DICER1-Related Tumor Predisposition: Identification of At-risk Individuals and Recommended Surveillance Strategies

Abstract

Purpose: DICER1-related tumor predisposition increases risk for a spectrum of benign and malignant tumors. In 2018, the International Pleuropulmonary Blastoma (PPB)/DICER1 Registry published guidelines for testing- and imaging-based surveillance of individuals with a known or suspected germline DICER1 pathogenic or likely pathogenic (P/LP) variant. One of the goals of the Registry is to continue to refine these guidelines as additional data become available.

Experimental design: Individuals were enrolled in the International PPB/DICER1 Registry, the International Ovarian and Testicular Stromal Tumor Registry, and/or the NCI Natural History of DICER1 Syndrome study.

Results: Review of participant records identified 713 participants with a germline DICER1 P/LP variant from 38 countries. To date, 5 cases of type I and 29 cases of type Ir PPB have been diagnosed by surveillance in enrolled individuals. One hundred and three individuals with a germline P/LP variant developed a primary ovarian Sertoli-Leydig cell tumor at a median age of 14 years (range: 11 months-66 years); 13% were diagnosed before 8 years of age, the current age of onset of pelvic surveillance. Additionally, 4% of Sertoli-Leydig cell tumors were diagnosed before 4 years of age.

Conclusions: Ongoing data collection highlights the role of lung surveillance in the early detection of PPB and suggests that imaging-based detection and early resection may decrease the risk of advanced PPB. DICER1-related ovarian tumors were detected before 8 years of age, prompting the Registry to recommend earlier initiation of ovarian surveillance with pelvic ultrasound beginning at the time of detection of a germline DICER1 P/LP variant.

Figure 1:

Violin plots by age at diagnosis of DICER1-related conditions among enrolled participants with a germline DICER1 P/LP variant; individuals with mosaicism or tumor-confined variants were excluded. A. Pleuropulmonary blastoma (PPB) and other thoracic tumors. B. Abdominal tumors, including kidney manifestations. Dashed line represents median and dotted lines represent first and third quartiles. Other Thoracic: congenital pulmonary airway malformation (n=2), bullae (n=2), thoracic Sertoli-Leydig cell tumor (n=1), sarcoma with rhabdomyoblastic differentiation indeterminate for PPB (n=1), malignant peripheral nerve sheath tumor (n=1), ganglioneuroblastoma (n=1), neuroblastoma (n=1) and mesothelial cyst (n=1). Other Abdominal: undifferentiated sarcoma with anaplasia (n=1), DICER1-associated cystic neoplasm of the liver (n=1), primitive malignant neoplasm (n=1), spindle cell sarcoma (n=1), neuroblastoma (n=1), embryonal rhabdomyosarcoma of the bladder (n=1) and liver hamartoma (n=1).

Figure 2:

Violin plots by age at diagnosis of DICER1-related conditions among enrolled participants with a germline DICER1 P/LP variant; individuals with mosaicism or tumor-confined variants were excluded. A. Female reproductive tract tumors including Sertoli-Leydig cell tumor (SLCT) and embryonal rhabdomyosarcoma (ERMS). B. Ciliary body medulloepithelioma (CBME), nasal chondromesenchymal hamartoma (NCMH), thyroid carcinoma and central nervous system (CNS) tumors. Dashed line represents median and dotted lines represent first and third quartile. *Does not include metachronous (second primary) SLCTs **Does not include metachronous genitourinary embryonal rhabdomyosarcoma (ERMS) Other Ovarian: sertoli cell tumor (n=3), juvenile granulosa cell tumor (n=2), mixed sex-cord stromal tumor (n=1), mucinous adenocarcinoma (n=1), yolk sac tumor (n=1), clear cell adenocarcinoma (n=1) and carcinoid tumor (n=1). Other Genitourinary: DICER1-associated sarcoma of the cervix (n=2), primitive neuroectodermal tumor of uterus (n=1) and cervical pleuropulmonary blastoma-like tumor (n=1). CNS: pineoblastoma (n=7), primary intracranial sarcoma, DICER1-mutant (n=5), medulloblastoma (n=2), undifferentiated round cell spinal tumor (n=1) and astrocytoma (n=1)

Figure 3.

Germline DICER1 testing framework.