CDC73 – Parathyroid Gland Carcinoma

CDC73 encodes parafibromin, a tumor suppressor whose inactivating germline or somatic variants underlie hereditary hyperparathyroidism-jaw tumor syndrome and sporadic parathyroid carcinoma. Inheritance is autosomal dominant with incomplete penetrance, and heterozygous loss-of-function variants predispose to carcinoma and primary hyperparathyroidism (PMID:12434154; PMID:14585940).

Genetic evidence includes >20 probands from ≥10 unrelated families with pathogenic CDC73 variants, including nonsense, frameshift, splice-site, and intragenic deletions. Many cases show biallelic inactivation via a second somatic hit (loss of heterozygosity or mutation), and recurrent germline c.358C>T (p.Arg120Ter) has been reported in familial and sporadic carcinomas (PMID:27679651). Parafibromin-negative parathyroid tumors demonstrate malignant features, supporting variant pathogenicity (PMID:21240254).

Functional studies demonstrate that CDC73 knockout is embryonic lethal in mice and that parafibromin is required for posttranscriptional histone mRNA processing and regulation of growth factors (Igf1, Igf2) (PMID:18212049). Mutations disrupting a bipartite nuclear localization signal or impairing protein stability abolish nuclear parafibromin, leading to cell cycle arrest and increased proliferation in vitro (PMID:20541447).

Contested findings include rare parathyroid carcinomas without CDC73 mutations or parafibromin loss, and secondary hyperparathyroidism cases showing intact CDC73 (PMID:18338208). However, these likely reflect distinct genetic etiologies or tissue-specific mechanisms.

Integration of genetic and experimental data confirms haploinsufficiency as the primary pathogenic mechanism. Germline testing for CDC73, coupled with parafibromin immunohistochemistry, enhances early detection of carcinoma and informs surgical management and family counseling. Additional large deletions and promoter mutations may require copy number and splicing assays for comprehensive diagnostics.

Key Take-home: Autosomal dominant CDC73 mutations are strongly and definitively associated with parathyroid carcinoma, and combined genetic testing and parafibromin staining guide diagnosis and surveillance in affected individuals.

References

• Nature Genetics • 2002 • HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome PMID:12434154
• The New England Journal of Medicine • 2003 • Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma PMID:14585940
• International Journal of Endocrinology and Metabolism • 2016 • Recurrence of Hyperparathyroid Hypercalcemia in a Patient With the HRPT-2 Mutation and a Previous Parathyroid Carcinoma in Hyperparathyroidism-Jaw Tumor Syndrome PMID:27679651
• Modern Pathology • 2011 • Downregulation of CASR expression and global loss of parafibromin staining are strong negative determinants of prognosis in parathyroid carcinoma PMID:21240254
• Molecular and Cellular Biology • 2008 • Parafibromin, a component of the human PAF complex, regulates growth factors and is required for embryonic development and survival in adult mice PMID:18212049
• Endocrine Pathology • 2011 • Identification of de novo germline mutations in the HRPT2 gene in two apparently sporadic cases with challenging parathyroid tumor diagnoses PMID:21360064

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