Abstract: MON 503

A Cell Cycle Division 73 (CDC73) Germline Mutation in a Patient with Acromegaly, Pancreatic Neuroendocrine Tumor (NET),and Primary Hyperparathyroidism: A Novel Association

Presenter: Lisa B Nachtigall


Abstract


Lisa B Nachtigall*1, Kate Lines2, Laura E. Dichtel1, Treena Cranston3, Shafaq Khairi1, Hannah Boon2, Babak Torabi Sagvand1, Xun Zhang1, Mark Stevenson2, Anne Klibanski1 and Rajesh V Thakker2
1Massachusetts General Hospital/Harvard Medical School, Boston, MA, 2University of Oxford, Oxford, United Kingdom, 3Oxford Molecular Genetics Laboratory, Churchill Hospital, Oxford, United Kingdom

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Lisa B Nachtigall*1, Kate Lines2, Laura E. Dichtel1, Treena Cranston3, Shafaq Khairi1, Hannah Boon2, Babak Torabi Sagvand1, Xun Zhang1, Mark Stevenson2, Anne Klibanski1 and Rajesh V Thakker2
1Massachusetts General Hospital/Harvard Medical School, Boston, MA, 2University of Oxford, Oxford, United Kingdom, 3Oxford Molecular Genetics Laboratory, Churchill Hospital, Oxford, United Kingdom

Background: We previously reported negative Multiple Endocrine Neoplasia -1 (MEN-1) genetic testing in acromegaly patients with clinical MEN-1, defined by the presence of at least 2 endocrine disorders: primary hyperparathyroidism (HPT), pituitary adenoma, and/or pancreatic neuroendocrine tumor (NET) or one of these and a first degree relative with MEN-1 (1). Since DNA results for MEN-1 mutations may be false negative (2), more extensive DNA sequencing analysis is required to exclude MEN-1 mutations. If the MEN-1 gene is excluded, other genes known to be associated with endocrine tumors might be involved.

Objectives: The goals of this study are to identify a genetic basis for the co-existence of acromegaly and primary HPT and to correlate genetic and clinical findings. Methods: 15 patients with acromegaly who had primary HPT and negative MEN-1 genetic screening (GeneDX) were identified from a large acromegaly database. Ten patients, including 7 in whom clinical characteristics have been previously been reported (1), provided a blood a sample with informed consent for genetic testing. DNA sequence analysis was performed for genes including: MEN1, CDC73, CDKN1A, CDKN1B, CDKN2B, CDKN2C and AIP. In addition, multiplex ligation-dependent probe amplification was used to search for deletions or duplications in MEN1, CDC73, CDKN1B and AIP genes.

Results: Clinical data: All subjects (7 women, 3 men) had growth hormone secreting macroadenomas and had at least 1 transsphenoidal surgery; in 40%, adenomas also stained for prolactin and 30% received pituitary radiation. The age at diagnosis of acromegaly ranged from 15-65 years and in 20% was less than age 25 years. Seven patients had parathyroidectomy: 5 had adenomas and 2 had hyperplasia. Other tumors included pancreatic NET, intraductal papillary mucinous neoplasm, and schwannoma. Cancers occurred in 30%: renal cell plus papillary thyroid cancer in one patient, cervical and breast cancer in the others, respectively. Only 1 had a family history of possible MEN-1. Genetic Data: A CDC73 heterozygous missense mutation Leu380Phe, was identified in a patient with acromegaly, mild HPT, pancreatic NET, and no known family history of endocrine tumors. Genetic abnormalities were not detected in any other patients.

Conclusions: In patients with acromegaly plus primary HPT, DNA sequencing of MEN-1, CDKN1A, CDKN1B, CDKN2B, CDKN2C and AIP genes was unrevealing and new mutations may explain the co-occurrence of parathyroid and pituitary adenomas. However, a mutation in CDC73, whose mutations usually cause the primary HPT jaw-tumor (HPT-JT) syndrome with higher association of parathyroid cancer (3), was identified, thereby expanding the spectrum of CDC73-related disorders and establishing a novel association of pancreatic NET and somatotropinoma with CDC73.

1. Torabi Sagvand B, Khairi S, Swearingen B, Klibanski A, Nachtigall L: The Prevalence of Multiple Endocrine Neoplasia 1 (MEN-1) in Acromegaly: Phenotype/Genotype Correlation. 14th International Pituitary Congress; 2015

2. Lemos MC, Thakker RV. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat. 2008;29:22–32

3. Newey PJ, Bowl MR, Cranston T, Thakker RV.. Cell division cycle protein 73 homolog (CDC73) mutations in the hyperparathyroidism-jaw tumor syndrome (HPT-JT) and parathyroid tumors. Hum Mutat. 2010;31:295–307

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