RET Proto-Oncogene (Chromosome 10) and Medullary Thyroid Cancer

L. David Roper
http://arts.bev.net/roperldavid/

This document describes my experience with the RET proto-oncogene and contains some links to web sites that were helpful to me. I cannot attest to the accuracy or correctness of the information given here or in the web pages which are linked. I make no recommendations to others making similar decisions to those I made.

In February 2002 my sister was found to have Medullary Thyroid Cancer (MTC) and had her thyroid removed. Since this type of cancer is often associated with a mutated RET proto-oncogene, her blood was sent to Mayo Medical Laboratories to test for the relevant mutation of that gene; she had it.

Since she had this dominant mutant gene it was indicated that her siblings should be tested. So in March 2002 my blood was sent to Mayo Medical Laboratories, and its report of 27 March indicated that I have the same mutation (C609Y location on chromosome 10) of the RET proto-oncogene as she has. (My younger daughter was tested, but did not have the mutated RET proto-oncogene.)

The RET proto-oncogene is associated with more than MTC, but also with a syndrome (three or more diseases together) called Multiple Endocrine Neoplasia (MEN-IIA) or Sipple's Syndrome that includes MTC plus pheochromocytoma adrenal-glands disease and parathyroid hyperplasia (overgrowth). MTC is the most serious of the three.

The standard recommendation of thyroid specialists is that owners of this mutant gene should have their thyroid removed (prophylactic thyroidectomy).

The reason for this recommendation is that, once MTC moves outside the thyroid, it is very difficult to stop. One of the best Internet sites I have found about MTC is: http://www.thyroidmanager.org/Chapter18/18-medullar.htm

It appears that the most important danger with the operation is possible damage to the vocal-cord nerves, which could cause a voice change.

After thyroidectomy one must take a daily pill to supply the thyroxin normally supplied to the body by the thyroid. (The medicine is called levity with trade names Levothroid, Synthroid, Unithroid and others.) It may take a while to determine the correct dose of thyroxin for a given individual.

I was very reluctant to have the prophylactic thyroidectomy. I calculated the lifetimes of my nearest fourteen ancestors; it is 79 years. None of the fourteen died of Medullary Thyroid Cancer. (My mother did have a goiter, which is a non-cancerous enlargement of the thyroid due to lack of iodine; iodized salt prevents this condition now.) Since I got the mutated RET gene from at least one and possibly three of these fourteen ancestors, there may be some other gene that counteracts the mutated RET proto-oncogene; by this reasoning my sister did not inherit the counteracting gene but perhaps I did. Related to this I found the following: "Most oncogenes appear to be closely related to normal growth factors, genes that control cell division, or to hormone receptors. In general, these genes, when turned on, promote cell growth, division and depress differentiation. Typically, activation of one such gene may not be enough to produce malignancy, but if accompanied by expression of another oncogene, or if gene mutation or reduplication occurs, the cell may progress toward a malignant potential." in http://www.thyroidmanager.org/Chapter18/18-cancerframe.htm. I also found http://www.thieme.de/abstracts/eced/abstracts2002/daten/p269.html. Of course, it is possible that the mutation occurred in the germ cell that my sister and I received from one of my parents, so that they did not have the gene in their somatic cells.

The standard test for presence of MTC is the amount of the polypeptide hormone calcitonin in the blood. The part of the thyroid that starts MTC are the C cells that produce calcitonin to reduce the calcium level when it is too high. (Parathyroid hormone increases the calcium level when needed. So these two hormones work together to keep the calcium level where it should be.) However, the early stages of MTC do not raise the calcitonin level enough to be detected. There is a test in which the calcitonin indicator for early-stage MTC can be found by infusion of pentagastrin and calcium into the blood stream before taking the blood sample for the test. (Pentagastrin is a gastric hormone that is not found in the blood stream; so this is an invasive test.) Most endocrinologists do not favor using this invasive test. (See below).

The web page http://www.medhelp.org/glossary/new/GLS_0882.HTM gives some details about calcitonin level. Apparently the normal level depends on the way the test is done. The web page linked just above lists it as 0-50 picograms per milliliter. However, my last test report lists it as 0-11.5 pg/mL. My test of 14 May 2003 shows my level as 3.7 pg/mL, far from the danger zone.

After a thyroidectomy one only takes thyroxin pills, not calcitonin. Despite the loss of the thyroid C cells, the body somehow manages to regulate its calcium level anyway. This appears to be a mystery. Muscles need calcium to contract, presumably in a specific range of concentration. I think what happens is that the skeleton absorbs the extra calcium, which should make it stronger.

I was referred by my primary-care physician to a local oncologist. He had several tests done, including calcitonin levels (without infusion) and ultrasound scan. None of the tests showed any trace of MTC.

