Paul Newey

Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1).

OBJECTIVE The aim was to provide guidelines for evaluation, treatment, and genetic testing for multiple endocrine neoplasia type 1 (MEN1). PARTICIPANTS The group, which comprised 10 experts, including physicians, surgeons, and geneticists from international centers, received no corporate funding or remuneration. PROCESS Guidelines were developed by reviews of peer-reviewed publications; a draft was prepared, reviewed, and rigorously revised at several stages; and agreed-upon revisions were incorporated. CONCLUSIONS MEN1 is an autosomal dominant disorder that is due to mutations in the tumor suppressor gene MEN1, which encodes a 610-amino acid protein, menin. Thus, the finding of MEN1 in a patient has important implications for family members because first-degree relatives have a 50% risk of developing the disease and can often be identified by MEN1 mutational analysis. MEN1 is characterized by the occurrence of parathyroid, pancreatic islet, and anterior pituitary tumors. Some patients may also develop carcinoid tumors, adrenocortical tumors, meningiomas, facial angiofibromas, collagenomas, and lipomas. Patients with MEN1 have a decreased life expectancy, and the outcomes of current treatments, which are generally similar to those for the respective tumors occurring in non-MEN1 patients, are not as successful because of multiple tumors, which may be larger, more aggressive, and resistant to treatment, and the concurrence of metastases. The prognosis for MEN1 patients might be improved by presymptomatic tumor detection and undertaking treatment specific for MEN1 tumors. Thus, it is recommended that MEN1 patients and their families should be cared for by multidisciplinary teams comprising relevant specialists with experience in the diagnosis and treatment of patients with endocrine tumors.

Cell division cycle protein 73 homolog (CDC73) mutations in the hyperparathyroidism-jaw tumor syndrome (HPT-JT) and parathyroid tumors†

The hyperparathyroidism‐jaw tumor (HPT‐JT) syndrome is an autosomal dominant disorder characterized by the occurrence of parathyroid tumors in association with ossifying fibromas of the maxilla and/or mandible. The gene responsible for HPT‐JT, known as CDC73, was identified in 2002 and encodes a 531 amino acid protein known as parafibromin. Parafibromin is predominantly a nuclear protein that interacts directly with β‐catenin and also forms part of the RNA polymerase associated factor‐1 complex (Paf1C) that regulates transcription. Heterozygous germline CDC73 mutations are detected in the majority of patients with HPT‐JT, and the demonstration of loss of heterozygosity (LOH) at the CDC73 locus in tumors from affected individuals is consistent with a tumor suppressor role. Somatic CDC73 mutations are a frequent finding in nonfamilial (i.e., sporadic) parathyroid carcinomas and have also been reported in benign sporadic parathyroid tumors as well as sporadic renal and fibro‐osseous jaw tumors. To date, 111 independent CDC73 mutations have been identified (68 germline; 38 somatic; 5 undefined), and these occur throughout the coding region and splice sites of the CDC73 gene, with the majority (>80%) predicting premature truncation of the parafibromin protein. These CDC73 mutations, together with their clinical and biological relevance, are reviewed. Hum Mutat 31:295–307, 2010.

Asymptomatic Children with Multiple Endocrine Neoplasia Type 1 Mutations May Harbor Nonfunctioning Pancreatic Neuroendocrine Tumors

CONTEXT Multiple endocrine neoplasia type 1 (MEN1) is characterized by the occurrence of parathyroid, pituitary, and pancreatic tumors. MEN1, an autosomal dominant disorder, has a high degree of penetrance, such that more than 95% of patients develop clinical manifestations by the fifth decade, although this is lower at approximately 50% by age 20 yr. However, the lower penetrance in the younger group, which is based on detecting hormone-secreting tumors, may be an underestimate because patients may have nonfunctioning tumors and be asymptomatic. OBJECTIVE The aim of the study was to evaluate the occurrence of nonfunctioning pancreatic neuroendocrine tumors in asymptomatic children with MEN1. PATIENTS Twelve asymptomatic Northern European children, aged 6 to 16 yr, who were known to have MEN1 mutations were studied. RESULTS Two asymptomatic children, who were aged 12 and 14 yr, had normal plasma fasting gastrointestinal hormones and were found to have nonfunctioning pancreatic neuroendocrine tumors that were more than 2 cm in size. Surgery and immunostaining revealed that the tumors did not have significant expression of gastrointestinal hormones but did contain chromogranin A and synaptophysin, features consistent with those of nonfunctioning pancreatic neuroendocrine tumors. The tumors had a loss of menin expression. The 14 yr old also had primary hyperparathyroidism and a microprolactinoma, and the 12 yr old had a nonfunctioning pituitary microadenoma. Three other children had primary hyperparathyroidism and a microprolactinoma. CONCLUSION Nonfunctioning pancreatic neuroendocrine tumors may occur in asymptomatic children with MEN1 mutations, and screening for such enteropancreatic tumors in MEN1 children should be considered earlier than the age of 20 yr, as is currently recommended by the international guidelines.

