Genetics is the study of the fundamental building blocks encompassing all living things. Through genetics, we are able to trace life’s potential for both good and harm; it is a key that unlocks a world of barely explored medical possibilities. 

To put a name on a genetic sequence and interpret how it will manifest—that is a wonder in itself. We can only imagine the amazement this would elicit in our medical predecessors, some of whom only had blunt tools to explore the landscape of the human body, health, and disease. 

In this article, we will explore what we know about the genetics of medullary thyroid carcinoma (MTC), specifically sporadic MTC and familial (inherited) MTC. Barletta and colleagues from Harvard University in Cambridge, Massachusetts, wrote a paper guiding readers on the genomics of both types of MTC, as well as their implications for clinical management. 

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RET Mutations Common in Sporadic MTC 

Approximately 75% of MTC cases are sporadic in nature, with the average age of diagnosis somewhere between 45 and 55 years of age. Around 50% of sporadic MTC cases have lymph node metastases at diagnosis, with 15% having distant metastases. 

The most common genetic mutations in sporadic MTC are RET mutations. What exactly are RET mutations? Barletta et al explained, “RET is a 21-exon gene located on the long arm of chromosome 10 (10q11.2). It encodes a tyrosine kinase transmembrane receptor and is involved in the normal development of the central and peripheral nervous systems as well as the genitourinary system and, in adults, is predominantly expressed in neural-crest-derived tissues.” 

Read more about MTC etiology

And its significance in cancer? They continued, “RET activates multiple pathways including the mitogen-activated protein kinase (MAPK) and the phosphoinositide 3-kinase (PI3K) pathways (among others), which, in turn, promote cell growth, proliferation, survival, and differentiation.” 

According to Larouche et al in their paper on the genetics of MTC, RET mutations differ from other mutations in that they represent gain-of-function mutations (most neoplastic mutations are loss-of-function mutations). 

RET mutations occur in roughly half of sporadic MTC cases. Importantly, RET status can serve as a prognostic indicator. RET mutations have been associated with poorer clinical outcomes. In one study, RET mutations were discovered to occur more frequently in MTC with lymph node and distant metastases; in other words, MTC patients with RET mutations typically present at more advanced stages of the disease. 

Familial MTC Takes Many Forms 

“As noted, up to 75% of MTC arise spontaneously, but notoriously, this tumor type is linked with familial disease that accounts for the remaining incidence,” prefaced Barletta et al. 

The familial forms of MTC follow an autosomal dominant pattern of inheritance. They are multiple endocrine neoplasia (MEN) types 2A and 2B as well as familial medullary thyroid carcinoma (FMTC). FMTC has been considered a subtype or a variant of MEN2A. 

According to Barletta and colleagues, recent classifications identify MEN2A and MEN2B as clinically distinct types of MEN2 syndrome and list 4 distinct types of MEN2A: 

  • Classical type MEN2A (patients typically have pheochromocytoma and/or hyperparathyroidism)
  • MEN2A with Hirschsprung disease
  • MEN2A with cutaneous lichen amyloidosis
  • FMTC-only (patients or families presenting with MTC only). 

Let’s examine some quick facts about MEN2A, MEN2B, and FMTC: 

  • MEN2A: represents 65% of inherited MTC, presenting age is typically 25 to 35 years, 14% will have lymph node metastases and 3% will have distant metastases. 
  • MEN2B: represents around 5% to 10% of inherited MTC, presenting age is typically 10 to 20 years, 38% will have lymph node metastases and 20% will have distant metastases. 
  • FMTC: represents around 25% of inherited MTC, presenting age is variable, and the percentage of patients with metastases is likewise variable.

As for medical intervention, Barletta et al wrote, “If MEN2A patients are known, they will often start having serum calcitonin screens at birth, with total thyroidectomy before the age of 5 based on serum calcitonin levels or once serum calcitonin levels become elevated. Intervention may be done earlier by parental request, as these patients will inevitably develop MTC.” 

The information presented in this article represents an opportunity for physicians to start treatment early, or commence prophylactic treatment if deemed necessary. “Given the clinical variability that depends on specific mutation present, it is recommended that all patients with a diagnosis of MTC have genetic testing performed,” Barletta et al wrote. 

Read more about MTC treatment 

Larouche et al provided a comprehensive explanation of why early genetic screening is crucial in saving lives. They wrote, “Early genetic screening of patients with a new diagnosis of MTC, first-degree relatives of index patients with RET-positive disease, and children with MEN2B phenotypes (cutaneous lichen amyloidosis or Hirschsprung disease) is paramount because prophylactic thyroidectomy can prevent MTC, which can develop into a life-threatening disease.”

Although we now have more therapies to treat MTC, surgical treatment is still considered the most effective option. “Treatment of MTC, whether positive or negative for germline RET mutation, is primarily surgical, including total thyroidectomy and neck dissection,” Larouche and colleagues wrote. 

However, there are hopes that our increased understanding of the genetics of MTC will open the door to future therapies that are less invasive and that are curative in nature.

Barletta and colleagues ended their study with eyes on the future: “Revolution in the development of small molecule pharmaceuticals that target specific gene products and gene-driven pathways without disruptions of broader, less specific physiologic functions has provided an opportunity for a more effective, more durable, and less morbid approach to treatment of patients with advanced MTC.” 


Barletta JA, Nosé V, Sadow PM. Genomics and epigenomics of medullary thyroid carcinoma: from sporadic disease to familial manifestationsEndocr Pathol. 2021;32(1):35-43. doi:10.1007/s12022-021-09664-3

Larouche V, Akirov A, Thomas CM, Krzyzanowska MK, Ezzat S. A primer on the genetics of medullary thyroid cancerCurr Oncol. Published online December 1, 2019. doi:10.3747/co.26.5553