Genetic Abnormalities in Primary Hyperparathyroidism (PHPT)

• Numerous genetic abnormalities have been identified in the development of PHPT, including:
  • Anomalies in tumor suppressor genes
  • Proto-oncogenes
• Specific DNA mutations in a parathyroid cell:
  • May confer a proliferative advantage over normal neighboring cells:
    • Thus allowing for clonal growth:
      • Large populations of these altered cells containing the same mutation within hyperfunctioning parathyroid tissue:
        • Suggest that such glands are a result of clonal expansion
• The majority of PHPT cases are:
  • Sporadic
• Nonetheless, PHPT also occurs within the spectrum of a number of inherited disorders such as:
  • Multiple endocrine neoplasia syndromes (MEN):
    • MEN type 1 (Wermer Syndrome)
    • MEN type 2A (Sipple Syndrome)
    • Isolated familial HPT
    • Familial HPT with jaw-tumor syndrome
      • All of these syndromes are inherited in an:
        • Autosomal dominant fashion
• MEN type 1 (Wermer Syndrome):
  • The earliest and most common presentation of MEN type 1 is:
    • PHPT:
      • Develops in approximately 80% to 100% of patients:
        • By age 40 years
  • These patients also are predisposed to the development of:
    • Pancreatic neuroendocrine tumors
    • Pituitary adenomas
    • Less frequently:
      • Skin angiomas
      • Lipomas
      • Adrenocortical tumors
      • Neuroendocrine tumors of the:
        • Thymus
        • Bronchus
        • Stomach
  • MEN type 1 has been shown to result from:
    • A germline mutation in a tumor suppressor gene:
      • Called MEN1 gene:
        • Located on chromosome 11q12-13:
          • That encodes Menin:
            • A protein that is postulated to interact with the transcription factors JunD and nuclear factor-κB in the nucleus, in addition to replication protein A and other proteins
  • Pre-symptomatic screening for mutation carriers for MEN type 1 is difficult:
    • Because generally MEN1 mutations result in a nonfunctional protein and are scattered throughout the translated nine exons of the gene
  • MEN1 mutations also have been found in kindred’s initially suspected to represent isolated familial HPT
  • Screening for mutation carriers for MEN type 1:
    • Has a very high detection rate:
      • Greater than 94%
    • In Sweden it is used for patients with PHPT with a first-degree relative with a:
      • Major endocrine tumor
      • Age of onset is less than 30 years and/or
      • If multiple pancreatic tumors / parathyroid hyperplasia is detected
• MEN type 2A (Sipple Syndrome):
  • Approximately 20% of patients with MEN type 2A develop PHPT:
    • Which is usually less severe
  • MEN type 2A is caused by a:
    • Germline mutation of the RET proto-oncogene:
      • Located on chromosome 10
    • Genotype and phenotype correlations have been noted in this syndrome:
      • In that individuals with mutations at:
        • Codon 634 are more likely to develop PHPT
• Patients with the familial HPT with jaw-tumor syndrome:
  • Have an increased predisposition to:
    • Parathyroid carcinoma
  • This syndrome maps to a tumor suppressor locus:
    • HRPT2 (parafibromin):
      • On chromosome 1
• Sporadic parathyroid adenomas and some hyperplastic parathyroid glands:
  • Have loss of heterozygosity (LOH) at 11q13:
    • The site of the MEN1 gene:
      • In approximately 25% to 40% of the cases
• Over expression of PRAD1:
  • Which encodes cyclin D1:
    • A cell cycle control protein:
      • Is found approximately 18% of parathyroid adenomas
  • This was proven to result from a rearrangement on chromosome 11:
    • That places the PRAD1 gene under the control of the PTH promoter
• Other chromosomal regions deleted in parathyroid adenomas and possibly reflecting loss of tumor suppressor genes include:
  • 1p, 6q, and 15q
• Amplified regions suggesting oncogenes have been identified at:
  • 16p and 19p
• RET mutations:
  • Are unusual in sporadic parathyroid tumors
• Sporadic parathyroid cancers:
  • Are characterized by uniform loss of the:
    • Tumor suppressor gene RB
      • Which is involved in cell cycle regulation
  • 60% have HRPT2 (CDC73) mutations
  • These alterations are rare in benign parathyroid tumors:
    • May have implications for diagnosis
  • The p53 tumor suppressor gene is also inactivated in a subset (30%) of parathyroid carcinomas

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