Observed genes

Polygenic score

Influential genes: PTCSC2,NRG1,DIRC3

PTCSC2 is a gene that has been linked to an increased risk of developing papillary thyroid carcinoma (PTC), the most common type of thyroid cancer.

NRG1 plays a role in the growth and development of multiple organ systems. An association of NRG1 gene and papillary thyroid cancer has been reported in scientific literature.

The DIRC3 gene has been shown to be downregulated in differentiated thyroid carcinomas (DTC). Moreover, its high expression in tumors may reduce the risk of tumor recurrence.

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Summary

Thyroid cancer is an abnormal growth of the cells originating in the thyroid gland, a gland producing hormones that regulate the body's metabolism. As thyroid cancer grows, it can cause voice changes and difficulty swallowing. One of the main risk factors is exposure to ionizing radiation and pre-existing thyroid disease. 

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Overview 

Thyroid cancer is a disease in which malignant cells form in the tissues of the thyroid gland - a small gland located on our neck producing hormones that regulate the body's metabolism. There are four different types of thyroid cancer, including papillary carcinoma, follicular carcinoma, medullary thyroid carcinoma, and anaplastic carcinoma - all of which have an individual prognosis, affect different cells and target different groups of patients:

• Differentiated thyroid cancer

• Papillary carcinoma represents 80% of thyroid carcinomas, affects younger patients (40 - 60 years old), and grows slowly with a good prognosis. 
• Follicular carcinoma represents 10% of thyroid carcinomas and has a worse prognosis. It tends to metastasize via blood to bones, lungs, and brain. 
• Medullary thyroid carcinoma develops from different types of cells than two previously mentioned tumors - parafollicular cells; those cells produce calcitonin, a hormone majorly important in calcium metabolism. Its growth is quite aggressive and may often occur familially - up to 25% of medullary thyroid carcinomas run in families.[1]

• Anaplastic carcinoma is an aggressive tumor that develops quickly, compresses surrounding structures, and quickly spreads via both blood and lymphatic systems. Fortunately, it represents overall only 2% of thyroid cancers. 

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Prevalence & Risk factors 

Over the last decades, the incidence of thyroid cancer has kept rising, mainly due to the increase in the usage of ultrasound examinations leading to the detection of even small tumors. A higher increase is observed in the more developed countries compared to less developed countries - however, the mortality rates are equal. The incidence also differs in sex and region, affecting three times more women than men and most affected countries in Europe being Lithuania, Italy, and Austria.[2] Thyroid cancer is nowadays the most common endocrine cancer and represents the seventh most common malignancy in women - but it is not even among the 15 common cancers in men.[3]

The exact reason for the malignant growth of the cells is unfortunately unknown, but certain risk factors can increase the risk of developing the disease. 

• The female sex increases the risk of developing thyroid cancer probably due to estrogens, which are generally present in higher levels in the female body. Unfortunately, the exact link still has not been discovered.
• Radiation exposure is also a proven risk for thyroid cancer, especially at a younger age. The most common radiation source is medical treatment, but radiation fallout from nuclear plant accidents or nuclear weapons can also be responsible. For example, a significant increase in thyroid cancer incidence was reported after the Chernobyl disaster, mainly among children and adolescents. 
• Inherited genetic syndromes, such as MEN 2A and MEN 2B, can cause thyroid cancer alongside other malignant processes. 

Although their influence is significantly lower, there are even more risk factors, including thyroid nodules, high BMI, lifestyle, diet, iodine deficiency, or autoimmune diseases.[4] 

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Genetics 

Recent progress in genome sequencing has offered a better understanding of the molecular mechanisms of thyroid cancer (TC). Familial forms of medullary thyroid cancer (MTC) have been described, but a person with an affected first degree relative with non-medullary thyroid cancer has a 4x to 10x higher risk of developing the disease as well.[11,12]

The molecular mechanisms of TC involve disruption of important cellular signaling pathways (a series of chemical reactions that result in the activation/deactivation of certain cellular functions: e.g. MAPK and PI3K/AKT).[11]

Mutations in the following genes have been described to cause TC: RET, RAS, P13K/AKT, BRAF, and TERT. Many research groups described an association of BRAF variant p.V600E (amino acid valine is replaced with glutamic acid on position 600) with poor outcomes of papillary thyroid cancer (PTC), including increased risk of recurrence and treatment failures. Observed hTERT mutations have a significantly higher prevalence in aggressive TC tumors and mutations of the BRAF, RAS, or RET genes are found in up to 70% of PTC cases. Overall, cancer-promoting mutations are identified in more than 90% of patients.[12,13]

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Here in Macromo, polygenic risk scores are used to determine the genetic risk. The polygenic risk score (PRS) is an estimate of the probability that an individual carries a given trait based on genetics, without considering environmental factors. Variants across their genome are summed and weighted according to their effect on the disease or trait.

