Speaker: Dr.
Stephen Marx, Chief, Genetics and Endocrinology Section
Metabolic Diseases Branch, National Institute of Diabetes and Digestive and
Kidney Diseases, National Institutes of Health
What is MEN1? MEN1 stands for multiple endocrine neoplasia type 1. This is a hereditary syndrome that causes tumors---mostly endocrine---in different organs. Sometimes, but not often, carcinoid tumors develop. The MEN1 gene makes a still mysterious protein that has been named “menin”.
MEN was recognized in the 1950s. An early name was Wermer’s syndrome. Often 3 “P’s” were involved---the pituitary, parathyroid, and pancreatic islets. MEN1 can cause more types of tumors (about 25 types) than any other known disease. If one is treated or removed, another may still occur later. It is a difficult disease to manage.
It was possible to identify the MEN1 gene with the help of about 15 families with some members with MEN1. Dr. Marx’s lab hopes that what they learn about inheritable endocrine cancers will at least sometimes also be useful in understanding and treating nonhereditary cancers---which most carcinoid cancers are. This hope has been supported by the finding that a MEN1 gene mutation contributes to about one-fourth of certain nonhereditary tumors, including bronchial carcinoids.
Treatment changes over the years. MEN used to be fatal in the 1950s. Too much gastric acid could perforate the stomach. Dr. Robert Zollinger devised the first treatment, surgery to remove the stomach. Later pharmacologic options were developed. Once the endocrine complications could be handled, it was possible to see non-endocrine complications too. About one-third would die in the 1950s and 1960s of MEN1-related cancers.
Types of carcinoid cancers with MEN1. MEN1 carcinoid cancer occurs in the foregut---including the thymus, bronchi, and stomach. In contrast most nonhereditary carcinoid occurs in the midgut and hindgut organs. Thymus carcinoid tends to be aggressive, developing relatively rapidly, and occurring mostly in men. Bronchial carcinoid is less aggressive although it can spread and occurs more in women. Stomach carcinoids have only been known about for 5 to 6 years. So far they do not seem aggressive. They may be uniquely dependent on somatostatin.
There are also entero-pancreatic MEN1 carcinoid tumors. They most commonly produce gastrin but other pancreatic islet hormones as well. They may be “nonfunctional”, not producing hormones.
In fact MEN1 carcinoids rarely produce hormones and rarely have carcinoid syndrome. They tend not to respond to sandostatin, and surgery is the major treatment method. The 40% who now die from their disease usually have either islet cancers or carcinoid tumors.
More MEN1 details. Individuals with MEN1 can have endocrine effects and/or cancer effects, plus the word “multiple” in the name indicates that there can be different types of tumors and syndromes all at the same time. And some of the tumors are not endocrine---for example, in skin or smooth muscle (such as uterine fibroid tumors). There may be tumors in multiple different organs or separate tumors all in one organ or nonsegmented gland (e.g., pancreatic islets).
While 1 in 30,000 carries the MEN1 gene, it has been found that about 1% to 2% of individuals with hyperparathyroidism have the MEN1 gene. Typically 90% of MEN1 individuals have parathyroid problems, 50% have gastrinomas, and 30% have pituitary effects.
The parathyroid tumors that can occur in MEN1 peak in individuals of ages 25 to 30; this contrasts with a peak at ages 45 to 50 for nonhereditary parathyroid tumors. Researchers think that the earlier age of onset suggests that the MEN1 gene might be some kind of growth suppressor in its normal state.
The MEN1 gene. In 1988 it was found that the MEN1 gene is located on the “q” arm of chromosome 11. In 1997 Dr. Marx’s lab identified the gene and its DNA sequence, enabling all labs to study the gene for the first time. Now these researchers are trying to understand more about the gene. They have found that about 80% of the mutations resulting in abnormal MEN1 product truncate the menin protein.
Menin studies. Because it is hard to grow the human tumors outside the body, one project involves overproduction of menin in mouse tumor cells. This tends to lead to smaller tumors. There is also a mouse model in which the mouse gets MEN1. This an lead to pituitary tumors, prolactinomas, parathyroid adenomas, and insulinomas. The giant hyperplastic islets seen in the pancreas have been predicted for humans and could be a future target for medical intervention.
Future. Dr. Marx would like to understand menin better. There are 6 to 7 proteins with which it interacts in cells but an exact biochemical pathway has not yet been determined. Other organisms appear to have MEN1-like genes, including birds, fish and fruit flies. In the fruit fly, overexpression of menin can affect the fly’s development. Another approach is to study the genes that affect the parathyroid and drugs that can affect the calcium levels of this gland. Perhaps someday a similar approach will result in being able to manage carcinoid tumors by turning off their hyperfunctions.