Endocrine Tumor Syndromes and Their Genetics

C. A. Stratakis, C.A., Stratakis, Federica Guaraldi, Giovanni Corona, Federica, Guaraldi, Giovanni, Corona

• Publisher: S. Karger
• Year: 2013
• Print ISBN: 9783318023305
• eBook ISBN: 9783318023312
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

In these times, a book should aspire to present the most significant advances in the field, reflect the themes of the moment, and provide a useful compendium for future reference. This book accomplishes all three objectives by discussing the changing world of modern genetics in endocrine tumors and its impact on clinical practice. Clinicians have to incorporate modern genetics and systems biology in their daily practice. Educators and researchers have to introduce molecular pathways and their genetic variability in their teaching, as well as understanding of classic physiology and pathophysiology. Taking these aspects into account, the chapters in this book cover both the classic multiple endocrine neoplasia (MEN) syndromes, as well as newly described ones, such as Carney triad and Carney-Stratakis syndrome. Furthermore, the genetics of paragangliomas as well as thyroid, parathyroid, and pituitary tumors are examined. Outlining the latest research and its obvious implications for our understanding the genetics of endocrine tumor formation and molecular biology of cancer and their potential therapeutic implications, this book is not only useful for researchers but even more so for practicing clinicians, in particular internists, endocrinologists, oncologists, pediatricians, surgeons, pathologists, geneticists, and genetic counselors.

Stratakis CA (ed): Endocrine Tumor Syndromes and Their Genetics.
Front Horm Res. Basel, Karger, 2013, vol 41, pp 1-15 (DOI: 10.1159/000345666 )

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Multiple Endocrine Neoplasia Type 1

Sunita K. Agarwal

Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Md., USA

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Abstract

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant tumor syndrome characterized by the occurrence of tumors in multiple endocrine tissues and nonendocrine tissues. The three main endocrine tissues most frequently affected by tumors are parathyroid (95%), enteropancreatic neuroendocrine (50%) and anterior pituitary (40%). Tumors are caused by a heterozygous germ-line-inactivating mutation in the MEN1 gene (1st hit) followed by somatic inactivating mutation or loss of the normal copy of the gene (2nd hit), leading to complete loss of function of the encoded protein menin. Most of the disease features and tumors are recapitulated in mouse models with heterozygous germline loss of the Men1 gene. Also, tissue-specific tumors are observed in mouse models with homozygous somatic loss of the Men1 gene specifically in MEN1-associated endocrine tissues. Hence, mouse models could serve as possible surrogates for studying MEN1 and related states. To gain insights into MEN1 pathophysiology, menin-interacting partners and pathways have been identified to investigate its tumor suppressor and other functions. Also, the 3D crystal structure of menin has been deciphered which could be useful to reveal the relevance of MEN1 gene mutations and menin's interactions. This chapter covers clinical, genetic and basic findings about the MEN1 syndrome, MEN1 gene and its product protein menin.

Copyright © 2013 S. Karger AG, Basel

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant tumor syndrome with no gender bias and with an approximate prevalence of 1 in 30,000 individuals. The disease, first described in two families in 1954, manifests as multiple hormone-secreting tumors, hormone nonsecreting tumors and nonendocrine tumors [1–3]. The disease manifests in adults around 40-50 years of age; however, early onset of the disease has been observed in a few children before the age 10 years [3]. Germline heterozygous mutation in the MEN1 tumor suppressor gene encoding menin, located on chromosome 11q13, predisposes to the development of tumors. This chapter covers the clinical, genetic and basic findings about the MEN1 syndrome, MEN1 gene and its protein product menin.

Table 1. Tumors associated with the MEN1 syndrome

Tumors	% penetrance (at age 40)
Endocrine (hormone-secreting or NF)
Parathyroid	90
Entero-pancreatic neuroendocrine
Gastrinoma^*	40
Insulinoma	10
NF^*, PPoma^*	20
Glucagonoma^*, VIPoma^*, Somatostatinoma^*, etc.	2
Anterior pituitary
Prolactinoma	20
GH + prolactin secreting	5
GH secreting	5
NF	5
ACTH-secreting	2
Adrenal
Cortex NF	25
Medulla	1
Foregut carcinoid
Gastric ECLoma NF	10
Thymic carcinoid^* NF	4
Bronchial carcinoid^* NF	2
Nonendocrine
Facial angiofibroma	85
Truncal collagenoma	70
Lipoma	30
Meningioma	5
Barrett's esophagus	5
Leiomyoma
Uterus (in female)	30
Esophagus	5
Ependymoma	1
NF = Nonfunctioning; GH = growth hormone; PPoma = tumor secreting pancreatic polypeptide; VIPoma = tumor secreting vasoactive intestinal polypeptide; ECLoma = tumor of enterochromaffin-like cells; ACTH = adrenocorticotropic hormone ^* Tumor type with malignant potential for 25% or more cases. Modified from Agarwal et al. [18].

