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Gregory J. Riely, MD, PhD


DICER1 Hotspot Mutations in NSCLC: Clinical Implications for Genetic Testing

By: Amanda E. Ruffino, BA
Posted: Thursday, February 1, 2024

William D. Foulkes, MBBS, PhD, of Jewish General Hospital, Montreal, and colleagues explored the association between DICER1 pathogenic variants and non–small cell lung cancer (NSCLC), focusing on the presence of hotspot mutations. Although the role of DICER1 pathogenic variants in NSCLC has been relatively unknown, the investigators aimed to elucidate the spectrum of lung pathologies associated with DICER1 hotspot pathogenic variants and to compare the mutational landscape of NSCLC cases with and without these hotspots. These findings were presented in The American Journal of Surgical Pathology.

DICER1 is known for its involvement in miRNA biogenesis. Its variants are linked to various specific pathologic entities, including pleuropulmonary blastoma, pulmonary blastoma, and well-differentiated fetal lung adenocarcinoma, all of which exhibit features resembling immature lung tissue.

The study analyzed DNA sequencing data from 12,146 NSCLCs, identifying 235 cases with at least one DICER1 pathogenic variants, of which 9 (3.8%) were DICER1 hotspot–positive. Histologic examination revealed that almost all hotspot-positive tumors fell within the histologic spectrum of pulmonary blastoma or well-differentiated fetal lung adenocarcinoma, whereas DICER1 non-hotspot double variants were classified as lung adenocarcinomas. Further comparison of the mutational landscape between hotspot-positive and hotspot-negative cases highlighted a significantly higher frequency of CTNNB1 mutations in the former group (5 of 9 vs 2 of 225; P < .00001).

The findings suggest that DICER1 somatic hotspots are not commonly implicated in the most prevalent types of NSCLC but rather selectively associate with morphologic features characteristic of lung tumor types such as pulmonary blastoma and well-differentiated fetal lung adenocarcinoma. As for clinical implications, the study recommends that patients exhibiting the specific tumor morphology associated with DICER1 hotspot–positive variants should undergo testing for these variants; if positive, genetic counseling should be considered.

Disclosure: Dr. Foulkes reported no conflicts of interest. For full disclosures of the other study authors, visit

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