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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).
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].
Genetics of Uterine Leiomyomata
Published in John C. Petrozza, Uterine Fibroids, 2020
C. Scott Gallagher, Cynthia C. Morton
The t(12;14)(q14-q15;q23-q24) is observed in nearly 20% of all cytogenetically abnormal UL and is associated with larger-sized neoplasms than karyotypically normal tumors [2,14,18,19,22–30]. Breakpoints on chromosome 12 span a large genomic region 5′ and 3′ of HMGA2 (high mobility group AT-hook 2) [31,32], which encodes a DNA architectural factor that regulates transcription [33,34]. Generally, balanced translocations result in dysregulated expression of the transcript (a gain or loss of function) or fusion genes (production of chimeric protein with novel function), as illustrated in Figure 5.1 [35–37]. Expression of HMGA2 is elevated in UL with t(12;14) compared to karyotypically normal UL and myometrium, suggesting the rearrangement has a gain-of-function effect on HMGA2 [38,39]. Truncation of HMGA2 with deletion of the 3′-UTR removes a site of transcription inhibition mediated by the microRNA let-7 [40,41]. Overexpression in both cases suggests HMGA2 harbors potential for dysregulated growth in UL, which is also supported by the observation of trisomy 12 in UL [9,13,18]. Interestingly, in a male with a pericentric inversion of chromosome 12 that results in constitutional truncation of HMGA2, extreme somatic overgrowth and multiple lipomas (another common mesenchymal tumor with documented frequent chromosomal rearrangements in HMGA2 [40,41]) were reported [31,42,43]. A number of additional “UL genes” have been implicated through chromosomal studies: HMGA1 at 6p21.3 [2,13,18,26,44,45], CUX1 at 7q22.1 [7,46], KAT6B at 10q22 [47], RAD51L1 at 14q23-q24 [18,37,48] and both COL4A5 and COL4A6 at Xq22.3 [7].
Distinctive phenotypes in two children with novel germline RUNX1 mutations - one with myeloid malignancy and increased fetal hemoglobin
Published in Pediatric Hematology and Oncology, 2020
Shruti Bagla, Katherine A. Regling, Erin N. Wakeling, Manisha Gadgeel, Steven Buck, Ahmar U. Zaidi, Leigh A. Flore, Michael Chicka, Charles A. Schiffer, Meera B. Chitlur, Yaddanapudi Ravindranath
Recently in mouse systems, hypo-functioning mutations of CUX1 were shown to induce CMML like features along with hyperplasia of platelet producing megakaryocytes.50 The chr7p localized CUX1, is a transcriptional regulator and is commonly mutated in cancer. 53 It has been implicated in both tumor progression and suppression.52 A majority of studies have reported upregulation of CUX1 with oncogenic properties in human cancer, except in AML with −7/-7q where an almost 50% down-regulation of CUX1 was reported, as expected from gene dosage effect.51CUX1 is also reported to be a regulator of chromatin looping, which is the primary mode of regulation of switch from fetal to adult hemoglobin. However, CUX1 haploinsufficiency alone may not be sufficient to cause elevated HbF, since, in JMML with monosomy 7, HbF is generally not elevated.45,58
Coexisting driver mutations in MPN: clinical and molecular characteristics of a series of 11 patients
Published in Hematology, 2018
L. De Roeck, L. Michaux, K. Debackere, E. Lierman, P. Vandenberghe, T. Devos
We analysed the DNA of six MPN patients with coexisting driver mutations (JAK2 V617F + BCR-ABL1: n = 3; CALR type 2 (p.K385Nfs*47) + BCR-ABL1: n = 1; JAK2 V617F + MPL W515R: n = 1; JAK2 V617F + CALR type 1 (p.Leu367Thrfs*46): n = 1) for mutations in 50 myeloid related genes. NGS revealed five (83%) additional somatic mutations in four non-driver genes, i.e. in FBXW7, TET2, ASXL1 and CUX1. Two patients presented with CUX1 mutation. Variants were classified according to the classification system of Sukhai et al, whereas class 1 and 2 variants are the most clinically relevant [34] (Table S3).
Molecular response of keloids to ionizing radiation: targeting FOXO1 radiosensitizes keloids
Published in International Journal of Radiation Biology, 2023
Min Hong, Xiaoqian Li, Yulan Liu, Wei Mo, Bin Shi, Shigao Chen, Tao Yan, Yuhong Shi, Daojiang Yu, Shuyu Zhang
Among the 38 dysregulated mRNAs, CUX1 is a CCAAT displacement protein, which is related to type I collagen expression both in vivo and in vitro (Fragiadaki et al. 2011). Zinc finger protein have been identified to as a transcription factor or co-factor. In mice, the expression levels of ZNF263 in gastric mucosa markedly increased following 6 and 12 Gy irradiation (Chen et al. 2019). A part of these dysregulated mRNAs might play an important role in the radiation resistance of keloids, and looking for radiation-sensitive genes will help us improve the level of radiotherapy for keloids.