Thyroid cancer (TC) begins when cells in the thyroid gland, the butterfly-shaped organ in the neck, grow out of control. While the majority of cases are considered sporadic, meaning they occur randomly, a significant minority has a strong genetic link that runs in families. Understanding the genetics of TC requires distinguishing between two types of changes: germline mutations, which are inherited from a parent, and somatic mutations, which are acquired during a person’s lifetime. The inherited forms, though less common, carry a much higher lifetime risk for developing the disease.
The Non-Inherited Majority of Thyroid Cancers
The vast majority of thyroid cancer cases are non-hereditary, accounting for about 90–95% of all diagnoses. These sporadic cancers primarily include the common types: Papillary Thyroid Carcinoma (PTC) and Follicular Thyroid Carcinoma (FTC). These cancers are driven by somatic mutations, which are acquired after conception and confined to the tumor cells.
These acquired genetic alterations cannot be passed on to children. One of the most prevalent somatic mutations is the BRAF V600E mutation, found in approximately 40% of classic papillary thyroid cancers. This mutation drives cell growth and division in the thyroid.
Other common somatic changes involve the RAS family of genes (NRAS, HRAS, and KRAS), often found in follicular thyroid carcinomas. These sporadic mutations can happen randomly during cell division or may be triggered by environmental factors, such as significant exposure to ionizing radiation during childhood. Since these changes are not inherited, a sporadic diagnosis in one family member does not raise the risk for their relatives.
Syndromes Linked to Hereditary Thyroid Cancer
Approximately 5–10% of all thyroid cancers have a hereditary component linked to a pathogenic germline variant. This inherited risk is most pronounced in Medullary Thyroid Cancer (MTC), a type that arises from the thyroid’s C cells, which produce the hormone calcitonin. About 25% of MTC cases are hereditary, making it the most strongly inherited form of thyroid malignancy.
The genetic basis for hereditary MTC is almost always a germline mutation in the RET proto-oncogene. This gene provides instructions for making a protein involved in cell signaling pathways controlling growth and survival. An inherited mutation causes this protein to be constantly active, leading to uncontrolled cell proliferation.
Mutations in the RET gene are responsible for Multiple Endocrine Neoplasia type 2 (MEN2), an inherited cancer syndrome. Individuals with MEN2 inherit the RET mutation in an autosomal dominant pattern, meaning a single altered gene copy is sufficient to confer a high risk of developing MTC and potentially other endocrine tumors. MEN2 has three subtypes: MEN2A, MEN2B, and Familial Medullary Thyroid Carcinoma (FMTC).
Rarer hereditary syndromes can also predispose individuals to papillary or follicular thyroid cancers. These include:
- Cowden syndrome, linked to mutations in the PTEN gene, which increases the risk of thyroid, breast, and endometrial cancers.
- Familial Adenomatous Polyposis (FAP), caused by a mutation in the APC gene, associated with an increased risk of papillary thyroid cancer.
- Carney complex type 1.
- DICER1 syndrome.
Genetic Screening and Family History Tracking
When a thyroid cancer diagnosis is made, particularly MTC, genetic testing is often recommended to determine if an inherited syndrome is present. Testing for germline mutations, such as the RET gene change associated with MTC, typically involves a simple blood sample. Identifying an inherited genetic change is beneficial because it allows for proactive management and screening of the affected individual and their relatives.
Genetic counseling is important before and after testing to interpret results and discuss implications for the patient and family. A diagnosis of an inherited mutation, such as in the RET gene, often leads to recommendations for increased surveillance or prophylactic surgery to remove the thyroid gland before cancer develops. The timing of this preventative surgery is determined by the specific RET mutation, as different mutations confer varying levels of risk.
Tracking a detailed family history is a powerful tool for identifying potential hereditary risk. Physicians look for patterns such as two or more first-degree relatives diagnosed with any type of thyroid cancer, or a diagnosis of MTC in any relative. Other flags suggesting an inherited predisposition include the onset of thyroid cancer at a young age (typically under 50) or the presence of multiple primary cancers in one person.