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Differential Genetic Diagnosis between Leiomyoma and Leiomyosarcoma
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Alba Machado-Lopez, Aymara Mas
At the molecular level, myometrial tumors show unbalanced karyotypes as well as non-specific and complex alterations, such as SNVs, small indels, amplifications, and gene fusions (36,37). Specifically, up to 50% of LM have cytogenetic abnormalities, mainly affecting 6p21, 7q, and 12q15 chromosome regions as the main drivers, whereas point mutations in gene MED12 are detected in up to 70% of tumors (38). Chromosomal rearrangements between HMGA1/HMGA2 and RAD51B, or between COL4A5 and COL4A6 are also frequent in LM, mainly resulting in overexpression of these genes or reduced expression of CUX1 or CUL1 due to 7q deletions (25). Furthermore, heterozygous mutations in the FH (fumarate hydratase) gene can cause Reed's syndrome, also known as hereditary leiomyomatosis, and renal cell cancer syndrome, which is characterized by multiple cutaneous and uterine leiomyomas (Figure 25.3).
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Compared with CML, the BCR-ABL1-negative MPNs demonstrate remarkable genetic complexity, with multiple somatic mutations impacting disease biology, in particular the number of non-driver mutations present, as well as the effect of the order of acquisition of these aberrations on the phenotypic characteristics of MPN and its treatment. The phenotypic driver mutations include JAK2V617F, MPL, CALR, and rarely, JAK2 exon 12. JAK2V617F is present in almost all patients with PV and in about 60% of those with ET or PMF; CALR is typically absent in PV and present in 20% ET and PMF. MPL mutation also tends to be absent in PV and present in 4% of ET and 6% of PMF.100 About 15% of all patients with ET and PMF are considered negative for all the driver mutations and labeled “triple negative” MPN. In addition to these mutations, several other somatic mutations have now been characterized, such as the epigenetic genes (ASXL1, TET2, EZH2, IDH1, IDH2, and DNMT3A), RNA splicing genes (SRSF2, U2AF1, U2AF2, and SF3B1), and transcription regulatory genes (TP53, IKZF1, NF-E2, and CUX1). Also, the order of mutation acquisition influences the biology and clinical features in MPN.101 A novel JAK2 insertion/deletion mutation, JAK2ex13InDel, associated with erythrocytosis and eosinophilia, possibly representing a variant of PV and chronic eosinophilic leukemia, was described in 2019.102
Familial Monosomy 7 Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
CUX1 (7q22.1) encodes a homeobox transcription factor, which acts as a haploinsufficient tumor suppressor. Loss of heterozygosity or inactivating point mutation in CUX is associated with myeloid tumor, uterine leiomyoma, breast cancer, and tumors of the endometrium, large intestine, and lung [19].
RNA methylation-related genes of m6A, m5C, and m1A predict prognosis and immunotherapy response in cervical cancer
Published in Annals of Medicine, 2023
Yan Wang, Yiwen Mao, Caizhi Wang, Xuefeng Jiang, Qionglan Tang, Lingling Wang, Jialei Zhu, Mengqiu Zhao
The prognosis of malignant tumors is associated with changes in the expression of multiple genes [12–15]. Liu et al. [12] found that SEMA3C strongly correlates with a shorter survival time in cervical cancer. Griesmannd et al. [13] found that the cut-like homology cassette 1 (CUX1) enhances pancreatic cancer proliferation by increasing the activation of MEK-ERK signaling upstream of the ADAM17 protein. Aly et al. [14] found that somatic mutations CUX1 gene can be found in myeloid neoplasms (MNs), Especially in myelodysplastic syndromes (MDSs), which also leads to DNA repair dysfunction, CUX1MT/DEL is also associated with poorer survival rates. Zhang et al. [15] found that CA2 inhibits tumor metastasis in HCC that is dependent on the α1 subunit of ATP1A1 in inpatients with hepatocellular carcinoma.
Pemigatinib for the treatment of myeloid/lymphoid neoplasms with FGFR1 rearrangement
Published in Expert Review of Anticancer Therapy, 2023
Craig W. Freyer, Mitchell E. Hughes, Alison Carulli, Adam Bagg, Elizabeth Hexner
The investigational multi targeted kinase inhibitor dovitinib (TKI258) has demonstrated activity against MLNFGFR1 cell lines, specifically those with ZNF198-FGFR1, BCR-FGFR1, and CUX1-FGFR1 fusions in pre-clinical studies [39,47,48]. To our knowledge, clinical use of dovitinib in MLNFGFR1 has yet to be reported. Two additional FGFR inhibitors are currently commercially available. Erdafitinib is pan-FGFR inhibitor (FGFR1–4) currently approved for locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 or FGFR2 genetic alterations [49] and infigratinib is FGFR1–3 inhibitor currently approved for locally advanced or metastatic cholangiocarcinoma with FGFR2 fusion or other rearrangement [50]. To our knowledge, neither of these agents have been studied in patients with MLNFGFR1, however the possibility of clinical efficacy makes these agents worthy of study in future trials or on a compassionate use basis.
Unfolding the Role of Splicing Factors and RNA Debranching in AID Mediated Antibody Diversification
Published in International Reviews of Immunology, 2021
Ankit Jaiswal, Amit Kumar Singh, Anubhav Tamrakar, Prashant Kodgire
A subsequent study revealed that the presence of H3K9me3 and H3K9Ac on the donor and acceptor switch region dictated which switch region will undergo recombination and target CSR [50]. Remarkably, it was found that AID is most frequently mistargeted to non-immunoglobulin genes SNHG3, MALAT1, BCL7A, and CUX1, those' are enriched in H3K9me3 chromatin mark [52]. How AID is the targeting of AID to the switch region is linked with histone modification? Remarkably, AID was found to interact with KAP1 and HP1 (both HP1 and KAP1 are generally linked to heterochromatin formation) to form a complex that mediates tethering of AID to the switch regions [53]. Moreover, interruption in AID, KAP1 and HP1 complex formation leads to defects in CSR while having no effect on SHM. Thus, KAP1 and HP1 are the crucial players that assist in AID tethering to switch region via recognition of specific chromatin mark. Furthermore, super-enhancers that contain hyperacetylation region assist in the targeting of AID to Ig genes (discussed under heading influence of transcription on AID targeting) [54,55]. H3K4me3 at the switch region is significant for DNA cleavage step in CSR. Moreover, inhibition of H3K4 methyltransferase showed depletion of H3K4me3 at the switch regions which results in the inhibition of CSR [56]. Thus, H3K4me3 plays a vital role in SHM and CSR [53].