Methylation Drivers and Prognostic Implications in Sinonasal Poorly Differentiated Carcinomas

Abstract

Background: Poorly differentiated sinonasal carcinomas (PDSNCs) are rare and aggressive malignancies, which include squamous cell carcinoma (SCC), sinonasal undifferentiated carcinoma (SNUC), and neuroendocrine carcinomas (NEC). Several epigenetic markers have been suggested to support the histopathological classification, predict prognosis, and guide therapeutic decision. Indeed, molecularly distinct subtypes of sinonasal carcinomas, including SMARCB1-INI1 or SMARCA4 deficient sinonasal carcinoma, isocitrate dehydrogenase (IDH)-mutant SNUC, ARID1A mutant PDSNCs, and NUT carcinomas, have recently been proposed as separate entities. Identification of aberrant DNA methylation levels associated with these specific epigenetic driver genes could be useful for prognostic and therapeutic purpose. Methods: Histopathological review and immunohistochemical study was performed on 53 PDSNCs. Molecular analysis included mutational profile by NGS, Sanger sequencing, and MLPA analyses, and global DNA methylation profile using LINE-1 bisulfite-PCR and pyrosequencing analysis. Results: Nine SWI/SNF complex defective cases and five IDH2 p.Arg172x cases were identified. A significant correlation between INI-1 or IDH2 defects and LINE-1 hypermethylation was observed (p = 0.002 and p = 0.032, respectively), which were associated with a worse prognosis (p = 0.007). Conclusions: Genetic and epigenetic characterization of PDSNCs should be performed to identify distinct prognostic entities, which deserved a tailored clinical treatment.

SMARCB1 (INI-1)-Deficient Sinonasal Carcinoma: A Systematic Review and Pooled Analysis of Treatment Outcomes

“…Of the remaining 192 patients, 72 patients whose individual baseline patient characteristics, treatment details, and survival outcomes could not be identified and verified [2,16,19,20,23,[28][29][30]34,35,38], and they were thus not included into our survival analysis. As a result, only 120 patients with data availability of baseline patient characteristics, disease stage, and survival outcomes in 25 publications were included for survival and prognostic factor analyses [1,2,11,[13][14][15][16][17]19,[21][22][23][24][25][26][27][31][32][33]36,37,[39][40][41][42]. Meanwhile, our institution had eight patients who had a complete set of baseline characteristics, treatment details, and survival outcomes, and who were treated between 2014 and 2021.…”

“…Similar to other histological and molecular types of sinonasal malignancies, its clinical presentation is often local or locoregionally advanced with T4a/T4b disease at diagnosis, rendering upfront complete resection very technically challenging. Its overall prognosis, however, is more dismal when compared to SMARCB1-retained, IDH2 R172-mutant, and IDH2 wild-type counterparts [28,33,36,44].…”

“…Additional molecular and genetic/genomic diagnostic tests were performed to confirm the status of SMARCB1 deletion in twenty-four patients: fluorescence in-situ hybridization (FISH) in nine patients [2,41], next generation sequencing (NGS) in two patients (including one from our institution) [25], NGS and FISH in one patient [11], NGS and chromogenic in-situ hybridization in four patients [19], and NGS and multiplex ligation-dependent probe amplification in eight patients [36]. Out of these twenty-four patients, monoallelic deletion was identified in three patients [2,36,41], and biallelic deletion was found in nineteen patients [2,11,19,25,36]. Normal results of FISH were noted in the remaining two patients [2].…”

IDH2: A novel biomarker for environmental exposure in blood circulatory system disorders (Review)

“…IDH2 is closely associated with therapeutic effectiveness and sensitivity. IDH2 is not only associated with blood circulation disorders, but also with other diseases, such as glioma (57), non-small cell lung cancer (58), solid papillary carcinoma with reverse polarity (SPCRP) (59), angioimmunoblastic T-cell lymphoma (AITL) (60), high-grade chondrosarcoma (61) and undifferentiated sinus carcinoma (62).…”

“…Undifferentiated sinus carcinoma is an infrequent, aggressive, highly malignant tumor with finite therapy choices (85,86), and women with this disease have a higher frequency of IDH2 mutations compared with men with the disease (87). IDH2 mutated undifferentiated sinus carcinoma subtypes have high levels of DNA methylation and a poor prognosis (62). As a prime component in anti-oxidative damage, wild-type IDH2 protects cochlear hair cells from ROS and prevents age-related hearing loss by providing NADPH (88,89).…”