First and foremost, most individuals with medullary thyroid cancer do not have an inherited medullary thyroid cancer caused by a mutation of the RET gene from one of their parents. In fact, about 75% of medullary thyroid cancers are spontaneous and not inherited. The second important point is that the genetics of medullary thyroid cancers is not a simple issue. As our understanding of mutations and cancers continue to increase on literally a daily basis, make sure that you have adequate counseling before considering genetic testing to determine whether a medullary thyroid cancer is inherited. Asking such questions can have profound effects upon you but also your family members and you must be adequately informed what the potential impact of genetic testing may have upon you and others. Last, the RET gene is only one gene that I will be discussing in this section. It is required to inherit medullary thyroid cancer. However, other genetic events can also occur in these cancers which may further effect how aggressive these medullary thyroid cancers may behave. Additionally, as our understanding of developing “genetic profiles” of cancers continues to develop, new targets may be useful to deliver or develop targeted therapy now and in the future.

Important- In medullary thyroid cancer, there is a lot written about the RET gene and how it may predict the potential behavior these thyroid cancers. Multiple endocrine neoplasia type 2 (MEN2) is a genetically inherited syndrome that is inherited in a fashion called autosomal dominance. What this means is that if your parent has this gene, you have a 50% chance of inheriting the abnormal gene. If that gene is autosomal dominant, that means that whatever that gene causes, if you inherit the gene, you will also see the traits associated with that gene. If an individual inherits a RET mutated gene, the risk of developing a medullary thyroid cancer by the age of 70 is 70 to up to 100% depending upon where the mutation is located on the RET gene.

Genes are made of complex sequences of amino acids (very small proteins). The RET gene can be mutated in many different locations along the gene. What you will see later in this section are numbers associated with the RET gene mutations. These are called codons and these numbers are used to describe the particular area of the gene which is mutated (abnormal).

There are three different variants of MEN2 (the principle common feature of all MEN subtypes is medullary thyroid cancer.

  • MEN2A
    • Medullary thyroid cancer
    • Pheochromocytoma (an adrenal gland tumor that can produce excess hormones and can drastically increase blood pressure and heart rate)
    • Primary hyperparathyroidism (a parathyroid tumor that causes elevated blood calcium)
    • May include Hirshsprung’s disease and cutaneous lichen amyloidosis
  • MEN2B
    • Medullary thyroid cancer
    • Pheochromcytoma
    • Intestinal neuromas (benign nerve lumps in the intestines)
    • Mucosal ganglioneuromas (benign nerve lumps predominantly occurring around the lips, tongues and eyelids)
  • Familial medullary thyroid cancer
    • Medullary thyroid cancer only!

Approximately 25% of medullary thyroid cancers are hereditary. Since the discovery of the RET gene mutations responsible for MEN2, as many as 50 different point mutations have been identified in this gene associated with development of medullary thyroid cancers. That is a lot of different possibilities of where the RET gene can be mutated. Importantly, different mutations of the RET gene produce, often times quite predictably, very different behaviors of medullary thyroid cancers. What this means is that if you have an inherited mutation of the RET gene, knowing your mutation allows your medullary thyroid cancer expert team to largely understand how your medullary thyroid cancer will present and behave like, and the other endocrine tumors which may be associated including the adrenal tumors called pheochromocytomas and parathyroid tumors.

Medullary Thyroid Cancer Most Common Genetic Mutations: Recommended Age for Prophylactic Thyroidectomy

Risk of Medullary Thyroid Cancer

Most Common RET Mutation

Age for Undergoing Prophylactic Thyroidectomy

Level I (high)

609

630

768

790

791

804

891

By 5-10 years of age

Level II (higher)

611

618

620

634

By 5 years of age

Level III (highest)

883

918

922

Within first six months of life (preferably first month of life)

Medullary Thyroid Cancer RET Mutations Predict How Some Cancers May Behave!

Approximately 85% of patients with hereditary (familial) medullary thyroid cancer a mutation if the RET gene at 634. Mutations in the RET gene occur in codons 609, 611, 618, and 620 account for another 10% or so. The early and aggressive medullary thyroid cancers possess mutations in the RET gene at codons 634 and 918, and require as early interventions as possible. In comparison, the 883 codon mutation of RET is associated with a much more indolent (slow growing and rarely spreading to lymph node type of medullary thyroid cancer). Thus, knowing the RET mutation, tells your thyroid cancer specialist quite a bit of information.

Specific RET Gene Mutations and What They Produce!

The below table is quite complicated and requires significant understanding and effort to understand its complexity. It is included here because it allows you to understand how far our understanding has come with the specific RET gene mutations that are know to be inherited and what they produce. In this way, the thyroid cancer team taking care of an inherited medullary thyroid cancer patient and their family members understands the diseases that can occur with specific mutations of the RET gene. Not only do we know what diseases that may occur, but we also know the risk for developing these diseases at a specific time in the patient’s lifetime. We may also know, for example the risk of spread to lymph nodes and distant sites. It allows us to counsel patients on how to observe for specific diseases and the timing screening evaluations. Further, it even allows us to counsel patients and family members on the indication and timing of prophylactic thyroidectomy for specific RET mutations.

American Thyroid Association Risk

RET Mutation

MEN Type

Diseases Associated

A

321

531/9

532

515

533

600

603

606

635;636

649

666

768

777

790

791

804

819

833

844

866

891

912

MEN2a, FMTC

MEN2a, FMT

MEN2a, FMTC

MEN2a, FMTC

MEN2a, FMTC

MEN2a, FMTC

MEN2a, FMTC

MEN2a, FMTC

MEN2a, FMTC

MEN2a, FMTC

MEN2a, FMTC

MEN2a, FMTC

MEN2a, FMTC

MEN2a, FMTC

MEN2a, FMTC

MEN2a, FMTC

MEN2a, FMTC

MEN2a, FMTC

MEN2a, FMTC

MEN2a, FMTC

MEN2a, FMTC

MEN2a, FMTC

MTC

MTC

MTC

MTC

MTC, PHE

MTC

MTC

MTC

MTC,PHE

MTC,PHT

MTC,PHE

MTC,PHE,HPT

MTC

MTC, PHE, HPT

MTC, PHE, HPT

MTC, PHE, HPT

MTC

MTC

MTC

MTC

MTC, PHE, HPT

MTC

B

609

611

618

620

630

631

633/9

634/12

804 +778

MEN2A, FMTC

MEN2A, FMTC

MEN2A, FMTC

MEN2A, FMTC

MEN2A, FMTC

MEN2A, FMTC

MEN2A, FMTC,

MEN2A, FMTC

MEN2A, FMTC

MTC,PHE,HPT,HSC

MTC,PHE,HPT,HSC

MTC,PHE,HPT,HSC

MTC,PHE,HPT,HSC

MTC,PHE,HPT

MTC

MTC,HPT

MTC,HPT

MTC

C

C634R

C634G

MEN2A

MEN2A, FMTC

MTC,PHE,HPT,CLA

MTC,PHE,HPT,CLA

D

804+805

804+806

804+904

883

918

MEN2B

MEN2B

MEN2B

MEN2B

MEN2B

MTC,PHE

MTC,PHE

MTC,HPT

MTC,PHE

MTC,PHE

FMTC= Familial Medullary Thyroid Cancer; MTC= Medullary Thyroid Cancer; MEN2A=Multiple Endocrine Neoplasia type 2A; PHE=Pheochromocytoma; HPT=Hyperparathyroidism; HSC= Hirshsprung’s disease; CLA= Cutaneous lichen amyloidosis; MEN2B= Multiple Endocrine Neoplasia type 2B