Comprehensive Molecular Profiling of Cribriform Tumors: Identification of Recurrent 6q/9q Codeletion and CD38...

Cribriform tumor is a distinctive cutaneous adnexal tumor with a cribriform growth pattern. Initially described as carcinomas, cribriform tumors exhibit an indolent clinical course. In contrast to many other adnexal skin neoplasms, the oncogenic driver of cribriform tumors is still unknown. This study aimed to provide a novel characterization of cribriform tumors, focusing on the molecular and gene expression profiles revealed by whole-transcriptome analysis using RNA sequencing and DNA methylation analysis, and describe the resulting novel genetic and protein biomarkers. The study analyzed 15 cases of cribriform tumors, including 5 female patients. The median age at diagnosis was 62 years (range, 37-86). The most common tumor locations were lower (n = 10) and upper extremities (n = 5). Histopathological analysis revealed that all tumors were dermally located, with subcutaneous extension in 11 cases. All cases exhibited a combination of trabecular, cystic, and cribriform growth patterns. Unsupervised clustering based on DNA methylation and transcriptomic profiles confirmed cribriform tumors as a strikingly homogeneous molecular entity, molecularly distinct from other adnexal neoplasms. The low-risk G2/M and Complexity INdex in SARComas (CINSARC) transcriptomic signatures detected in all tested cases further supported the indolent nature of this neoplasm. Copy number variation analysis derived from DNA methylation analysis revealed recurrent 6q/9q codeletion in 7 of 8 tested cases. This codeletion was confirmed by fluorescence in situ hybridization targeting the 6q and 9q loci in 6 cases tested. RNA sequencing data did not reveal any recurrent specific fusions or specific pathogenic variants. Gene expression analysis focusing on differentially expressed genes between cribriform tumors and other cutaneous tumors revealed overexpression of CD38 in all cribriform tumors. Consistent with these findings, immunohistochemical analysis demonstrated CD38 expression in all cribriform tumors but not in controls (n = 29). In conclusion, our findings support that cribriform tumors represent a homogeneous group of cutaneous adnexal neoplasms characterized by recurrent 6q/9q codeletions and CD38 expression.