by Jason Wasserman MD PhD FRCPC
March 30, 2026
If your pathology report or genetic test results mention a RET mutation or a RET fusion, these refer to two distinct types of change in the RET gene that play important roles in different types of thyroid cancer. RET mutations — where a specific letter in the gene’s code is altered — are the primary driver of medullary thyroid carcinoma and are closely linked to a hereditary syndrome that can affect multiple family members. RET fusions — in which the RET gene is abnormally joined to another gene — are found in a subset of papillary thyroid carcinomas and have become an important treatment target in advanced disease. Understanding which type of RET alteration you have, and in which cancer, is the key to understanding what the result means for your treatment and for your family.
What the test looks for
The RET gene provides the instructions for making a receptor protein — also called RET — that sits on the surface of certain cells and receives signals that tell the cell to grow, divide, and survive. In healthy cells, this receptor switches on only when the right signal arrives, and switches off again once the signal has passed.
Two fundamentally different types of change can disrupt this normal behaviour in thyroid cancer:
- RET point mutations. A point mutation is a change at a single specific location in the gene’s code — one letter of the DNA sequence is altered in a way that changes the shape or behaviour of the RET protein. In medullary thyroid carcinoma, specific point mutations in the RET receptor keep it permanently active, continuously driving growth signals even in the absence of external stimulation. These mutations are highly specific in their location — particular codons (positions in the gene) are mutated far more often than others, and the specific codon affected predicts both the risk of aggressive disease and the likelihood of hereditary cancer syndromes in the family.
- RET fusions. A fusion occurs when a structural rearrangement in the cancer cell’s chromosomes causes the RET gene to break and rejoin with a different gene, creating an abnormal hybrid gene. The fusion protein produced by this hybrid gene contains the active signalling domain of RET permanently attached to another protein, thereby producing a receptor that is continuously switched on. RET fusions are found in papillary thyroid carcinoma, not medullary thyroid carcinoma, and are somatic changes — they arise in the cancer cells during a person’s lifetime and are not inherited.
These two types of RET alteration behave differently, arise in different thyroid cancer subtypes, and have different implications for treatment and hereditary risk. The rest of this article addresses them separately.
RET mutations in medullary thyroid carcinoma
Why is the test done
RET testing is a central part of the workup for all patients diagnosed with medullary thyroid carcinoma. It serves two equally important purposes.
The first is to determine whether the cancer has a hereditary cause. Approximately 25% of medullary thyroid carcinomas are caused by an inherited germline RET mutation — meaning the mutation was present from birth and exists in every cell in the body, not just the tumour. Patients with germline RET mutations carry a high lifetime risk of medullary thyroid carcinoma, and many also have elevated risks of other tumours as part of a hereditary syndrome called multiple endocrine neoplasia type 2 (MEN2). Identifying a germline mutation enables relatives to be tested and, if they carry it, to undergo preventive surgery or surveillance before cancer develops.
The second purpose is to guide treatment in advanced or metastatic disease. When medullary thyroid carcinoma has spread beyond the neck and requires systemic therapy, the specific RET mutation identified — or the confirmation that no RET mutation is present — informs the choice between targeted RET inhibitors and other systemic agents.
Germline versus somatic RET mutations
Like BRCA testing in ovarian cancer, RET testing in medullary thyroid carcinoma distinguishes between two types of mutation with different implications:
- Germline RET mutation. Found in the blood — present in every cell in the body. This means the mutation was inherited and can be passed to biological children. Approximately 25% of medullary thyroid carcinoma cases are caused by germline RET mutations. All first-degree relatives (parents, siblings, children) of a person with a germline RET mutation should be offered genetic testing, because carriers can develop medullary thyroid carcinoma — often at a younger age and more aggressively than sporadic cases — and preventive thyroidectomy performed before cancer develops is highly effective.