Clinical Characteristics of MEN1

MEN1 is characterized by the occurrence of tumors in multiple endocrine tissues and in nonendocrine tissues (table 1). The three main endocrine tissues most frequently affected by tumors in MEN1 are parathyroid (95%), enteropancreatic neuroendocrine (50%) and anterior pituitary (40%). Typical MEN1 is defined as tumor in two of the three main endocrine tissues, which in familial MEN1, includes at least one relative with tumor in one of the three main endocrine tissues [3]. In addition, an MEN1 patient could present with many other hormone-secreting, hormone nonsecreting and nonendocrine tumors: adrenal cortical tumor, foregut carcinoid (bronchial, thymic or of the gastric enterochromaffin-like cells), facial angiofibroma, truncal collagenoma, lipoma, meningioma, Barrett's esophagus, leiomyoma (uterine in females, or in the esophagus), and ependymoma [3]. Approximately 25% of MEN1 patients die from cancer due to malignant gastrinoma (enteropancreatic neuroendocrine tumor) or foregut carcinoid tumor [3].

Primary hyperparathyroidism from parathyroid hormone-secreting multiple parathyroid adenomas is usually the first clinical manifestation observed in MEN1 patients typically between 20 and 25 years of age [3]. In a few patients, the first clinical manifestation has been observed as tumors of the enteropancreatic neuroendocrine tissues (multiple gastrinoma) or anterior pituitary (prolactinoma) [3]. Eventually the patients develop various combinations of the 20 or more tumor types associated with the MEN1 syndrome (table 1). MEN1-associated endocrine tumors are named after the hormones that these tissues produce because majority of these tumors secrete excessive amounts of hormone. Some endocrine tumors can be hormone non-secreting, therefore, clinically nonfunctioning (NF). The frequently observed skin lesions, facial angiofibroma (85%), truncal collagenoma (70%), and lipoma (30%) have been considered to be helpful for presymptomatic diagnosis prior to the appearance of the hormone-secreting tumors [3]. The earliest manifestation of MEN1 has been reported in two cases of insulinoma at age 6 years, and one case with pituitary macro-adenoma secreting prolactin and growth hormone at age 5 years or earlier [3]. Hence, routine periodic monitoring for tumors in asymptomatic MEN1 at-risk individuals by biochemical tests (for substances secreted by the hormone-secreting tumors) and imaging tests has been recommended beginning in early childhood at age 5 years [3].

Genetics of MEN1

Genetic linkage studies in kindreds, and loss-of-heterozygosity (LOH) studies in tumors established linkage of the MEN1 syndrome to chromosome 11q13 in 1988 [4]. Subsequently, in 1997, the MEN1 gene was identified by a positional cloning approach [5, 6]. The 9-kb MEN1 gene contains 10 exons transcribed into a 2.8-kb mRNA which encodes a 610 amino acid protein named menin (NCBI Reference Sequence: NM_130799.2, human menin isoform-2). Screening of the coding region and splice junctions has identified a heterozygous germline mutation of the MEN1 gene in 70% of typical MEN1 index cases (familial or sporadic). No germline promoter mutations have been reported, and large deletions have been reported as rare in the MEN1 gene [7]. Germline-inactivating mutation (1st hit) predisposes to the development of tumors in adults; tumors arise after loss of the remaining normal copy of the MEN1 gene (2nd hit), classifying the MEN1 gene as a tumor suppressor gene. More than 95% of tumors from MEN1 patients show LOH at chromosome 11q13 [7].

MEN1 gene mutation analysis has helped to identify the cause of various sporadically occurring tumors of the same types that are observed in the MEN1 syndrome. Somatic LOH at chromosome 11q13 is observed in 5-50% of such noninherited commonly occurring sporadic tumors [7]. Somatic MEN1 gene mutation analysis has revealed that a fraction of these tumor types possess inactivating mutation in the MEN1 gene: parathyroid adenoma (18%), gastrinoma (38%), insulinoma (14%), VIPoma (57%), nonfunctioning pancreatic tumor (16%), glucagonoma (60%), adrenocortical tumor (2%), bronchial carcinoid...

Table of contents

• Cover Page
• Front Matter
• Multiple Endocrine Neoplasia Type 1
• Multiple Endocrine Neoplasia Type 2
• von Hippel-Lindau Syndrome
• Carney Complex
• Multiple Endocrine Neoplasia Type 4
• Novel Hereditary Forms of Pheochromocytomas and Paragangliomas
• Carney Triad
• Genetics of Pituitary Adenomas
• Clinical Behavior and Genetics of Nonsyndromic, Familial Nonmedullary Thyroid Cancer
• Genetic Defects Associated with Familial and Sporadic Hyperparathyroidism
• Endocrine Tumors Associated with Neurofibromatosis Type 1, Peutz-Jeghers Syndrome and Other Familial Neoplasia Syndromes
• Author Index
• Subject Index