Whole-Exome Sequencing Studies of Nonhereditary (Sporadic) Parathyroid Adenomas

CONTEXT Genetic abnormalities, such as those of multiple endocrine neoplasia type 1 (MEN1) and Cyclin D1 (CCND1) genes, occur in <50% of nonhereditary (sporadic) parathyroid adenomas. OBJECTIVE To identify genetic abnormalities in nonhereditary parathyroid adenomas by whole-exome sequence analysis. DESIGN Whole-exome sequence analysis was performed on parathyroid adenomas and leukocyte DNA samples from 16 postmenopausal women without a family history of parathyroid tumors or MEN1 and in whom primary hyperparathyroidism due to single-gland disease was cured by surgery. Somatic variants confirmed in this discovery set were assessed in 24 other parathyroid adenomas. RESULTS Over 90% of targeted exons were captured and represented by more than 10 base reads. Analysis identified 212 somatic variants (median eight per tumor; range, 2-110), with the majority being heterozygous nonsynonymous single-nucleotide variants that predicted missense amino acid substitutions. Somatic MEN1 mutations occurred in six of 16 (∼35%) parathyroid adenomas, in association with loss of heterozygosity on chromosome 11. However, no other gene was mutated in more than one tumor. Mutations in several genes that may represent low-frequency driver mutations were identified, including a protection of telomeres 1 (POT1) mutation that resulted in exon skipping and disruption to the single-stranded DNA-binding domain, which may contribute to increased genomic instability and the observed high mutation rate in one tumor. CONCLUSIONS Parathyroid adenomas typically harbor few somatic variants, consistent with their low proliferation rates. MEN1 mutation represents the major driver in sporadic parathyroid tumorigenesis although multiple low-frequency driver mutations likely account for tumors not harboring somatic MEN1 mutations.

Mutant Prolactin Receptor and Familial Hyperprolactinemia

Hyperprolactinemia that is not associated with gestation or the puerperium is usually due to tumors in the anterior pituitary gland and occurs occasionally in hereditary multiple endocrine neoplasia syndromes. Here, we report data from three sisters with hyperprolactinemia, two of whom presented with oligomenorrhea and one with infertility. These symptoms were not associated with pituitary tumors or multiple endocrine neoplasia but were due to a heterozygous mutation in the prolactin receptor gene, PRLR, resulting in an amino acid change from histidine to arginine at codon 188 (His188Arg). This substitution disrupted the high-affinity ligand-binding interface of the prolactin receptor, resulting in a loss of downstream signaling by Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5). Thus, the familial hyperprolactinemia appears to be due to a germline, loss-of-function mutation in PRLR, resulting in prolactin insensitivity.

Parafibromin--functional insights.

Parafibromin is a predominantly nuclear protein with a tumour suppressor role in the development of hereditary and nonhereditary parathyroid carcinomas, and the hyperparathyroidism‐jaw tumour syndrome, which is associated with renal and uterine tumours. Parafibromin is a component of the highly conserved PAF1 complex, which regulates transcriptional events and histone modifications. The parafibromin/PAF1 complex regulates genes involved in cell growth and survival, and via these, parafibromin plays a pivotal role in embryonic development and survival of adults.

Role of multiple endocrine neoplasia type 1 mutational analysis in clinical practice.

OBJECTIVE To review and assess the role of MEN1 mutational analysis in clinical practice. METHODS Articles relevant to MEN1 mutation testing and screening were reviewed. RESULTS Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant disorder characterized by the combined occurrence of tumors of the parathyroid glands, pancreatic islet cells, and anterior pituitary gland. MEN 1 is associated with premature mortality attributable primarily to malignant pancreatic neuroendocrine tumors and foregut carcinoids. The MEN1 gene is located on chromosome 11q13, and germline MEN1 mutations are highly penetrant and lead to tumor development in >99% of patients by the age of 45 years. Current consensus guidelines recommend an integrated program of mutational analysis of the MEN1 gene and a combination of biochemical and radiologic screening to detect the early development of tumors and thereby reduce the morbidity and mortality associated with MEN 1. Our results reveal that MEN1 mutational analysis helps to confirm the clinical diagnosis, identify asymptomatic family members who have a MEN1 mutation and require screening from an early age, and identify the 50% of family members who do not have the MEN1 mutation and can therefore have the burden of screening and anxiety regarding potential disease removed. Moreover, MEN1 mutational analysis helps to resolve diagnostic challenges due to phenocopies, which occur in 5% to 10% of families with MEN 1. CONCLUSION MEN1 mutational analysis facilitates clinical management and provides benefits to patients and families with MEN 1.

