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.

Figures

FIG 1.

Estimated neoplasm-free survival and hazard of first neoplasm—cancers plus DICER1-associated neoplasms cystic nephroma and nasal chondromesenchymal hamartoma—incidence among nonproband DICER1 carriers of the National Cancer Institute DICER1 study. (A and B) Estimated neoplasm-free survival among these individuals. See Appendix Table A7 (online only) for penetrance of neoplasm diagnosis by decade. (C and D) Estimated hazard of first neoplasm diagnosis. Female participants are denoted in red and male in blue. Dashed lines indicate nonparametric estimates (Kaplan-Meier curves). Solid lines indicate spline-estimated cumulative incidence and hazard. Left panels display curves to age 20 years and right panels to age 60 years. Common vertical axis markers of 0.5% event-free survival and 0.025 hazard are indicated by horizontal dashed lines and bold axis markers, and age 20 years is similarly marked on the horizontal axis.

FIG 2.

Estimated probability of neoplasm development accounting for competing risks—cumulative incidence—of specific DICER1-associated neoplasms among probands and nonprobands from the National Cancer Institute DICER1 study: type I pleuropulmonary blastoma (PPB; red), type II PPB (green), type III PPB (orange), cystic nephroma (purple), and Sertoli-Leydig cell tumor (SLCT; gray). Hatched multicolor lines denote overlap of multiple neoplasm cumulative risks. Cumulative incidence to (A) age 6 years and (B) age 60 years. Tick marks denote censoring times.

FIG 3.

Age of neoplasm diagnosis and neoplasm type for the 116 DICER1 carriers (151 neoplasms; proband and nonproband) from all three studies. Specific DICER1-associated neoplasms are highlighted in color: type I pleuropulmonary blastoma (PPB; red), type II PPB (green), type III PPB (orange), Sertoli-Leydig cell tumor (SLCT; purple), and cystic nephroma (gray). Diagnoses to (A) age 10 years and (B) age 60 years. Gray boxes span from the first to the third quartile of observed diagnoses, and vertical bars in the boxes indicate median diagnosis age. NCMH, nasal chondromesenchymal hamartoma.

FIG A1.

Diagram of counts of multiple primary DICER1-associated neoplasms: Pleuropulmonary blastoma (PPB, all types, except type Ir), malignant peripheral nerve sheath tumor (MPNST), nasal chondromesenchymal hamartoma (NCMH), Sertoli-Leydig cell tumor (SLCT), rhabdomyosarcoma, cystic nephroma, and thyroid cancer. Each neoplasm type is displayed as a vertex; for each pair of neoplasm, a line between their corresponding vertices indicates the number of individuals with at least one primary neoplasm of each type. The weight and color of the line, along with the number printed in a bubble on each line, indicate the number of individuals. Vertices with no shared line (eg, cystic nephroma and MPNST) indicate that no participants had a primary neoplasm of each type. One participant had multiple primary rhabdomyosarcomas, and three participants had multiple primary SLCTs. Data are also presented in Appendix Table A8 (online only).

FIG A2.

Study flow diagram detailing participant, neoplasm, and malignancy counts in the study (excluding type Ir PPB and thyroid nodules). NCI, National Cancer Institute; PPB, pleuropulmonary blastoma.