Cohesins: Crossroad Between Cornelia de Lange Spectrum and Cancer Predisposition.

The cohesin complex plays crucial roles in DNA repair, chromatid separation, and gene transcription regulation. Pathogenic variants in cohesins or dysfunctional transcriptional regulators lead to cohesinopathies, a broader group of disorders including Cornelia de Lange Spectrum (CdLSp), for which the prevalence of cancer cases remains unclear. Here, we aimed to assess the prevalence of oncological events in CdLSp and elucidate the role of cohesin variants in cancer predisposition. We developed a custom next-generation sequencing (NGS) panel targeting predisposition and pathogenic genes, which we applied on N = 120 samples of pediatric patients with acute lymphoblastic leukemia (ALL), identifying 11 out of 229 total-10 germline and 1 somatic-variants in cohesin genes. Data of N = 205 brain tumors were extracted by bioinformatic analysis of data from open-source databases carrying 19 somatic variants. In a cohort of 54 CdLSp patients, the largest cohort from a single center, with a median age of 13 years, the hypothesis of an increased prevalence of cancer in CdLSp was not confirmed. Our findings highlight a significant involvement of germline NIPBL variants in CdLSp, whereas RAD21 and STAG1/2 are predominantly found as somatic variants in neoplasms. However, a distinct genetic or molecular pattern distinguishing variants leading to CdLSp from tumors was not identified. Hence, we advocate for further investigation into the relationship between cohesin variants and cancer predisposition in a larger cohort of patients, with a longer observation time and including different types of malignancies, with more focus on epigenetic approaches.