Whole-exome sequencing studies of nonfunctioning pituitary adenomas.

CONTEXT The tumorigenic role of genetic abnormalities in sporadic pituitary nonfunctioning adenomas (NFAs), which usually originate from gonadotroph cells, is unknown. OBJECTIVE The objective of the study was to identify somatic genetic abnormalities in sporadic pituitary NFAs. DESIGN Whole-exome sequencing was performed using DNA from 7 pituitary NFAs and leukocyte samples obtained from the same patients. Somatic variants were confirmed by dideoxynucleotide sequencing, and candidate driver genes were assessed in an additional 24 pituitary NFAs. RESULTS Whole-exome sequencing achieved a high degree of coverage such that approximately 97% of targeted bases were represented by more than 10 base reads; 24 somatic variants were identified and confirmed in the discovery set of 7 pituitary NFAs (mean 3.5 variants/tumor; range 1-7). Approximately 80% of variants occurred as missense single nucleotide variants and the remainder were synonymous changes or small frameshift deletions. Each of the 24 mutations occurred in independent genes with no recurrent mutations. Mutations were not observed in genes previously associated with pituitary tumorigenesis, although somatic variants in putative driver genes including platelet-derived growth factor D (PDGFD), N-myc down-regulated gene family member 4 (NDRG4), and Zipper sterile-α-motif kinase (ZAK) were identified; however, DNA sequence analysis of these in the validation set of 24 pituitary NFAs did not reveal any mutations indicating that these genes are unlikely to contribute significantly in the etiology of sporadic pituitary NFAs. CONCLUSIONS Pituitary NFAs harbor few somatic mutations consistent with their low proliferation rates and benign nature, but mechanisms other than somatic mutation are likely involved in the etiology of sporadic pituitary NFAs.

Challenges and controversies in management of pancreatic neuroendocrine tumours in patients with MEN1

Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder, is characterised by the occurrence of pancreatic neuroendocrine tumours (P-NETs) in association with parathyroid and pituitary tumours. P-NETs, which include gastrinomas, insulinomas, and non-functioning tumours, occur in more than 80% of MEN1 patients and account for 50% of disease-specific deaths. However, there is no consensus about the optimal methods for detecting and treating P-NETs in MEN1 patients, and extrapolations from approaches used in patients with non-familial (sporadic) P-NETs require caution because of differences, such as the younger age of onset, multi-focality of P-NETs, and concomitant presence of other tumours in MEN1 patients. Thus, the early detection of P-NETs by circulating biomarkers and imaging modalities, and their appropriate treatments by surgical approaches and/or radionuclide therapy, chemotherapy, and biotherapy pose challenges and controversies. These challenges and controversies will be reviewed and possible approaches proposed.

Whole-Exome Sequencing Studies of Parathyroid Carcinomas Reveal Novel PRUNE2 Mutations, Distinctive Mutational Spectra Related to APOBEC-Catalyzed DNA Mutagenesis and Mutational Enrichment in Kinases Associated With Cell Migration and Invasion

CONTEXT Cell division cycle 73 (CDC73), encoding the protein parafibromin, is the most prevalent mutated gene in familial and sporadic parathyroid carcinoma (PC). OBJECTIVE To identify additional genetic abnormalities in PCs. DESIGN Whole-exome sequencing was performed using DNA from seven pairs of matched PCs and one triplet containing double primary tumor and normal leukocyte. Somatic variants were confirmed using Sanger sequencing and recurrently mutated genes were assessed in 13 additional PCs as well as 40 parathyroid adenomas (PA). RESULTS PC had an average of 51 somatic variants/tumor (range 3-176) with approximately 58% of variants occurring as nonsynonymous single nucleotide variants. The importance of CDC73 in PC is reinforced with a remarkable preferential amplification of the mutant CDC73 allele. Furthermore, recurrent germ line and somatic mutations in prune homolog 2 [Drosophila] (PRUNE2) were found in PC and computationally predicted to be deleterious; in addition, recurrent mutations in kinase genes related to cell migration and invasion were found. PRUNE2 showed recurrent mutations in 18% (4/22) of PCs with additional screening in 40 PAs revealing only one rare missense polymorphism (Asp1677Asn). For the first time, the mutational signature associated with apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)-catalyzed cytosine-to-uracil deamination is found in a subset of PC. CONCLUSION This study outlines the genetic landscape of PC and attempts to characterize the mutational processes shaping the PC genome.