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Medullary thyroid carcinoma in medical management of thyroid disease
Published in David S. Cooper, Jennifer A. Sipos, Medical Management of Thyroid Disease, 2018
Mimi I. Hu, Elizabeth G. Grubbs, Julie Ann Sosa
The presence of a somatic RET mutation has been found to be associated with a lower survival rate (44). The role of somatic copy number alteration as a mechanism for MTC tumorigenesis has been recently studied; the loss of somatic cyclin-dependent kinase inhibitor 2C (CDKN2C), an inhibitor of the retinoblastoma pathway necessary for tumor cell cycle activation, is associated with the presence of distant metastasis at presentation as well as decreased overall survival, a relationship enhanced by concomitant RET M918T mutation (45).
Hereditary primary hyperparathyroidism and multiple endocrine neoplasia
Published in Philip E. Harris, Pierre-Marc G. Bouloux, Endocrinology in Clinical Practice, 2014
MEN1 is caused by a mutation in the MEN1 gene that was localized to chromosome 11q13 in 198831 and identified as the MEN1 gene in 1997.32,33 The MEN1 gene contains ten exons that span 9.8 kb of genomic DNA and produce a major transcript of 2.9 kb. Exons 2–10 encode a 610 amino acid protein called menin. To date, there are >1340 loss-of-function mutations spread across the MEN1 gene.34 Most are unique to each family. In some geographical areas, founder MEN1 mutations have been identified such as in Tasmania, Finland and the Burin peninsula of Newfoundland. The majority are truncating (nonsense and frameshift mutations), but missense, splice, and in-frame mutations are also found. One to four percent have larger deletions of several exons or the whole gene.9 Clinically, mutation testing is performed on DNA isolated from peripheral blood (EDTA tube). DNA sequencing combined with a test for larger deletions will detect mutations in 31%–65% of all sporadic cases and 90% of all familial MEN1 cases.8,9 The remaining familial 10% may be phenocopies; have mutations in the MEN1 gene that cannot be found by conventional methods; or have a mutation in a gene that is involved in the same signaling pathway. To date, mutations have been found in CDKN1B (11 published cases, representing up to 2% of all MEN1 cases without a MEN1 mutation and denoted MEN4, OMIM 610755). Single mutations have also been reported in other cyclin-dependent kinase inhibitors: CDKN2B, CDKN2C, and CDKN1A.35
Multiple Myeloma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Genetic events include translocations, loss of heterozygosity, gene amplification, gene mutation, and as yet poorly understood epigenetic changes, and establishing correlates between abnormalities and clinical outcome has been difficult. Translocations involving chromosome 14q32 occur in 50% of cases, and these usually involve the heavy chain switch regions of the IgH gene although recently breakpoints involving VDJ have been described. These translocations occur in all cells of the clone and at the MGUS stage and are felt to be an initiating event. Several partner chromosomes have been identified with breakpoints frequently near the site of cellular protooncogenes, e.g. cyclin D1 on 11q13, fibroblast growth factor receptor 3 (FGFR3) and MMSET on 4p16, CCND3 on chromosome 6p21, and MAF genes on chromosome 16q23. The t(4;14) translocation occurs in 15% of cases and is associated often with an IgA M-protein and a poor outcome possibly partly overcome with bortezomib-based therapy. Due to the reciprocal nature of this translocation, two oncogenes are activated, FGR3 and MMSET, although their exact contributions remain controversial. The t(11;14) with overexpression of cyclin D1 is associated with an intermediate prognosis, and sensitivity to bcl-2 inhibition (venetoclax) with often lymphoplasmacytoid morphology and CD20 expression. About 20% of myelomas have a unique non-recurrent partner chromosome translocating to 14q32. Myeloma lacking an IgH translocation tends to have hyperdiploidy although there is some overlap between the two groups and hyperdiploidy is associated with a better prognosis. Similar to IgH translocations, hyperdiploidy is an early event found in MGUS stage and is characterized by multiple trisomies typically involving the odd-numbered chromosomes (i.e. 3, 5, 7, 9, 11, 15, 19, 21). Loss of 13q is common, occurring in 58% of myelomas, involves loss of the Rb gene, although homozygous loss or inactivation is not common, and co-associates with other poor prognostic markers such as t(4;14). Chromosome 1q gain and loss of chromosome 1p (probably affecting CDKN2C and FAM46C genes) are poor prognostic events although the relevant genes affected on 1q are not clear. Loss of tumor suppressor genes requires inactivation of both alleles and a number of genes have been identified as being relevant as tumor suppressor genes in myeloma including BIRC2, TRAF3, FAM46C, and DIS3.
