Thyroid Tumors, NRAS, G12S (c.34G>A)

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Expand Collapse Thyroid Tumor  - General Description This year about 56,000 people in the U.S. (77% of them women) will be told by a doctor that they have thyroid cancer. About half of these new patients will be at least 50 years old. However, more than 500,000 patients with thyroid cancer remain alive today.

The thyroid is a butterfly-shaped gland found at the base of the throat, near the windpipe (trachea). The 2 wings (lobes) of the thyroid are connected by a thin piece of tissue called the isthmus. The thyroid uses iodine from food and iodized salts to make hormones that control the heart rate, body temperature, the speed with which food is changed into energy (metabolism) and the level of calcium in the blood. Based on their appearance under the microscope, the 4 main types of thyroid cancer are papillary, follicular, medullary and anaplastic. For treatment purposes, thyroid cancers are often classified as differentiated (papillary or follicular) or poorly differentiated (medullary or anaplastic). If a cancer cell is well-differentiated, it has most of the characteristics of a normal cell. On the other hand, poorly differentiated cancer cells don't look like normal cells.

Follicular thyroid cancer is a slow-growing cancer that forms in follicular cells, which are epithelial cells that take up iodine and make certain thyroid hormones. Papillary thyroid cancer, which appears as finger-like shapes under the microscope, also begins in follicular cells and is slow-growing. It is the most common type of thyroid cancer, usually appearing before the age of 45 years. It is more common in women than in men. Medullary thyroid cancer accounts for about 4% of all thyroid cancers. It begins in C cells, which make calcitonin, a hormone that helps keep calcium at the right level in the blood. Anaplastic thyroid cancer is a rare, aggressive form of cancer whose cells don't look at all like normal thyroid cells.

Thyroid cancer (and other tumors) can spread (metastasize) from the place where it started (the primary tumor) in 3 ways. First, it can invade the normal tissue surrounding it. Second, cancer cells can enter the lymph system and travel through lymph vessels to distant parts of the body. Third, the cancer cells can get into the bloodstream and go to other places in the body. In these distant places, the cancer cells cause secondary tumors to grow. The main places to which thyroid cancer spreads are the lungs, liver, and bones.

To find out whether the cancer has entered the lymph system, a surgeon removes all or part of a node near the primary tumor and a pathologist looks at it through a microscope to see if cancer cells are present. Several kinds of imaging can also be performed to determine if the cancer has spread. These include chest x-rays, ultrasound and CT scans.

The FDA has approved the targeted therapy vandetanib (Capreisa) for treatment of medullary thyroid cancer that is locally advanced and can't be removed by surgery or that has metastasized. No targeted therapies are yet available for treatment of anaplastic thyroid cancer. Therefore, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2012
Thyroid cancer represents approximately 3% of new malignancies occurring annually in the United States, with an estimated 56,460 cancer diagnoses and 1,780 cancer deaths per year. Of these cancer diagnoses, 2% to 3% are medullary thyroid cancer (MTC).

MTC arises from the calcitonin-secreting parafollicular cells of the thyroid gland. MTC occurs in sporadic and familial forms and may be preceded by C-cell hyperplasia (CCH), although CCH is a relatively common abnormality in middle-aged adults.

Average survival for MTC is lower than that for more common thyroid cancers (e.g., 83% 5-year survival for MTC compared with 90-94% 5-year survival for papillary and follicular thyroid cancer). Survival is correlated with stage at diagnosis. Decreased survival in MTC can be accounted for, in part, by a high proportion of late-stage diagnoses.

In addition to early stage at diagnosis, other factors associated with improved survival in MTC include smaller tumor size, younger age at diagnosis, familial versus sporadic form and diagnosis by biochemical screening (i.e., screening for calcitonin elevation).

A Surveillance, Epidemiology, and End Results (SEER) population-based study of 1,252 MTC patients found that survival varied by extent of local disease. For example, the 10-year survival rates ranged from 95% for disease confined to the thyroid gland to 40% for those with distant metastases.

