Neoplasm and Malignancy Risk in Nonproband Carriers of Pathogenic Germline Variants in DICER1


Key Points

  • Neoplasms occurred in 5.3% of DICER1 variant carriers by 10 years of age and in 19.3% by 50 years of age.
  • Significantly elevated risks were observed for all cancers excluding nonmelanoma skin cancers, gynandroblastoma, Sertoli-Leydig cell tumor, and thyroid cancer.  

In a study reported in the Journal of Clinical Oncology, Stewart et al identified the risk of neoplasms and malignancies among nonproband carriers of pathogenic germline variants in DICER1. The nonproband carriers were the biologic relatives of probands enrolled in three cohorts of individuals harboring the familial DICER1 variants. The DICER1 variants are the cause of DICER1 syndrome, an autosomal-dominant, pleiotropic tumor-predisposition disorder.

The study included 102 nonproband DICER1 variant carriers. Nonprobands were used in the analysis to reduce ascertainment bias. Neoplasm diagnoses were confirmed by review of pathology reports or central review of surgical pathology materials. Cancer standardized incidence ratios were determined relative to the Surveillance, Epidemiology, and End Results (SEER) program (which does not capture all DICER1-associated neoplasms).

Risk of Neoplasm and Malignancies

By the age of 10 years, 5.3% of nonproband DICER1 carriers had developed a DICER1-associated neoplasm (4.0% of females and 6.6% of males). By the age of 50 years, 19.3% had developed a neoplasm (26.5% of females, 10.2% of males), indicating that after 10 years of age, risk for females was elevated vs that in males.

Standardized incidence ratios analysis among 201 proband and nonproband DICER1 carriers showed greatly increased significant risks for known DICER1 syndrome–associated neoplasms, including gynandroblastoma, pleuropulmonary blastoma, embryonal rhabdomyosarcoma, Sertoli-Leydig cell tumor, and thyroid carcinoma. These findings reflect the fact that many study patients were ascertained on the basis of having a DICER1-associated neoplasm.

Cancer standardized incidence ratio analysis among the 102 nonprobands, representing 3,344 person-years of follow-up, showed a significantly elevated risk for all cancers, excluding nonmelanoma skin cancers (standardized incidence ratio = 2.1), gynandroblastoma standardized incidence ratio = 1.0 × 105), Sertoli-Leydig cell tumor (standardized incidence ratio = 2.7 × 103), and thyroid cancer (standardized incidence ratio = 19). Nonsignificantly elevated standardized incidence ratios were observed for prostate cancer (4.4) and melanoma (3.2).

The investigators concluded, “This work provides the first quantitative analysis of site-specific neoplasm risk and excess malignancy risk in 102 systematically characterized nonproband DICER1 carriers. Our findings inform DICER1 syndrome phenotype, natural history, and genetic counseling.”

Douglas R. Stewart, MD, of the National Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute. The study authors' full disclosures can be found at

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