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Signs & symptoms 

It's quite common for patients with thyroid cancer to experience only mild symptoms or none. The changes that might indicate the disease include:

• A painless lump in the front of the neck
• Difficulty swallowing
• Difficulties breathing
• Swelling in the neck
• Persistent cough
• Hoarseness or other voice changes
• Pain in the throat or neck 

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If you experience any of these symptoms, don't hesitate to contact your doctor. But don't panic; in many cases, the causes of those symptoms are non-cancerous medical conditions.[5] Lumps in the thyroid gland are very common, and in 95% bening - it's estimated that more than half of the population will have at least one thyroid nodule by the age of 60.[6]

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Diagnosis 

If any present symptoms increase the suspicion of thyroid cancer, your doctor will do a thorough anamnesis, physical examination and might indicate further steps. A blood test, called a thyroid function test, is used to assess thyroid hormone levels. Abnormal thyroid levels usually indicate issues other than cancer, such as hypo or hyperfunctioning thyroid gland. To find suspicious areas and their characteristics, various imaging methods are used. One of the most used methods is ultrasound, especially because it's quick, cheap, and usually readily available. Ultrasound uses high-frequency sound waves and creates a real-time image of the inside of your body. A biopsy must be performed to assess whether a thyroid lump is cancerous. During biopsy, a small amount of tissue is extracted with a needle and analyzed in the lab. This histopathologic examination is the only method able to confirm the diagnosis, sometimes the biopsy is only obtained during the surgery to decide about the next step intraoperatively.[7]

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Therapy 

Thyroid cancer therapy highly depends on the type of cancer and how much it has spread. A widespread method is a surgery called a thyroidectomy, in which the thyroid gland or its parts are surgically removed. Another commonly used procedure is radioactive iodine treatment, in which a radioactive substance is swallowed in the form of a drink or a capsule and absorbed in the gut. It then travels to the thyroid gland, and attacks cancerous cells locally. Iodine is a main component in the synthesis of thyroid hormones, which is why the therapy works very well and only affects the gland while sparing the body. Some newer methods include thyroid hormone therapy and targeted cancer drugs that directly target the cancer cells and try to minimize the damage to healthy cells. If other treatments aren't successful, external radiotherapy might be used - a method in which radioactive beams try to damage the cancer cells from a machine outside the body. Chemotherapy isn't commonly used for thyroid cancer, only if cancer has spread or returned and can't be sufficiently treated by the other treatment options.[8]

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Prevention 

As in all cancers, thyroid cancer can't be fully prevented, and most of the patients didn't have any known risk factors causing the development of the disease. But as we already know, proven risk factors exist, and it's therefore always beneficial to limit exposure to them to the minimum. 

• Limit radiation exposure. Many professions, mainly in healthcare, include working in an environment with an increased risk of radiation exposure; healthcare workers should therefore wear a protective vest and neck protector and limit their exposure to the minimum. Radiation treatment can also no longer be used for less serious diseases.
• Consider genetic counseling if you have a positive family history of thyroid cancer. Most familial cases can be prevented by removing the thyroid gland and supplementing its hormones.[9]
• Don't underestimate regular preventive checkups. An early diagnosis is key to the successful treatment of the disease. 
• Adhere to a healthy lifestyle, including diet and physical movement.[10]

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Prognosis

On the opposite of the incidence of thyroid cancer, mortality rates have decreased in Europe over time. Thyroid cancer has overall the highest survival rate and the best prognosis of all malignant tumors, except for some rare histological types (such as the previously mentioned anaplastic thyroid carcinoma, which is one of the most aggressive cancers in humans). The 5-year relative survival rate in Europe ranges from 80-90%. Due to the increased detection and better diagnostics, many thyroid tumors are found in the initial stages and might be effectively treated.[2]

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Recommendations

• Limit radiation exposure to the minimum, especially around your head and neck.
• Adhere to regular preventive checkups. It's the key to an early diagnosis and, therefore, a good prognosis. 
• Be aware of your family history of thyroid cancer.
• Don't hesitate to contact your doctor if you find lumps in your neck or experience difficulty swallowing, breathing, or a hoarse voice.

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