Genetics and Cancer - Medullary Thyroid Cancer (MTC)

The genetics of medullary thyroid cancer (MTC):

Thyroid cancer is rare in the United States, and about 3 percent to 4 percent of all cases are medullary thyroid cancers (MTC). Most cases are sporadic and occur in the absence of a family history. Familial cases represent multiple endocrine neoplasia type 2 (MEN 2).

What is multiple endocrine neoplasia type 2 (MEN 2)?

Multiple endocrine neoplasia type 2 (MEN 2) is a genetic disorder associated with a high lifetime risk of developing medullary thyroid cancer. MEN 2 is caused by germline (inherited) mutations in the RET proto-oncogene located on chromosome 10. Proto-oncogenes are responsible for promoting cell growth. When altered, or mutated, they become oncogenes that can promote uncontrolled cell growth and ultimately tumor formation. Having a mutation in just one of the two copies of a particular proto-oncogene is enough to cause a change in cell growth. For this reason, oncogenes are said to be "dominant" at the cellular level (although the change in cell growth may or may not be detectable at a clinical level). However, the process of developing a cancer actually requires mutations in multiple growth control genes. Therefore, inheriting a mutation in one copy of the RET gene is just the first step in the process. The remainder of the mutations necessary for tumor development are acquired (not inherited). What causes additional mutations to develop is unknown. Possible causes include chemical, physical, or biological environmental exposures or chance errors in DNA replication.

What are the subtypes of MEN 2?

All multiple endocrine neoplasia cases are inherited in an autosomal dominant manner, which means that offspring of an affected person are at 50 percent risk for inheriting the gene mutation. There are three subtypes of MEN 2, depending upon what other clinical characteristics are present (in addition to medullary thyroid cancer):

  • multiple endocrine neoplasia (MEN) 2A (60 percent to 90 percent of MEN cases)
    Characteristics include:

    • a high lifetime risk of medullary thyroid cancer

    • average age of medullary thyroid cancer diagnosis between 15 to 20 years

    • increased risk of pheochromocytoma (a tumor of the chromaffin cells, which are present in the adrenal gland; usually benign, or noncancerous) and parathyroid adenoma or hyperplasia

    • 95 percent of cases have an affected parent*, while 5 percent are de novo (new occurrences in a family)

    • 95 percent of cases have a mutation in the RET gene

* In some cases, a child may be diagnosed with MTC before the parent is diagnosed.

  • familial MTC (5 percent to 35 percent of MEN cases)
    Characteristics include:

    • four or more individuals with MTC

    • average age of onset of MTC may be later than with MEN 2A

    • 100 percent of cases have an affected parent*

    • no pheochromocytoma or parathyroid disease

    • 85 percent of cases have a mutation in the RET gene

* In some cases, a child may be diagnosed with MTC before the parent is diagnosed.

  • multiple endocrine neoplasia (MEN) 2B (5 percent of MEN cases)
    Characteristics include:

    • a high lifetime risk of MTC

    • onset of MTC in infancy or very early childhood

    • increased risk of pheochromocytoma (a tumor of the chromaffin cells, which are present in the adrenal gland; usually benign, or noncancerous)

    • parathyroid disease is uncommon

    • ganglioneuromatosis (inflammation of the nerve cells) in the gastrointestinal tract (40 percent)

    • distinctive facial appearance with neuromas (tumors) of the tongue, lips, eyes; lips may look "blubbery"

    • tall, thin, "Marfanoid" body type (75 percent)

    • 50 percent of cases have an affected parent, while 50 percent are de novo (new occurrences in a family)

    • 95 percent of cases have a mutation in the RET gene

The American Society of Clinical Oncologists (ASCO) classifies MEN 2 as a "group 1" disorder, which means that genetic testing (in this case for mutations in the RET gene) is considered part of the standard management for first-degree relatives (parent, siblings, children) of affected individuals. Persons who are mutation-positive may have their thyroid removed as a preventive measure, followed by biochemical screening for the other endocrine tumors. Genetic testing of unaffected relatives is most useful when a germline mutation has already been identified in an affected family member.

Medical Reviewer: [Foster, Sara M. RN, MPH, Stump-Sutliff, Kim RN, MSN, AOCNS] Last Annual Review Date: 2011-03-20T00:00:00-06:00 Copyright: Copyright © 2007 Staywell Content Services, Inc. except where otherwise noted.

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