- Somatic RET mutation. Found only in the tumour cells, not in the blood. This means the mutation developed in the cancer during the person’s lifetime and is not inherited. Approximately 40–50% of sporadic (non-hereditary) medullary thyroid carcinomas carry somatic RET mutations. A somatic mutation does not affect family members and does not indicate a hereditary syndrome.
Because the distinction between germline and somatic has such important implications for family members, standard practice is to perform both tumour testing and blood-based germline testing for all patients diagnosed with medullary thyroid carcinoma — even those with no family history of the disease. A meaningful proportion of germline carriers have no family history that would suggest it.
MEN2 and codon-specific risk stratification
When a germline RET mutation is identified, the specific codon (position in the gene) that is mutated determines which hereditary syndrome the patient has and how aggressively medullary thyroid carcinoma is likely to behave. This is called codon-specific risk stratification, and it directly guides decisions about preventive surgery.
The three hereditary syndromes associated with germline RET mutations are:
- Multiple endocrine neoplasia type 2A (MEN2A). The most common inherited RET syndrome. In addition to medullary thyroid carcinoma, patients with MEN2A have an increased risk of pheochromocytoma (a tumour of the adrenal gland that produces adrenaline) and hyperparathyroidism (overactivity of the parathyroid glands, causing high calcium levels). MEN2A is caused by mutations at several codons, most commonly codon 634. The timing of recommended preventive thyroidectomy depends on the specific codon.
- Multiple endocrine neoplasia type 2B (MEN2B). A less common but more aggressive syndrome caused almost exclusively by a mutation at codon 918. Medullary thyroid carcinoma in MEN2B tends to develop in infancy or early childhood and is the most aggressive form of hereditary medullary thyroid carcinoma. Preventive thyroidectomy is recommended within the first six months of life for infants with this mutation. MEN2B is also associated with pheochromocytoma and with characteristic physical features, including mucosal neuromas (small bumps on the lips and tongue) and a tall, thin body type.
- Familial medullary thyroid carcinoma (FMTC). A form of hereditary medullary thyroid carcinoma without the other tumours seen in MEN2A or MEN2B. Mutations at lower-risk codons cause FMTC and are generally associated with a later age of onset and a less aggressive course than MEN2A or MEN2B.
Based on codon-specific risk data, the American Thyroid Association classifies germline RET mutations into three risk categories — highest risk, high risk, and moderate risk — each with specific recommendations for the timing of preventive thyroidectomy and the frequency of biochemical screening. If a germline RET mutation is identified, your genetic counsellor and endocrinologist will explain which category applies to your mutation and what the recommendations mean for you and your family members who are carriers.
How the test is performed
RET testing in medullary thyroid carcinoma is performed on two sample types:
Germline testing is performed on a blood sample. DNA is extracted from white blood cells — which carry the patient’s constitutional genetic code — and analysed by sequencing to look for mutations across the entire RET gene. This test is arranged through a genetics clinic or oncology programme and is accompanied by pre- and post-test genetic counselling.
Tumour testing is performed on tissue obtained during surgery or biopsy. DNA from the tumour cells is analysed using next-generation sequencing (NGS), which can identify point mutations in the RET gene, as well as other clinically relevant alterations, in a single test. A mutation found in tumour tissue is then compared to the germline result to determine whether it is somatic or germline in origin.
How results are reported
RET germline results are typically reported as:
- Pathogenic or likely pathogenic variant detected. A mutation has been identified that is known or strongly expected to cause disease. The report will specify the codon affected, the exact mutation, and the associated syndrome risk category. This is a positive result with direct implications for the patient and their family.
- No pathogenic variant detected. No germline RET mutation was identified. This result makes hereditary MEN2 unlikely, though it does not rule out all hereditary cancer risk — other genes may be relevant in rare cases, and a genetics referral is still appropriate to review the full picture.
- Variant of uncertain significance (VUS). A change in the RET gene was found, but its clinical significance has not yet been established. VUS results should not be used to make treatment decisions and require discussion with a genetic counsellor. Classifications may be updated over time as more data accumulate.
