HMGA2 is a highly sensitive marker for DICER1-related tumours.

Loss of DICER1 function disrupts let-7 microRNA biogenesis and relieves repression of its target HMGA2, whose protein accumulates in the nucleus.

DICER1-related tumour predisposition encompasses some thirty rare paediatric and adolescent tumours, including pituitary blastoma where let-7 deregulation drives HMGA2 overexpression. The authors tested this hypothesis on 78 lesions with confirmed pathogenic DICER1 variants: CNS spindle cell sarcoma, ovarian Sertoli-Leydig cell tumour, pleuropulmonary blastoma, cystic nephroma, embryonal rhabdomyosarcoma of ovary or cervix, thyroid follicular nodular disease and seven rarer diagnoses. By immunohistochemistry, scoring any nuclear staining as positive, all lesion types were positive in every sample of each category except one case, but in only 50% of thyroid lesions; normal control tissues were uniformly negative. Excluding thyroid lesions, positivity reached 98%, whether the DICER1 variant was germline or somatic. The authors therefore propose HMGA2 as an exclusion test: a suspected lesion that is negative would be unlikely to benefit from germline DICER1 testing.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The practical value is real: an immunostain available in any pathology laboratory can triage germline DICER1 testing requests for rare paediatric tumours, provided one accepts that the proposed role is exclusion rather than confirmation, since the marker does not distinguish germline from somatic variants. The limitation is the very permissive definition of positivity, any nuclear staining: it maximises reported sensitivity but leaves specificity and inter-observer reproducibility uncharacterised against morphologically similar control tumours. The thyroid subgroup, positive in only half of cases, must remain explicitly outside the scope of this test.

Analysis by Dr Thibaut Benquey