Emerging protein kinase inhibitors for the treatment of multiple myeloma
Published in Expert Opinion on Emerging Drugs, 2019
Judith Lind, Felix Czernilofsky, Sonia Vallet, Klaus Podar
Multiple myeloma (MM), the second most common hematologic malignancy worldwide, is a clonal plasma cell (PC) malignancy characterized by the production and secretion of monoclonal antibodies, hypercalcemia, renal disease, anemia, osteolytic lesions, as well as immunodeficiency [1]. It develops through branching pathways that are initiated by a “genetic hit“ in a pro-B cell or germinal center (GC) B cell, providing clonal advantage to malignant PCs thereby ultimately leading to the development of Monoclonal Gammopathy of Unknown Significance (MGUS). Disease-initiating events in MM include hyperdiploidy (48–75 chromosomes) with ≥2 trisomies in odd chromosomes 3, 5, 7, 9, 11, 15, 19, 21, or non-hyperdiploidy with chromosomal translocations that predominantly affect the IgH locus at chromosome 14. Generated by aberrant class switch recombination (CSR) these translocations put an oncogene under the direct control of the IgH enhancer. Activated oncogenes include CCND1, FGFR3/MMSET, Maf, MafB, and CCND3 in translocations t(11;14) (14%), t(4;14) (~11%), t(14;16) (3%), t(14;16) (<3%), t(14;20) (1.5%), and t(6;14) (<1%), respectively. Additional genetic hits as well as the selective pressure within the BM microenvironment subsequently trigger the transition from MGUS to smoldering MM (SMM), MM, and ultimately PC leukemia (PCL). Late genetic hits include del17p affecting p53 (8%), del1p with loss of CDKN2C, FAF1 and FAM46C (30%), 1q gain with amplifications of 679 genes, i.e. CKS1B, ANP32E, Bcl9, and PDZK1 (40%), t(8;14) and copy-number variations (CNV) affecting Myc as well as somatic mutations activating MAPK-, NFkB-, and DNA-repair pathways. Advances of our understanding in MM pathogenesis have led to the introduction of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAbs) which have significantly prolonged patient survival 3- to 4-fold, from 4 years to at least 8 to 10 years. Nevertheless, MM remains an incurable disease. Novel therapies are therefore needed.
Lappaol F regulates the cell cycle by activating CDKN1C/p57 in human colorectal cancer cells
Published in Pharmaceutical Biology, 2023
Rui-Yi Yang, Jia-Yi Tan, Zhe Liu, Xiao-Ling Shen, Ying-Jie Hu
The normal cell cycle sequentially goes through G1, S, G2, and M phases for cell proliferation. The transition between the cell cycle phases of eukaryotic cells is governed by the ordered activation of a set of cyclin–CDK complexes, and CDKNs inhibit the activities of these complexes at appropriate check points. Ultra-powerful ‘engines’ (such as cyclins and CDKs) and defective ‘brakes’ (such as CDKNs) lead to uncontrolled cell cycle and excessive cell proliferation (Lim and Kaldis 2013). Therefore, cell cycle dysregulation is a common process in the development of cancer (Peng et al. 2021). Known to date, CDKNs are divided into two distinct families, INK4 and CIP/KIP. Members of the INK4 family (CDKN2A/p16INK4a, CDKN2B/p15INK4b, CDKN2C/p18 INK4c, and CDKN2D/p19 INK4d) specifically inhibit the activities of CDK4 and CDK6, whereas CIP/KIP members (CDKN1A/p21CIP1, CDKN1B/p27KIP1, CDKN1C/p57KIP2, and CDKN3CIP2) control a broad spectrum of cyclin–CDK complexes. In this study, CDKN1C/p57 was the most significantly upregulated among all 127 LAF-induced DEPs. CDKN1C/p57, which is highly homologous to CDKN1B/p27, has also been identified as a tumor suppressor (Lee et al. 1995; Matsuoka et al. 1995). Low expression of CDKN1C/p57 has been observed in many types of tumors and is significantly correlated with poor prognosis and aggressive form of the disease (Pateras et al. 2009; Borriello et al. 2011; Lai et al. 2021). During colorectal carcinogenesis, CDKN1C/p57 downregulation is associated with the transition from adenoma to carcinoma and large size of the tumor (Noura et al. 2001; Li et al. 2003). The association between cancer and CDKN1C/p57 expression suggests that increase in CDKN1C/p57 levels may be advantageous for cancer therapy. Similar to CDKN1A/p21 and CDKN1B/p27, CDKN1C/p57 inhibits a series of cyclin–CDK complexes, including CCNE–CDK2, CCNA–CDK2, CCNE–CDK3, CCND1–CDK4, CCND2–CDK4, and to a lesser extent, CCNB–CDK1 and CCND2–CDK6 (Lee et al. 1995; Matsuoka et al. 1995; Reynaud et al. 2000). CCNA–CDK2 has previously been identified as an imperative kinase for DNA replication and S-phase progression (Fotedar et al. 1996; Morgan 2008). In addition, CCNA–CDK2 regulates the timing of CCNB–CDK1 activation during the late S/G2 phase and mediates the S phase exit and G2 phase transition of cells (Oakes et al. 2014). Downregulation of CCNA2 and CDK2 induces the cell cycle at S phase (Cheng et al. 2020). Consistent with the upregulation of CDKN1C/p57 by LAF, the expression of CCNA2, CDK2, CCNB1, and CDK1 was subsequently inhibited, leading to S-phase arrest in SW480 CRC cells.