Somatic tumour testing reports will describe the specific mutation found in the tumour, its location in the gene, and may include information relevant to targeted therapy eligibility.
What the result means for treatment
For most patients with localised medullary thyroid carcinoma, the RET result guides hereditary risk assessment and family management more than it changes the initial surgical treatment — total thyroidectomy with central neck dissection is the standard approach regardless of RET status. However, in patients with advanced, recurrent, or metastatic medullary thyroid carcinoma that requires systemic therapy, the RET result becomes directly treatment-relevant.
Selpercatinib (Retevmo) and pralsetinib (Gavreto) are selective RET inhibitors approved for RET-mutated medullary thyroid carcinoma. These drugs block the constitutively active RET protein with high precision. In the LIBRETTO-001 trial, selpercatinib achieved an objective response rate of approximately 69% in previously treated patients with RET-mutated medullary thyroid carcinoma, with a median duration of response exceeding two years. Response rates in treatment-naïve patients were even higher. Pralsetinib showed comparable efficacy in the ARROW trial, with an objective response rate of approximately 60% in previously treated patients.
These results represent a substantial advance over the older multikinase inhibitors — vandetanib and cabozantinib — which inhibit RET among many other targets and were previously the main systemic options for advanced medullary thyroid carcinoma. The selective RET inhibitors achieve higher response rates with a more manageable side effect profile.
Tumours without a RET mutation — approximately 10–15% of sporadic medullary thyroid carcinomas carry RAS mutations instead, and a small proportion have neither — are not expected to respond to selective RET inhibitors. In these cases, vandetanib, cabozantinib, or enrolment in a clinical trial is discussed as a systemic option.
RET fusions in papillary thyroid carcinoma
Why is the test done
RET fusions are found in approximately 10–20% of papillary thyroid carcinomas overall, with substantially higher rates in specific populations: they are found in up to 50–60% of papillary thyroid carcinomas arising in people who were exposed to radiation in childhood — including survivors of the Chernobyl nuclear accident and patients who received radiation therapy to the neck during childhood — and in up to 40–70% of papillary thyroid carcinomas diagnosed in children and adolescents. RET fusions activate the same MAPK growth-signalling pathway as BRAF V600E mutations, and they produce a similar clinical picture: papillary thyroid carcinoma with a tendency toward lymph node metastases and extrathyroidal extension.
RET fusion testing in papillary thyroid carcinoma is done for two reasons. In patients with indeterminate thyroid nodule biopsies, identifying a RET fusion substantially increases the probability that the nodule is malignant and may guide the decision to proceed with surgery. In patients with advanced or radioiodine-refractory papillary thyroid carcinoma requiring systemic therapy, a RET fusion identifies eligibility for selective RET inhibitor treatment.
How the test is performed
RET fusions in papillary thyroid carcinoma are detected using next-generation sequencing — ideally RNA-based NGS, which directly sequences the fusion transcript and is the most sensitive method for detecting rearrangements. DNA-based NGS can also identify RET fusions at the genomic level. Fluorescence in situ hybridisation (FISH) can detect RET rearrangements using split-signal probes and may be used at centres where NGS is not routinely available for thyroid nodule workup. All tests are performed on tumour tissue from surgery or biopsy.
RET fusions are somatic changes — they are not present in normal cells and are not inherited. Blood-based germline testing is not indicated when a RET fusion is identified in papillary thyroid carcinoma. This is an important distinction from RET mutations in medullary thyroid carcinoma, where germline testing is a standard part of the workup.
How results are reported
RET fusion results are reported as fusion detected or no fusion detected. When a fusion is detected, the report will typically identify the partner gene — common partners in papillary thyroid carcinoma include CCDC6, NCOA4, and others — and may describe the specific breakpoint. The partner gene does not change the fundamental treatment implication; the actionable finding is the presence of a RET fusion regardless of the partner.
What the result means for treatment
For most patients with localised papillary thyroid carcinoma, a RET fusion result is primarily used for diagnostic support and risk stratification, rather than directly triggering targeted drug therapy. RET fusions are associated with a higher rate of lymph node metastases compared to RET-negative papillary carcinomas, which may influence the extent of surgery and follow-up.
