Thyroid cancer originates in the thyroid gland, a butterfly-shaped organ located at the base of the neck that produces hormones regulating metabolism. The relationship between genetics and thyroid cancer is complex, involving both inherited predispositions and acquired genetic alterations.
The Role of Genetics in Cancer Development
Cancer development is a genetic process, driven by changes in a cell’s DNA. These genetic changes, known as mutations, can alter the function of specific genes that control cell growth and division. Mutations are broadly categorized into two types: germline and somatic. Germline mutations are inherited from a parent and are present in every cell of the body from birth, including reproductive cells.
Conversely, somatic mutations are acquired during a person’s lifetime and are not inherited. These changes occur in specific cells and are typically confined to the tumor. Genes involved in cancer development often fall into two groups: oncogenes and tumor suppressor genes. Oncogenes are modified proto-oncogenes that promote cell growth and division, becoming activated when mutated. Tumor suppressor genes, in contrast, normally regulate cell division and can initiate cell death, but when mutated, they lose their ability to control cell growth, leading to uncontrolled proliferation.
Inherited Thyroid Cancer Syndromes
Some forms of thyroid cancer have a clear inherited genetic basis, often presenting as part of broader hereditary syndromes. Multiple Endocrine Neoplasia Type 2 (MEN2) is a notable example, caused by germline mutations in the RET gene. This syndrome significantly increases the risk of medullary thyroid cancer (MTC), a less common but often more aggressive type of thyroid cancer. Individuals inheriting the RET mutation have a high likelihood of developing MTC. MEN2 is inherited in an autosomal dominant pattern, meaning a child has a 50% chance of inheriting the mutated gene if one parent carries it.
Familial Adenomatous Polyposis (FAP) is another inherited condition linked to papillary thyroid cancer (PTC). FAP is caused by germline mutations in the APC gene and is primarily characterized by numerous colon polyps. While the absolute risk is low, the relative risk for women with FAP can be significantly higher.
Cowden Syndrome, associated with germline mutations in the PTEN tumor suppressor gene, also elevates the risk for thyroid cancer, primarily follicular and papillary types. This syndrome involves a predisposition to benign growths and an increased risk for several cancers, including breast, endometrial, and thyroid cancers.
Genetic Changes in Sporadic Thyroid Cancer
Most thyroid cancers are sporadic, arising from genetic changes acquired during a person’s lifetime. These somatic mutations occur within thyroid cells and drive cancer development.
A common somatic mutation found in papillary thyroid cancer (PTC), the most prevalent type, is in the BRAF gene, particularly the V600E variant. This mutation is present in a significant proportion of PTCs and is associated with activation of cellular signaling pathways that promote cell growth.
Mutations in the RAS genes (HRAS, KRAS, NRAS) are also frequently observed in sporadic thyroid cancers, particularly in follicular thyroid cancer (FTC) and some PTCs. These RAS mutations can lead to uncontrolled cell proliferation and are typically mutually exclusive with BRAF mutations.
Another significant somatic alteration in FTC is the PAX8/PPARĪ³ rearrangement, a fusion of two genes that contributes to tumor growth. Additionally, mutations in the TERT promoter region are found in various thyroid cancer types, including PTC and FTC. These are often associated with more aggressive tumor behavior and a poorer prognosis, especially when co-occurring with BRAF or RAS mutations. These somatic changes provide targets for understanding tumor biology and developing treatments.
Genetic Testing and Family Implications
Genetic testing is considered for individuals with a personal or family history suggestive of a hereditary thyroid cancer syndrome. This is particularly relevant for those diagnosed with medullary thyroid cancer, as about 25% of these cases are hereditary and linked to RET gene mutations. Testing may also be recommended if there is a strong family history of thyroid cancer, especially if multiple close relatives have been affected or if cancer developed at an early age. Genetic counseling plays a significant role in this process, helping individuals understand the benefits and limitations of testing, interpret results, and assess their personal and family risk.
If a germline mutation is identified, it has substantial implications for family members, who may also be at risk. Predictive testing for at-risk relatives allows for increased surveillance, early detection, and sometimes prophylactic measures, like thyroid surgery, to prevent cancer development.