HMGA2 is a highly sensitive marker for DICER1-related tumours

DICER1 is a microRNA biogenesis enzyme that, when mutated, results in a rewiring of the transcriptome. Germline pathogenic variants (PVs) in DICER1 result in DICER1-related tumour predisposition (DRTP) characterized by 30 or more different, generally rare, paediatric or adolescent-onset tumours. One of these, pituitary blastoma, upregulates let-7 targets such as HMGA2, with overexpression at the protein level. In this study, we determined if HMGA2 upregulation involves other tumours characteristic of DRTP.

Seventy-eight lesions with confirmed DICER1 PVs were studied including CNS spindle cell sarcoma, Sertoli-Leydig cell tumour of the ovary, pleuropulmonary blastoma, cystic nephroma, embryonal rhabdomyosarcoma of ovary or cervix, thyroid follicular nodular disease and seven other more rare diagnoses. Using immunohistochemistry and scoring any degree of nuclear staining for HMGA2 as positive, we found that all lesion types were positive. This was seen in all samples within each category (except one case), but in only 50% of thyroid lesions. Normal control tissues were uniformly negative.

The widespread expression in DICER1-related lesions, benign or malignant, suggests that HMGA2 expression is an early event in the pathogenesis. As HMGA2 is implicated in epithelial to mesenchymal transition, over-expression of HMGA2 in DICER1-related lesions could be driving this transition. Excluding thyroid lesions, immunostaining for HMGA2 shows 98% positivity in DICER1-related lesions, in DRTP or in tumours with somatic mutations. HMGA2 immunostaining could serve as a useful exclusion test; patients with lesions suspected of being DICER1-related, but negative for HMGA2, would be unlikely to benefit from germline DICER1 testing.