Gene fusion involving HMGIC is a frequent aberration in uterine leiomyomas

Mine, Nobuya; Kurose, Kouichi; Nagai, Hisaki; Doi, Daisuke; Ota, Yujiro; Yoneyama, Kihei; Konishi, Hideyuki; Araki, Tsutomu; Emi, Mitsuru

doi:10.1007/s100380170059

Cited by 38 publications

(27 citation statements)

References 23 publications

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“…A truncated gene was found in 11 ovarian tumors of the present cohort. HMGA2 has previously been found disrupted, due to rearrangement of chromosomal band 12q15, in different benign connective tissue tumors, including lipomas (17), pleomorphic salivary gland adenomas (18), uterine leiomyomas (19) and lung hamartomas (20). The alterations involve exon 3 and cause the deletion of downstream regions, resulting in a truncated transcript that is able to evade miRNA-dependent gene silencing.…”

Section: Discussionmentioning

confidence: 99%

A novel truncated form of HMGA2 in tumors of the ovaries

et al. 2016

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Abstract. Neoplasms of the ovary are the second most common tumor of the female reproductive system, and the most lethal of the gynecological malignancies. Ovarian tumors are divided into a copious number of different groups reflecting their different features. The present study analyzed 187 ovarian tumors (39 sex-cord stromal tumors, 22 borderline tumors and 126 carcinomas) for the expression of the high-mobility group AT-hook 2 (HMGA2) gene, for mutations in the isocitrate dehydrogenase (NADP(+)) 1, cytosolic (IDH1), isocitrate dehydrogenase (NADP(+)) 2, mitochondrial (IDH2) and telomerase reverse transcriptase (TERT) genes, and for methylation of the O 6 -methylguanine-DNA methyltransferase (MGMT) promoter. Reverse transcription-polymerase chain reaction analysis showed that HMGA2 was expressed in 74.5% of the samples (120/161). A truncated transcript of HMGA2 was identified in 11 cases. A novel truncated form of HMGA2 was found in 4 serous high-grade carcinomas. Only 4 tumors (4/185) showed the TERT C228T mutation. No IDH1 or IDH2 mutations were found. Methylation of the promoter of MGMT was found in 2 borderline tumors (2/185). HMGA2 was expressed, in its truncated and native form, in different ovarian tumors, even the less aggressive types, underscoring the general importance of this gene in ovarian tumorigenesis. Mutations involving TERT, as well as MGMT promoter methylation, are rare events in ovarian tumors. IntroductionTumors of the ovaries account for 30% of all cancers of the female genital system; they are a heterogeneous group of neoplasms, divided into a number of different subgroups, depending largely on histological and cytological features (1).The majority (90%) of ovarian tumors are epithelial in nature. Malignant epithelial ovarian tumors are currently divided into high-grade serous, low-grade serous, endometrioid, mucinous and clear cell carcinomas (2).Borderline tumors of the ovary are neoplasms of low malignant potential. These tumors present with cellular atypia, but are not invasive. A few of these tumors share genomic and molecular features with carcinomas (3), but it remains unclear as to whether this is a feature of only a subset or of borderline tumors in general.Sex-cord stromal tumors account for 8% of all ovarian tumors and are further classified based on their predominant cell content; for example, granulosa cell tumors contain ≥10% granulosa cells. The thecoma-fibroma group of tumors is dominated by theca cells (thecoma), stromal fibroblasts (fibroma) or the two cell types in different proportions (thecofibroma) (4).Heterogeneity among ovarian tumors biologically and clinically represents a considerable challenge. The molecular and genetic profiles of the tumors could aid in predicting their inherent aggressiveness and could also provide keys to more specific treatments. As a contribution toward this goal, the present study analyzed 187 samples of different types of ovarian tumors, namely, granulosa cell tumors, thecofibromas, fibromas, teratomas, borderline tumors and infiltrat...

