Prevalence and spectrum analysis of germline DICER1 variants of solid tumors: Decoding the mysterious signals of the genome.

Abstract

10578 Background: DICER1 syndrome is a rare genetic condition predisposing to multiple cancer types and causes by germline DICER1 variants. Deleterious mutations identified were mostly located in the RNase III domain. VUSs found in other domains may be also crucial in the inheritance of high-risk neoplasms although there is insufficient evidence. Our study aimed at describing the spectrum of DICER1 variants detected in solid tumors to improve the identification of potentially high-risk DICER1 variants. Methods: Germline mutations including SNV, small INDEL in 448 patients with solid tumors were analyzed by next-generation sequencing (NGS) panel. The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines. Results: In total, 3 (0.67%) patients (diagnosed as bladder cancer, schwannoma, and medulloblastoma) were identified harboring truncating pathogenic (P)/likely pathogenic (LP) germline mutations in the RNase III domain. The remaining 445 (99.33%) patients carried 447 uncertain significance (VUS) mutations, of which 416 (92%) were missense mutations lied in different domains and 52% (234/450) located in exon 20-23. The median age was 60 years old with an age range from 0 to 90. The higher frequency cancer type contained lung cancer (35.9%), glioma (10.0%), liver cancer (8.4%). In addition, the two highest frequencies of DICER1 missense variants were c.3334A > G (p. Asn1112Asp, n = 58) and c.3227G > A (p. Ser1076Asn, n = 53), which lied in unknown functional domain of the protein and had been reported in Clinvar. Their clinical significance and pathogenicity remain further study. Conclusions: In our study, DICER1 germline mutations mostly occurred in exon 20-23 and 92% were missense mutations. We reported 3 new cases of tumors associated with DICER1 syndrome, which expanded the DICER1-related tumor spectrum. Understanding the clinical significance of germline DICER1 VUS could improve the identification of potentially high-risk variants. Reclassifying these variants could make them useful for predictive, prognostic, and preventive purposes in clinical practice.