While the majority of MTC cases are sporadic, approximately 20-25% are hereditary because of mutations in the RET proto-oncogene. Mutations in the RET gene cause multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominant disorder associated with a high lifetime risk of MTC. Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant endocrinopathy that is genetically and clinically distinct from MEN 2. However, the similar nomenclature for MEN 1 and MEN 2 may cause confusion. Of note, there is no increased risk of thyroid cancer for MEN 1.

Historically, MEN 2 has been classified into three subtypes based on the presence or absence of certain endocrine tumors in the individual or family:

- MEN 2A
- Familial medullary thyroid carcinoma (FMTC)
- MEN 2B

All three subtypes impart a high risk of developing MTC. MEN 2A has an increased risk of pheochromocytoma and parathyroid adenoma and/or hyperplasia. MEN 2B has an increased risk of pheochromocytoma and includes additional clinical features such as mucosal neuromas of the lips and tongue, distinctive faces with enlarged lips, ganglioneuromatosis of the gastrointestinal tract and an asthenic Marfanoid body habitus. FMTC has been defined as the presence of at least four individuals with MTC without any other signs or symptoms of pheochromocytoma or hyperparathyroidism in the proband or other family members.

Some families previously classified as FMTC will go on to develop one or more of the MEN 2A-related tumors, suggesting that FMTC is simply a milder variant of MEN 2A. Offspring of affected individuals have a 50% chance of inheriting the gene mutation.

The age of onset of MTC varies in different subtypes of MEN 2. MTC typically occurs in early childhood for MEN 2B, predominantly early adulthood for MEN 2A and middle age for FMTC.

DNA-based germline testing of the RET gene (chromosomal region 10q11.2) identifies disease-causing mutations in more than 95% of individuals with MEN 2A and MEN 2B and in about 88% of individuals with FMTC.

Source: National Cancer Institute, 2012
This year about 56,000 people in the U.S. (77% of them women) will be told by a doctor that they have thyroid cancer. About half of these new patients will be at least 50 years old. However, more than 500,000 patients with thyroid cancer remain alive today.

The thyroid is a butterfly-shaped gland found at the base of the throat, near the windpipe (trachea). The 2 wings (lobes) of the thyroid are connected by a thin piece of tissue called the isthmus. The thyroid uses iodine from food and iodized salts to make hormones that control the heart rate, body temperature, the speed with which food is changed into energy (metabolism) and the level of calcium in the blood. Based on their appearance under the microscope, the 4 main types of thyroid cancer are papillary, follicular, medullary and anaplastic. For treatment purposes, thyroid cancers are often classified as differentiated (papillary or follicular) or poorly differentiated (medullary or anaplastic). If a cancer cell is well-differentiated, it has most of the characteristics of a normal cell. On the other hand, poorly differentiated cancer cells don't look like normal cells.

Follicular thyroid cancer is a slow-growing cancer that forms in follicular cells, which are epithelial cells that take up iodine and make certain thyroid hormones. Papillary thyroid cancer, which appears as finger-like shapes under the microscope, also begins in follicular cells and is slow-growing. It is the most common type of thyroid cancer, usually appearing before the age of 45 years. It is more common in women than in men. Medullary thyroid cancer accounts for about 4% of all thyroid cancers. It begins in C cells, which make calcitonin, a hormone that helps keep calcium at the right level in the blood. Anaplastic thyroid cancer is a rare, aggressive form of cancer whose cells don't look at all like normal thyroid cells.

Thyroid cancer (and other tumors) can spread (metastasize) from the place where it started (the primary tumor) in 3 ways. First, it can invade the normal tissue surrounding it. Second, cancer cells can enter the lymph system and travel through lymph vessels to distant parts of the body. Third, the cancer cells can get into the bloodstream and go to other places in the body. In these distant places, the cancer cells cause secondary tumors to grow. The main places to which thyroid cancer spreads are the lungs, liver, and bones.

To find out whether the cancer has entered the lymph system, a surgeon removes all or part of a node near the primary tumor and a pathologist looks at it through a microscope to see if cancer cells are present. Several kinds of imaging can also be performed to determine if the cancer has spread. These include chest x-rays, ultrasound and CT scans.

