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. 2020 Jun 8;21(11):4098. doi: 10.3390/ijms21114098

Figure 2.

Figure 2

PHLDA3 gene defects are observed in lung and pancreatic neuroendocrine tumors (NETs). (A) Among lung NETs having wild-type p53, 63% exhibited loss of PHLDA3, whereas among lung NETs having a nonfunctional p53, only 13% exhibited loss of PHLDA3. Nonfunctional p53 can be caused by deletion as well as mutation. Abnormalities in p53 can result in upregulated expression of the protein, which may be detected by immunohistochemistry. Genomic sequencing is also preformed to analyze p53 mutations. Chromosome copy number alterations in PHLDA3 are analyzed by comparative genomic hybridization (CGH). (B) High frequency of PHLDA3 loss of heterozygosity (LOH) is found in pancreatic neuroendocrine tumors (PanNETs), which commonly have wild-type p53. (C) Two-hit inactivation of PHLDA3 in PanNETs. One of the PHLDA3 loci undergoes LOH and the other undergoes methylation. (D) PanNET tumorigenesis requires the functional loss of both PHLDA3 and MEN1. PHLDA3 and MEN1 suppress cell proliferation in normal islet cells. Loss of both PHLDA3 and MEN1 function is necessary for PanNET tumorigenesis. (E) Functional loss of PHLDA3 contributes to PanNET progression. Loss of MEN1 function leads to islet hyperplasia and/or atypia over time, and additional loss of PHLDA3 function is required for tumor formation and progression.