The DICER1 gene provides instructions for creating a protein that controls cell development and growth throughout the body. This protein regulates the balance between cell proliferation and specialization. When a mutation occurs, this regulatory function is disrupted, leading to a breakdown in growth control. This failure allows cells to multiply without restraint, which is the underlying mechanism for tumor formation. The presence of a DICER1 mutation is linked to a specific, hereditary predisposition that increases an individual’s lifetime risk for developing a variety of tumors.
The Role of the DICER1 Gene
The protein produced by the DICER1 gene acts as an endoribonuclease, an enzyme that cuts genetic material. Its primary function is to process double-stranded RNA molecules into much smaller fragments called microRNAs (miRNAs). This cleavage step is performed by the enzyme’s RNase III domains, which precisely trim the precursor molecule to release the mature microRNA. These mature microRNAs are then incorporated into a protein complex that targets messenger RNA (mRNA).
By binding to specific mRNA molecules, microRNAs effectively repress protein synthesis, thereby silencing the activity of certain genes. This process governs biological processes such as cell division and differentiation. The DICER1 protein acts as a brake on cellular growth, ensuring that cells do not divide or mature inappropriately.
A mutation often results in an abnormally short or non-functional DICER protein, leading to a deficiency in mature microRNAs. This deficiency allows for the uncontrolled cell growth that defines tumor development.
Understanding the DICER1 Syndrome
A mutation in the DICER1 gene causes an inherited condition named DICER1 tumor predisposition syndrome. This condition results from a germline mutation, meaning the genetic change is present in every cell of the body and was inherited from a parent. Inheritance follows an autosomal dominant pattern, meaning an individual needs only one copy of the altered gene to have the predisposition. Any person carrying the mutation has a 50% chance of passing it on to each of their children.
The syndrome demonstrates reduced penetrance, meaning that not every individual who inherits the mutation will ultimately develop tumors. The specific mechanism involves a two-step process where the inherited germline mutation is followed by a second, somatic mutation that occurs only in the cells of the tumor later in life. This second genetic change is typically a missense mutation in a specific region of the gene, which fully inactivates the protective function in that cell line. Sporadic mutations occur only in the tumor cells without any prior inherited germline change, and these cases are not considered part of the inherited DICER1 Syndrome.
Associated Tumors and Conditions
The spectrum of tumors associated with the DICER1 mutation involves both benign and malignant growths across multiple organ systems. The most serious and common manifestation, particularly in infants and young children, is Pleuropulmonary Blastoma (PPB). PPB is a rare, malignant tumor that develops in the lungs or the tissue covering the lungs, and it typically presents before the age of six years.
Another well-recognized tumor is the Sertoli-Leydig Cell Tumor (SLCT), a type of ovarian sex-cord stromal tumor that typically develops in affected females during their teens or twenties. Some SLCTs can produce male hormones, leading to symptoms like facial hair growth or irregular menstrual cycles in affected women. The kidneys are also commonly affected, primarily by Cystic Nephroma, which is characterized by multiple fluid-filled cysts and is generally non-cancerous in its initial presentation.
The thyroid gland frequently develops abnormalities, most often presenting as Multinodular Goiter (MNG), an enlargement of the gland due to the growth of multiple nodules. While these nodules are usually benign, individuals with the mutation have an increased risk for developing differentiated thyroid cancer, such as papillary or follicular types.
Less common, but characteristic, tumors are also associated with the syndrome. These include ciliary body medulloepithelioma (an eye tumor) and nasal chondromesenchymal hamartoma (a growth in the nasal cavity). Other tumors seen include certain brain tumors (pineoblastoma and pituitary blastoma) and embryonal rhabdomyosarcoma.
Genetic Testing and Surveillance Protocols
Identifying the DICER1 mutation involves genetic testing, typically performed on a blood sample to look for the inherited germline pathogenic variant. These tests use techniques like next-generation sequencing panels to analyze the entire gene sequence for the specific alteration. Genetic counseling is important, helping families understand the inheritance pattern, interpret results, and manage the medical risk for the individual and their relatives.
Once a germline mutation is confirmed, an age-specific surveillance program is recommended to detect tumors at their earliest stage. For the most serious risk, Pleuropulmonary Blastoma (PPB), surveillance involves a six-monthly chest X-ray starting from birth and continuing until at least six years of age. Some protocols also recommend a baseline, low-dose chest CT scan in the first year of life. Renal ultrasound is performed on the same six-month schedule, from birth up to age six, to screen for cystic nephroma.
For older children and adults, the focus shifts to other at-risk organs. A thyroid ultrasound is recommended every three years, typically starting around age eight and continuing into adulthood. Gynecologic screening is advised for females to monitor for Sertoli-Leydig cell tumors, often involving annual physical exams and pelvic ultrasounds starting at the onset of puberty. These surveillance protocols are designed to balance the benefits of early detection with the potential harms of repeated imaging and associated radiation exposure in young children.