The FDA has approved the targeted therapy vandetanib (Capreisa) for treatment of medullary thyroid cancer that is locally advanced and can't be removed by surgery or that has metastasized. No targeted therapies are yet available for treatment of anaplastic thyroid cancer. Therefore, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2012
Thyroid cancer represents approximately 3% of new malignancies occurring annually in the United States, with an estimated 56,460 cancer diagnoses and 1,780 cancer deaths per year. Of these cancer diagnoses, 2% to 3% are medullary thyroid cancer (MTC).

MTC arises from the calcitonin-secreting parafollicular cells of the thyroid gland. MTC occurs in sporadic and familial forms and may be preceded by C-cell hyperplasia (CCH), although CCH is a relatively common abnormality in middle-aged adults.

Average survival for MTC is lower than that for more common thyroid cancers (e.g., 83% 5-year survival for MTC compared with 90-94% 5-year survival for papillary and follicular thyroid cancer). Survival is correlated with stage at diagnosis. Decreased survival in MTC can be accounted for, in part, by a high proportion of late-stage diagnoses.

In addition to early stage at diagnosis, other factors associated with improved survival in MTC include smaller tumor size, younger age at diagnosis, familial versus sporadic form and diagnosis by biochemical screening (i.e., screening for calcitonin elevation).

A Surveillance, Epidemiology, and End Results (SEER) population-based study of 1,252 MTC patients found that survival varied by extent of local disease. For example, the 10-year survival rates ranged from 95% for disease confined to the thyroid gland to 40% for those with distant metastases.

While the majority of MTC cases are sporadic, approximately 20-25% are hereditary because of mutations in the RET proto-oncogene. Mutations in the RET gene cause multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominant disorder associated with a high lifetime risk of MTC. Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant endocrinopathy that is genetically and clinically distinct from MEN 2. However, the similar nomenclature for MEN 1 and MEN 2 may cause confusion. Of note, there is no increased risk of thyroid cancer for MEN 1.

Historically, MEN 2 has been classified into three subtypes based on the presence or absence of certain endocrine tumors in the individual or family:

- MEN 2A
- Familial medullary thyroid carcinoma (FMTC)
- MEN 2B

All three subtypes impart a high risk of developing MTC. MEN 2A has an increased risk of pheochromocytoma and parathyroid adenoma and/or hyperplasia. MEN 2B has an increased risk of pheochromocytoma and includes additional clinical features such as mucosal neuromas of the lips and tongue, distinctive faces with enlarged lips, ganglioneuromatosis of the gastrointestinal tract and an asthenic Marfanoid body habitus. FMTC has been defined as the presence of at least four individuals with MTC without any other signs or symptoms of pheochromocytoma or hyperparathyroidism in the proband or other family members.

Some families previously classified as FMTC will go on to develop one or more of the MEN 2A-related tumors, suggesting that FMTC is simply a milder variant of MEN 2A. Offspring of affected individuals have a 50% chance of inheriting the gene mutation.

The age of onset of MTC varies in different subtypes of MEN 2. MTC typically occurs in early childhood for MEN 2B, predominantly early adulthood for MEN 2A and middle age for FMTC.

DNA-based germline testing of the RET gene (chromosomal region 10q11.2) identifies disease-causing mutations in more than 95% of individuals with MEN 2A and MEN 2B and in about 88% of individuals with FMTC.

Source: National Cancer Institute, 2012
Expand Collapse NRAS  - General Description
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NRAS is a gene that provides the code for making NRAS, a GTPase that converts GTP to GDP. This protein is part of the MAP kinase signaling cascade that relays chemical signals from the outside of the cell to the cell's nucleus, and is primarily involved in controlling cell division. When NRAS is attached (bound) to GDP, it is in its “off” position and can't send signals to the nucleus. But when a GTP molecule arrives and binds to NRAS, NRAS is activated and sends its signal, and then it converts the GTP into GDP and returns to the "off" position. HRAS and KRAS are other GTPases that are similar to NRAS.

