Genetic Testing For Hereditary Cancer!
Medullary Thyroid Cancer has shown to exist in both sporadic and familial forms. Medullary Thyroid Cancer (MTC) makes up 4% of all thyroid cancer in the United States, but more interestingly, 20-25% of all MTC cases present as familial, Hereditary (Kloos, Eng, Evans...). In the last decade and a half, there has been a testing technique developed called RET genetic screening, named after the RET gene mutations that cause both the sporadic and familial varieties of MTC, that can exist as an early warning system for the family of all those effected by any type of MTC. This system has enabled the ten year survival rate to reach 75% (Kloos, Eng, Evans...) and detailed, long-term information from both Italian and Islamic health centers and laboratories. Does the data truly show that it is actually the cause of great survival rates?
First, a little history:
The RET gene, found on the tenth chromosome, which codes for the RET protein, was discovered in 1985 and soon afterword in 1993 and 1994, the three types of genetic mutations causing MTC (MEN 2A, FMTC, and MEN 2B) were linked to germ line RET mutations ( Kloos, Eng, Evans...). Meaning, familial MTC is caused by a heritable genetic mutation in the RET gene that causes an excess in RET protein expression, which is correlated with the progression of other genetic mutations that directly cause the specific cancer.
MEN 2 MTC:
MEN 2 or Multiple Endocrine Neoplasia, is a major class of concern for the larger grouping of MTC. It exists as an autosomal dominant cancer form and therefore has a 50% to be inherited by the offspring of a carrier. This fact makes it the main focus of RET genetic screening (Kloos Eng, Evans...). MEN 2 can be can be sorted into two groups, a and b. MEN 2a is defined as and MTC carcinoma occurring alongside phechromocytom and parathyroid adenomas, where MEN 2b is defined as an MTC carcinoma occurring alongside a marfanoid habitus and pheochromocytoma. The third term and other MEN2 subtype, FMTC, is used when only MTC occurs (Elisei, Romei, Cosci...).
RET Testing Results Among Italian Patients:
Over the last 13 years, the department of endocrinology at the University of Pisa has RET screened 807 individuals; a little over half of the diagnosed patients showed sporadic MTC, 289 were patients' relatives, and the rest, 37 patients, with evidence of clinical MEN 2 MTC. On top of the already known MEN 2 patients, 35 of the sporadic MTC patients turned out to have a germ line mutation, increasing the overall proportion of those with hereditary cancer in the study, and of the 37 who were already classified as clinical MEN 2 patients, RET germ line mutations occurred in 36 cases. These 72 total hereditary cases could be traced through different families of patients.
As we talked about in class on Monday, April 15th, the first hallmark of cancer is sustaining proliferative signaling and RET genetic mutations to the RET signaling/ receptor protein directly allows for this action. The 72 patients in the above study had the mutations tracked to the exact location in the protein. The results are shown in figure 1 below:
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| Figure 1: "Distribution of germline RET mutations found in our series of MEN 2 cases according to different RET gene domains, codons, and exons. One of 72 families was negative for germline RET mutations (not reported in this figure). Please note that mutations in codons 618 and 634 were associated with both FMTC and MEN 2A phenotypes. N, Number." - The above figure and figure caption were from the study in Italy done by Elisei, Romei, Cosci... at the University of Pisa. The figure above beautifully illustrates that MEN2A mutations only occur in the Cystein Rich Domain, an extracellular domain, MEN2B mutations only occur in the Tyrosine Kinase Domain, an intracellular domain, and FMTC mutations occurred in both domains. Conclusions: As previously stated, the test was performed on a total of 807 individuals, 35 of the cases found to have the hereditary cancer, were individuals who had no idea that they had the disease. 18 of these 35 people didn't even know they had a relative that presented the cancer. That is 18 to 35 lives that were saved, or at the very least, greatly improved by the early detection offered by the RET genetic screening. Although that is only about 4.3% of the total number of people participating in the study, that is actually a truly amazing statistic. On a wider scale, could almost 5% of thyroid cancer be detected well before metastasis is even possible? Hopefully!
After reading this study I am really not sure of the statistics provided by the American Thyroid Association given about the percentage of MTC cases that are hereditary. They claim up to 25% (Kloos, Eng, Evans... ), where the case study only showed 4.3% of their cancer patients showed genetic cases. 807 seems like a rather large sample size to have such a statistical discrepancy. I will look at both of these sets of numbers critically as I go forward with my research. I truly don't know if there is something different about the study, such as a prevalence of Italians from the Pisa area to develop a larger than normal amount of non-hereditary MTC, or that there is simply not a big enough sample size. Hey, maybe it's just the result of too much good wine and pasta!
On a darker and more serious note, even with this great testing technology, there has been no significant decrease in cancer stage or TNM measurement in the last decade, which means only half of patients being diagnosed before stage III and IV even today (Elisei, Romei, Cosci...). So why are patients not being diagnosed earlier? And does this mean that the awesome, 75% 10-year survival rate of MTC cannot be attributed to genetic testing and if not, can it be attributed to any portion of the 75%? I believe that because many people do not discover their cancer until stage III or IV, many of their family members do not get tested until this point and therefore have a larger chance of already having a later stage version of the cancer themselves. Also, the many easily visible symptoms of thyroid cancer (Lump in neck, Swollen Lymph nodes, horse voice, difficulty swallowing, neck pain, and throat pain) are not prevalent till later stages or TNM ratings, specifically when the tumor reaches a large size and begins spreading to the lymph nodes (Walker), which theoretically would contribute to a cycle of one person not knowing if they have MTC until a later stage and their relatives then not getting tested until then, giving them a better chance of having a later stage MTC themselves. Either way, I hope to learn much more about the various intricacies of hereditary thyroid cancer, treatment, genetic testing, and whether genetic testing is making a difference on a global scale. |
Sources:
Kloos, Richard, Charis Eng, Douglass Evans, Gary Francis, Robert Gagel, Hossein Gharib, Jeffery Moley, and Furio Pacini. "Medullary Thyroid Cancer: Management Guidelines of the American Thyroid Association."THYROID.19.6(2009).Web.17Apr.2012.<http://www.thyroid.org/professionals/ publications/documents/MTC_Guidelines.pdf>.
Elisei, Rossella, Christina Romei, Barbara Cosci, Laura Agate, Valeria Bottici, Eleonora Molinaro, Mariangela Sculli, and Paulo Miccoli. "RET Genetic Screening in Patients with Medullary Thyroid Cancer and Their Relatives: Experience with 807 Individuals at One Center." JCEM. 92.12 (2007): n. page. Web. 17 Apr. 2012. <http://www.thyroid.org/professionals/publications/documents/MTC_Guidelines.pdf>.
Walker, Kamiah. "Thyroid Cancer Symptoms."endocrineweb. vertical health, 03 sep 2012. Web. 17 Apr 2012. <http://www.endocrineweb.com/conditions/thyroid-cancer/thyroid-cancer-symptoms>.
