25) These findings suggest that loss of tumor suppressor genes such as CDKN1B, CDKN2A, ARF, CDKN2B, RB1, and TP53, and resultant functional loss of cell cycle checkpoint controlling proteins, may lead to dysregulation of G1/S transition of the cell cycle and tumorigenesis.
3-q27 Change % of patients Candidate genes Loss 50-78 RB1 Loss 50-67 CDKN1B, ETV6 Loss 50-66 CDKN2A, CDKN2B, MTAP Loss 50-55 NOTCH, TRAF2, CARD9 Loss 21-44 SMAD5, MSH3, MCC, APC Loss 33-36 CYP1A1 Loss 29 PTPN23 Loss 22-29 CDKN2D, PRKCSH Loss 22 TP53 Loss 21 MAD1L1 Loss 11-21 PARK2 Table 3: Summary of the most frequent genomic alterations in BPDCN.
A total of 12 TGF-3 pathway downstream genes were found to be differentially expressed (Table 3), which are related to regulation of cell cycle progression (CDC6, CDKN1B, GADD45B, NFKBIA), cytokine and growth factors (1110, TNFSF10, PDGFA, angiogenesis (NOTCH1, VEGFA, PDGFA) and ECM deposition (FN1).
B binding protein Transforming growth factor, beta 2 TCFBR2 Transforming growth factor, beta receptor II TCF/Smad pathway SMAD1 SMAD family member 1 SMAD6 SMAD family member 6 S0X4 SRY (sex determining region Y)-box 4 SP1 Spl transcription factor CTNNB1 CREB binding protein Ras/MAPK(non-Smad) RHOA Ras homolog gene family, pathway member A RH08 Ras homolog gene family, member B MAP3K7 Mitogen-activated protein kinase kinase kinase 7 MAPK14 Mitogen-activated protein kinase 14 Downstream effector BCL2L1 BCL2-like 1 CDC6 Cell division cycle 6 homolog CDKN1B Cyclin-dependent kinase inhibitor 1B CEBPB CCAAT/enhancer binding protein (C/EBP), beta FN1 Fibronectin 1 CADD45B Growth arrest and DNA-damage-inducible.
90007 1A (p21, Cip1) CDKN1B
Cyclin-dependent kinase inhibitor -1.
Activated Akt also promotes cell cycle transition through the regulation of CDKN1B [encoded by cyclin-dependent kinase inhibitor 1B (CDKN1B)], GSK3B [encoded by glycogen synthase kinase 3 beta (GSK3B)], and mTOR [encoded by mammalian target of rapamycin (MTOR)] signaling.
The most studied regulation in this context is the regulation of CDKN1B by miR-221/-222 (12, 36-38).
Susceptibility to pituitary neoplasia related to MEN-1, CDKN1B
and AIP mutations: an update.
Francis et al (55) noted specific mutations in CDKN1B in 7 of 50 small intestinal NETs, suggesting p27 as a tumor suppressor gene in these NETs.
Somatic mutation of CDKN1B in small intestine neuroendocrine tumors.
2) Blastic plasmacytoid dendritic cell neoplasm cells demonstrate a recurrent combination of deletions in several tumor suppressor genes, including RB1, CDKN1B
, CDKN2A, and tumor protein p53 (TP53).
The wide array of molecular-based PCa markers includes proliferation index (Ki-67), microvessel density, nuclear morphometry, tumor suppressor genes (eg, TP53, CDKN1A, CDKN1B
, NKX3-1, PTEN, and the retinoblastoma gene Rb), oncogenes (eg, BCL2, MYC, EZH2, and ERBB2 [formerly HER2/neu]), adhesion molecules (eg, CD44 and E-cadherin), the PI3K/Akt/mTOR (mammalian target of rapamycin) pathway, (30,31) apoptosis regulators (eg, survivin and transforming growth factor p1), androgen receptor status, neuroendocrine differentiation markers, and prostate tissue lineage-specific markers (PSA, prostate-specific acid phosphatase, and prostate-specific membrane antigen).