with the signature rearrangements and fusion genes for each tumour.

The advances in molecular technologies have allowed a better understanding of the molecular basis of odontogenic cysts and tumours. PTCH1 mutations have been reported in a high proportion of odontogenic keratocyst. BRAF p.V600E are recurrent in ameloblastoma and KRAS p.G12V/R in adenomatoid odontogenic tumour, dysregulating the MAPK/ERK pathway. Notably, BRAF p.V600E is also detected in ameloblastic carcinoma, but at a lower frequency than in its benign counterpart ameloblastoma. Recently, adenoid ameloblastoma has been shown to be BRAF wild‐type and to harbour CTNNB1 (β‐catenin gene) mutations, further suggesting that it is not an ameloblastoma subtype. CTNNB1 mutations also occur in other ghost‐cell‐containing tumours, including calcifying odontogenic cysts, dentinogenic ghost cell tumours and odontogenic carcinoma with dentinoid, but the link between CTNNB1 mutations and ghost cell formation in these lesions remains unclear. Regarding mixed tumours, BRAF p.V600E has been reported in a subset of ameloblastic fibromas, ameloblastic‐fibrodentinomas and fibro‐odontomas, in addition to ameloblastic fibrosarcoma. Such mutation‐positivity in a subset of samples can be helpful in differentiating some of these lesions from odontoma, which is BRAF‐wild‐type. Recently, FOS rearrangements have been reported in cementoblastoma, supporting its relationship with osteoblastoma. Collectively, the identification of recurrent mutations in these aforementioned lesions has helped to clarify their molecular basis and to better understand the interrelationships between some tumours, but none of these genetic abnormalities is diagnostic. Since the functional effect of pathogenic mutations is context and tissue‐dependent, a clear role for the reported mutations in odontogenic cysts and tumours in their pathogenesis remains to be elucidated.

Background: TERT promoter mutations increase telomerase activity, conferring cell immortality. The coexistence of TERT promoter mutations with BRAFV600E is associated with aggressiveness. Ameloblastoma and ameloblastic carcinoma are infiltrative neoplasms that harbor BRAFV600E; however, it remains unknown if these odontogenic tumors also show TERT promoter mutations.Methods: Genomic DNA of paraffin‐embedded ameloblastomas (n = 6) and ameloblastic carcinomas (n = 3) were Sanger‐sequenced to assess the hotspot TERT promoter mutations C228T and C250T. BRAFV600E status was screened by TaqMan allele‐specific quantitative polymerase chain reaction.Results: None of the samples harbored TERT promoter mutations. The BRAFV600E mutation was positive in 3 of 6 of ameloblastomas and in 1 of 3 of ameloblastic carcinomas.Conclusion: The absence of TERT promoter mutation in the samples indicates that this molecular event is not relevant to the tumors' pathogenesis. Further studies are necessary to explore undefined genetic or epigenetic mechanisms related to TERT‐upregulation in ameloblastoma, and the telomerase activity in ameloblastic carcinoma.