DNA methylation-based classification of sinonasal tumors

Abstract

The diagnosis of sinonasal tumors is challenging due to a heterogeneous spectrum of various differential diagnoses as well as poorly defined, disputed entities such as sinonasal undifferentiated carcinomas (SNUCs). In this study, we apply a machine learning algorithm based on DNA methylation patterns to classify sinonasal tumors with clinical-grade reliability. We further show that sinonasal tumors with SNUC morphology are not as undifferentiated as their current terminology suggests but rather reassigned to four distinct molecular classes defined by epigenetic, mutational and proteomic profiles. This includes two classes with neuroendocrine differentiation, characterized by IDH2 or SMARCA4/ARID1A mutations with an overall favorable clinical course, one class composed of highly aggressive SMARCB1-deficient carcinomas and another class with tumors that represent potentially previously misclassified adenoid cystic carcinomas. Our findings can aid in improving the diagnostic classification of sinonasal tumors and could help to change the current perception of SNUCs.

Molekulare Tumordiagnostik als Triebfeder der Präzisionsonkologie

“…Während Datensätze aus herkömmlichen NGS-Panels, die heutzutage in der Routinediagnostik zur Identifizierung einzelner Mutationen verwendet werden, mit klassischen Datenanalyse-Strategien gehandhabt werden können, profitieren hochdimensionale Genomik-und Proteomik-Datensätze von Verfahren des maschinellen Lernens. Sie helfen dabei die Dimensionalität zu reduzieren und heterogene Datenarten, wie Genregulationen in Netzwerken oder DNA-Methylierungsdaten zu integrieren [49,50,51,52].…”

Sinonasal Cancer: Improving Classification, Stratification and Therapeutic Options

“…They also reported that IDH2 -mutated tumors are associated with a worse outcome, which is different from what had been published in the literature beforehand [ 25 , 36 ] and larger studies are required to confirm these findings. Having said this, their reported association of IDH2 -mutation as well as SMARCB1 deficiency with aberrant global methylation was later confirmed by a very recent large methylation study on sinonasal cancers [ 8 ].…”

“…A detailed description of diagnostically relevant genetic aberrations can be found in the paper by Taverna et al in this Special Issue [ 7 ]. In addition, methylation profiling has been shown to allow the classification of sinonasal tumor subtypes, even identifying subgroups of tumors within SNUC and SNEC [ 8 ]. A similar approach to aid and finetune the diagnosis of the multitudinous subtypes of brain tumors has now been implemented by the WHO Classification of Tumors [ 9 ].…”

Recent advances in epigenetic anticancer therapeutics and future perspectives

“…DNA methylation is the firstly recognized epigenetic alterations and it is closely connected with the development of cancer. When the promoter region of genes was methylated, the accessibility to regulatory regions in the DNA was blocked and the transcription factors or other transcriptional regulators can't bind with the promoter of genes, which lead to the repression of gene transcription ( Jurmeister et al, 2022 ). Specifically, various tumor suppressor genes (TSGs) were identified to be hypermethylated thus facilitating the development of cancer via TSGs silencing, such as BRCA1 ( Das et al, 2022 ) and CDKN2A ( Maeda et al, 2003 ).…”