Germline CDKN1B variant type and site are associated with phenotype in MEN4

Reut Halperin, Liat Arnon, Sapir Nasirov, Limor Friedensohn, Michal Gershinsky, Alona Telerman, Eitan Friedman, Rinat Bernstein-Molho, Amit Tirosh

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Multiple endocrine neoplasia 4 (MEN4) is a rare multiglandular endocrine neoplasia syndrome clinically hallmarked by primary hyperparathyroidism (PHPT), pituitary adenoma (PitAd), and neuroendocrine tumors (NET), clinically overlapping MEN1. The underlying mutated gene - CDKN1B, encodes for the cell-cycle regulator p27. Possible genotype-phenotype correlations in MEN4 have not been thoroughly assessed. Prompted by the findings in three Israeli MEN4 kindreds, we perf ormed a literature review on published and unpublished data from previously reported MEN4/CDKN1B cases. Univariate analysis analyzed time-dependent risks for developing PHPT, PitAd, or NET by variant type and position along the gene. Overall, 74 ME N4 cases were analyzed. PHPT risk was 53.4% by age 60 years (mean age at diagnosis age 50.6 ± 13.9 years), risk for PitAd was 23.2% and risk for NET was 16.2% (34.4 ± 21. 4 and 52.9 ± 13.9 years, respectively). The frameshift variant p.Q107fs was the most common variant identified (4/41 (9.7%) kindreds). Patients with indels had higher risk for PHPT vs point mutations (log-rank, P = 0.029). Variants in codons 94-96 were associated with higher risk for PHPT (P < 0.001) and PitAd (P = 0.031). To conclude, MEN4 is clinically distinct from MEN1, with lower risk and older age for PHPT diagnosis. We report recurren t CDKN1B frameshift variants and possible genotype-phenotype correlations.

Original languageEnglish
Article numbere220174
JournalEndocrine-Related Cancer
Volume30
Issue number1
DOIs
StatePublished - 1 Jan 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 Society for Endocrinology Published by Bioscientifica Ltd.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Keywords

  • CDKN1B
  • MEN4
  • hyperparathyroidism
  • neuroendocrine tumor
  • pituitary adenoma

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