In patients with advanced, unresectable, or radioiodine-refractory papillary thyroid carcinoma, a RET fusion identifies eligibility for selective RET inhibitor therapy. Selpercatinib is approved for RET fusion-positive thyroid cancers, including papillary thyroid carcinoma, that are radioiodine-refractory and require systemic treatment. In the LIBRETTO-001 trial, selpercatinib achieved an objective response rate of approximately 79% in previously treated patients with RET fusion-positive thyroid cancers, with a median duration of response exceeding 18 months. This result compares very favourably to the multikinase inhibitors previously used in this setting.
If your papillary thyroid carcinoma is localised and has been successfully treated with surgery and radioactive iodine, the RET fusion result is less likely to influence further treatment decisions directly. However, it remains part of the molecular picture used to assess recurrence risk.
Implications for family members
The hereditary implications of a RET result depend entirely on the type of alteration found and the cancer type:
- Germline RET mutation (medullary thyroid carcinoma). This is a hereditary finding with direct implications for biological relatives. Each first-degree relative has a 50% chance of carrying the same mutation. Family members who test positive can access preventive thyroidectomy and appropriate surveillance for other MEN2-associated tumours. This is one of the most actionable hereditary cancer findings in all of oncology — preventive surgery performed before medullary thyroid carcinoma develops is essentially curative. A genetic counsellor will guide the process of cascade testing and help you navigate conversations with family members.
- Somatic RET mutation (medullary thyroid carcinoma). Found only in the tumour, not inherited. No implications for family members.
- RET fusion (papillary thyroid carcinoma). A somatic alteration arising in the tumour cells. Not inherited and not present in normal cells. No implications for family members. A RET fusion in a papillary thyroid carcinoma does not indicate MEN2 and does not warrant germline RET testing or family cascade testing.
What happens next
For patients with medullary thyroid carcinoma, if germline RET testing has not yet been performed, it should be arranged — ideally through a genetics clinic or endocrinology programme with experience in hereditary thyroid cancer. This applies even when there is no family history of medullary thyroid carcinoma, since a meaningful proportion of germline carriers present without a known family history. If a germline mutation is confirmed, a genetic counsellor will coordinate cascade testing for relatives and advise on the appropriate timing of preventive measures for those who test positive.
If medullary thyroid carcinoma has spread beyond what surgery can address, or if it recurs after initial treatment, your oncologist will review the RET mutation result as part of planning systemic therapy. If a RET mutation is present, selective RET inhibitor therapy — selpercatinib or pralsetinib — will be discussed. If no RET mutation is present, other systemic options, including vandetanib, cabozantinib, or clinical trials, will be considered.
For patients with papillary thyroid carcinoma, if the cancer is localised and responding to standard treatment, the RET fusion result will be incorporated into risk stratification and follow-up planning. If the cancer has progressed to an advanced or radioiodine-refractory stage, your oncologist will discuss targeted therapy options, including selpercatinib if a RET fusion is present, alongside other systemic agents such as lenvatinib or sorafenib.
For patients with either cancer type where molecular testing has not yet been performed, it is worth asking your endocrinologist or oncologist whether testing is available and appropriate for your situation.
Questions to ask your doctor
- Has RET testing been performed on my tumour, and if so, was a mutation or a fusion identified?
- If I have medullary thyroid carcinoma, has germline RET testing been arranged, and if not, how do I access it?
- If a germline RET mutation is confirmed, what does the specific codon mean for my risk and the timing of any further action?
- Should my family members be tested, and how should I approach telling them the results?
- If my cancer is advanced or has stopped responding to radioactive iodine, am I eligible for a selective RET inhibitor such as selpercatinib or pralsetinib?
- If no RET alteration is present, what other molecular alterations were found, and are any of them actionable?
- Are there clinical trials I should be aware of based on my RET result?
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