The oncologist referred me to a physician at the Endocrine Clinic at University of Virginia Medical Center. On 19 June the endocrine physician there strongly advised that I have the prophylactic thyroidectomy. He personally did an extensive ultrasound scan and stated that my thyroid is irregular. He found a small irregularity (about 4 mm) but did not think it is cancer. He ordered several more tests, including CEA (CarcinoEmbryonic Antigen) and TSH (Thyroid Stimulating Hormone). My wife and I decided that we would go ahead and schedule an operation at the earliest data available (6 Sept) for the thyroid surgeon and decide for sure about the operation after the results of the new tests came in.

When I asked the endocrine physician about the pentagastrin and calcium infusion test for calcitonin, he seemed to discount it without much explanation. I have written him a note asking for a fuller explanation as to why I should not just take that infusion calcitonin test every x months instead of having the operation. I found the following information in a web page http://www.thyroidmanager.org/Chapter18/18-medullar.htm: "MTC is unique since it can be detected in MEN-II or MEN-III families by genetic analysis and screening tests measuring pentagastrin-stimulated CT secretion before the disease reaches clinical detectability. In families with familial MTC, MENIIa, and IIB, repeatedly observed elevations to well above the normal range (e.g., peak values of 30-100 pg/ml) constitute a basis for operation. In these patients focal tumors or C-cell hyperplasia may be found after near-total or total thyroidectomy is performed. Since C-cell hyperplasia precedes the development of malignancy, it is currently believed logical to operate at this stage of the disease even in young children with MENIIB. Patients with MENIIA or familial MTC are similarly followed, tend to develop tumor later, and 20-40% may never develop cancer." The "basis for operation" is the calcitonin level with infusion test, not just the presence of the mutant RET proto-oncogene. I sent an e-mail comment to the web master for http://www.thyroidmanager.org requesting that the site include more information about the use of pentagastrin-stimulated CT secretion as a test to determine whether thyroidectomy is to be recommended in persons with the C609Y (or other relevant location) mutant RET proto-oncogene on chromosome 10. I got the following e-mail response from a Italian physician associated with the web page: I received from Dr. ..., your question about the utility of pentagastrin test in patients with C609Y ret mutation. This mutation has been reported in association with familial isolated medullary thyroid cancer (FMTC). As it is the case with mutations in other codons associated with FMTC, the consensus agreement proposed in several congress of the MEN 2 study group is that the pentagastrin test is always advised in gene carriers of FMTC to ascertain whether some minimal disease is already present. If a significant response of calcitonin to pentagastrin stimulation is present (or if some other clinical features are suspicious) thyroidectomy is advise, if not, thyroidectomy may be delayed, although some authors prefer to propose surgery even if pentagastrin test is negative. I hope that this clarification may answer your question.

I recently found other web pages that discussed pentagastrin infusion:

After the blood tests were done the endocrinologist called me to say that the tests all showed normal thyroid function with no visible cancer. He said that the probability of me getting MTC is not large, something similar to the probability that I would get killed in a car wreck if I did not wear a seat belt. Wearing a seat belt and having a thyroidectomy are both inconveniences, but he felt that it was worth the inconvenience to lower the probabilities for death. I asked him again about the pentagastrin-stimulated calcitonin test, and he said that it is quite rigorous; one patient described it being like a train running through the body.

We had an interesting talk with the thyroid surgeon during the visit to the University of Virginia. One of the most interesting bits of information was: Because it is difficult to remove the thyroid without damaging the four small parathyroid glands, he also removes the parathyroids, minces them and then inserts them into a neck muscle. They then continue their normal functions after blood vessels grow to them. A permanent suture is placed at the site so that it can be found easily in the future if needed.

After consultation with the oncologist, I decided to not have the thyroidectomy and to have my calcitonin level checked every 6 months. At the same time my chromogranin A (test for neuroendocrine tumors) and PTH (parathyroid hormone) levels are tested. Here are the results up to May 2006:

Normal:
0-11.5
8-97
2-18
Date
Calcitonin
PTH
Chromogranin-A
10-May-2002
7.4
15
11-Sep-2002
5.7
1-May-2003
3.7
184*
4
5-Nov-2003
5.4
61
59
7-May-2004
7.1
80
11
5-May-2005
6
68
3
28-May-2006
3.4
70
3
*The lab had never done this test before; I think they botched it.

In early 2003 another sister of mine was detected as having a high calcitonin level. She had her thyroid removed and a small amount of MTC was found.

I believe that MTC is related to more than one gene.

Some useful references are:

I found the following book helpful in making the decisions described above: Does It Run in the Family?: A Consumer's Guide to DNA Testing for Genetic Disorders by Doris Teichler-Zallen. A new version of this book will be out soon.

L. David Roper (http://arts.bev.net/roperldavid/)