When mutated, however, NRAS can act as an oncogene, causing normal cells to become cancerous. The mutations can shift the NRAS protein into the "on" position all the time. These NRAS mutations are said to be somatic, because instead of coming from a parent and being present in every cell (hereditary), they are acquired during the course of a person's life and are found only in cells that become cancerous.

Tumor mutation profiling performed clinically at the MGH Cancer Center has identified the highest incidence of NRAS mutations in melanoma (~30%), acute myeloid leukemia (~15%) and thyroid carcinoma (5-10%).

Source: Genetics Home Reference
NRAS (neuroblastoma RAS viral oncogene homolog) is a member of the closely related RAS gene family that also includes KRAS and HRAS. These RAS members are small GTPases that mediate extracellular signals to the downstream effectors RAF, PI3K and RALGDS. RAS members are involved in regulating diverse cellular processes including survival, proliferation and differentiation. While activating mutations in the RAS genes lead to sustained GTPase activation that contributes to oncogenesis, each oncogene exerts clear differences. Mutational hotspots in NRAS reside primarily in amino acid residues 12, 13 or 61 and function to suppress apoptosis.

Clinical tumor genotyping performed at the MGH Cancer Center has identified the highest incidence of NRAS mutations in melanoma (~30%), acute myeloid leukemia (~15%) and thyroid carcinoma (5-10%).

Source: Genetics Home Reference
PubMed ID's
18372904, 21779495
Expand Collapse G12S (c.34G>A)  in NRAS
The NRAS G12S mutation arises from a single nucleotide change (c.34G>A) and results in an amino acid substitution of the glycine (G) at position 12 by a serine (S).
The NRAS G12S mutation arises from a single nucleotide change (c.34G>A) and results in an amino acid substitution of the glycine (G) at position 12 by a serine (S).

NRAS mutations occur in 5-15% of thyroid cancers and are characteristic of the follicular subtype. They are found in tumors that do not have BRAF mutations or other classical gene rearrangements. NRAS mutations have also been associated with more aggressive disease and distant metastasis.

The therapeutic implications of NRAS mutations in thyroid cancer are unknown at this time. Preclinical laboratory studies have shown that NRAS-mutant cancer cells are sensitive to downstream pathway MEK inhibitors. Based on clinical evidence obtained in melanoma, MEK inhibitors may be a feasible approach for the treatment of NRAS-mutant tumors, with an approximate 20% response rate to single-agent MEK162 treatment. This strategy is currently being investigated in other tumor types, including thyroid cancer. While it remains unclear whether NRAS mutations will predict response to MEK inhibitors in thyroid cancer, many trials are already evaluating a combination therapy approach that additionally targets the PI3K/AKT/mTOR pathway.

NRAS mutations occur in 5-15% of thyroid cancers and are characteristic of the follicular subtype. They are found in tumors that do not have BRAF mutations or other classical gene rearrangements. NRAS mutations have also been associated with more aggressive disease and distant metastasis.

The therapeutic implications of NRAS mutations in thyroid cancer are unknown at this time. Preclinical laboratory studies have shown that NRAS-mutant cancer cells are sensitive to downstream pathway MEK inhibitors. Based on clinical evidence obtained in melanoma, MEK inhibitors may be a feasible approach for the treatment of NRAS-mutant tumors, with an approximate 20% response rate to single-agent MEK162 treatment. This strategy is currently being investigated in other tumor types, including thyroid cancer. While it remains unclear whether NRAS mutations will predict response to MEK inhibitors in thyroid cancer, many trials are already evaluating a combination therapy approach that additionally targets the PI3K/AKT/mTOR pathway.

PubMed ID's
23404751, 22650231, 22404480, 23414587

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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene, (M) - Mutation
Trial Status: Showing all 1 result Per Page:
Protocol # Title Location Status Match
NCT00585195 A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer MGH Open D
MGH has many open clinical trials for other cancers not shown on the Targeted Cancer Care website. They can be found on the MassGeneral.org clinical trials search page.

Additional clinical trials may be applicable to your search criteria, but they may not be available at MGH. These clinical trials can typically be found by searching the clinicaltrials.gov website.
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