Neoplasm Risk Among Individuals With a Pathogenic Germline Variant in DICER1

Abstract

Purpose DICER1 syndrome is an autosomal-dominant, pleiotropic tumor-predisposition disorder caused by pathogenic germline variants in DICER1. We sought to quantify risk, hazard rates, and the probability of neoplasm incidence accounting for competing risks (“cumulative incidence”) of neoplasms (benign and malignant) and standardized incidence ratios for malignant tumors in individuals with DICER1 pathogenic variation. Patients and Methods We combined data from three large cohorts of patients who carry germline pathogenic variation in DICER1. To reduce ascertainment bias, we distinguished probands from nonprobands. Neoplasm diagnoses were confirmed by review of pathology reports and/or central review of surgical pathology materials. Standardized cancer incidence ratios were determined relative to the SEER program, which does not capture all DICER1-associated neoplasms. For all malignancies and benign tumors (“neoplasms,” excluding type Ir pleuropulmonary blastoma and thyroid nodules), we used the Kaplan-Meier method and nonparametric cumulative incidence curves to estimate neoplasm-free survival. Results We calculated the age at first neoplasm diagnosis (systematically ascertained cancers plus DICER1-associated neoplasms pleuropulmonary blastoma, cystic nephroma, and nasal chondromesenchymal hamartoma) in 102 female and male nonproband DICER1 carriers. By age 10 years, 5.3% (95% CI, 0.6% to 9.7%) of nonproband DICER1 carriers had developed a neoplasm (females, 4.0%; males, 6.6%). By age 50 years, 19.3% (95% CI, 8.4% to 29.0%) of nonprobands had developed a neoplasm (females, 26.5%; males, 10.2%). After age 10 years, female risk was elevated compared with male risk. Standardized cancer incidence ratio analysis of 102 nonproband DICER1 carriers, which represented 3,344 person-years of observation, showed significant cancer excesses overall, particularly of gynecologic and thyroid cancers. Conclusion 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.

The prevalence of germline DICER1 pathogenic variation in cancer populations

“…In the modest‐sized TARGET (pediatric) germline data available, we observed nonhotspot missense (LP) DICER1 variation in one child with a neuroblastoma (one child with Wilms tumor also harbored a DICER1 Likely Pathogenic variant). In an analysis of 209 DICER1 ‐carriers from the International PPB/ DICER1 Registry and NCI DICER1 syndrome study, one case of neuroblastoma was observed, a nonsignificant excess compared with US cancer registry (SEER) data (Stewart et al, ). In two large ( n = 240; n = 71) somatic sequencing studies of neuroblastoma, no somatic DICER1 variation was observed (Pugh et al, ; Sausen et al, ).…”

Ten years of DICER1 mutations: Provenance, distribution, and associated phenotypes

“…The penetrance of DICER1 pathogenic variants is generally low and is higher in females than in males. In a recent study by Stewart et al () ~5% of nonproband DICER1 heterozygotes were documented to have developed a neoplasm by age 10 years, which increased to ~20% by age 50 years. It can be hypothesized that the reduced penetrance of DICER1 syndrome (in non‐RNase IIIb mosaic patients) may be attributable to the unique nature of the DICER1 alterations required to initiate tumourigenesis (Brenneman et al, ).…”

“…Several lines of evidence can be used to evaluate germline DICER1 VUSs. These include assessing whether the observed VUS cosegregates with DICER1 syndrome‐related disease in the affected family with the caveat that the DICER1 syndrome phenotype is incompletely penetrant (Stewart et al, ). Another consideration is whether the VUS is paired with an RNase IIIb hotspot mutation in one or more associated tumors.…”

“…The penetrance of DICER1 pathogenic variants is generally low and is higher in females than in males. In a recent study by Stewart et al (2019) (Brenneman et al, 2015). Cells in a person bearing a germline loss-of-function variant will inevitably acquire random somatic mutations over time during DNA replication (Blokzijl et al, 2016;Vogelstein et al, 2013).…”

Multinodular goitre is a gateway for molecular testing of DICER1 syndrome

“…DICER1 families are at increased risk of developing thyroid cancer but although penetrance for MNG is high, only a small percentage of patients progress to DTC . Thyroid evaluation is recommended every 3 years unless nodules are detected for DICER1 ‐positive patients from 8 years of age, and age‐appropriate guidelines established by endocrine society should be followed for the evaluation of nodules when detected .…”