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Section: Discussionmentioning

confidence: 99%

A novel truncated form of HMGA2 in tumors of the ovaries

et al. 2016

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“…The most frequent cytogenetic abnormalities in leiomyomas (especially in uterus) are on the one hand a reciprocal translocation t(12;14) (q15; q23-24) with an extragenic breakpoint at the 5 0 part of HMGA2 and on the other hand, a deletion of the long arm of chromosome 7. 23,40 But FISH showed complex rearrangements on chromosomes 3, 6, 10 and 12. 41,42 Cytogenetic abnormalities of HMGA2 are reported in 40-50% of uterine leiomyomas.…”

Section: Hmga2 In Mesenchymal Tumorsmentioning

confidence: 97%

“…This supports the idea of the implication of HMGA2 in pathogenesis, although its function is not yet well understood in these neoplasms. 4 However, this gene is also a target of chromosomal rearrangements in some benign solid tumors 19,20 such as mesenchymal tumors: [21][22][23][24] in particular, HMGA2 is a prominent feature of conventional lipomas as 75% of these harbor translocation t(3;12) involving it, 3,25,26 but it is also overexpressed or amplified in atypical lipomatous tumor/well-differentiated [27][28][29] and dedifferentiated liposarcomas. Given the involvement of HMGA2 in mesenchymal tumors and particularly adipocytic tumors and the availability of antibodies usable on paraffin-embedded tissues, we evaluated immunohistochemical expression of this gene in a large series of mesenchymal tumors in order to define its value and limitations for histotyping.…”

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confidence: 99%

Value and limitation of immunohistochemical expression of HMGA2 in mesenchymal tumors: about a series of 1052 cases

et al. 2010

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The high mobility group A (HMGA2) gene encodes a protein that alters chromatin structure and regulates the transcription of many genes; it is implicated in both benign and malignant neoplasias, but its rearrangements are a feature of development of several mesenchymal tumors. Given its implication in these tumors and particularly adipocytic tumors, and the availability of antibodies usable on paraffin-embedded tissues, we evaluated the immunohistochemical expression of this gene in a series of 1052 mesenchymal tumors. The objective was to define the value and limitations of HMGA2 immunohistochemical expression for histotyping, and compare with molecular data reported in the literature. We thus analyzed 880 cases on tissue microarray and 182 cases on whole sections (211 adipocytic tumors, 628 sarcomas, 213 benign mesenchymal tumors, and 10 normal adipose tissues). A nuclear immunostaining was detected in 86% of conventional and intramuscular lipomas, in 86% of well-differentiated liposarcomas and in 67% of dedifferentiated liposarcomas, as opposed to 16% of other benign adipose tumors and to 15% of non-well-differentiated liposarcoma/dedifferentiated liposarcoma sarcomas. Among benign mesenchymal tumors and lesions, it was detected in 90% of nodular fasciitis and in 88% of benign fibrous histiocytomas with respective specificities of 85 and 100%, and in 90% of aggressive angiomyxoma, contrary to other vulvovaginal tumor types, which expressed HMGA2 only rarely. The normal adipose tissue was always negative for HMGA2. Although not specific, immunohistochemical detection of the HMGA2 protein is helpful for the distinction of normal adipose tissue from well-differentiated lesions, particularly on biopsy or on re-excision. It is less sensitive than MDM2/CDK4 for dedifferentiated liposarcomas diagnosis, but it appears more specific to distinguish dedifferentiated liposarcomas from other poorly differentiated sarcomas. Finally, and may be more importantly, HMGA2 is useful for the diagnosis of benign fibrous histiocytoma, nodular fasciitis and vulvovaginal benign mesenchymal tumors.

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“…Rearrangements in the HMGA genes are found in various benign mesenchymal tumors such as lipomas (125,126), pleiomorphic adenomas of the salivary glands (127), uterine leiomyomas (128)(129)(130), angiomyxomas (131), pulmonary chondroid hamartomas (130,132), and endometrial polyps (133)(134)(135). Since most translocations involve the HMGA2 gene, the focus of this section will mainly be on HMGA2.…”

Section: Rearrangements Of Hmga1 and Hmga2 Genes In Human Benign Tumorsmentioning

confidence: 99%

The HMGA proteins: A myriad of functions (Review)

Cleynen

Ven²

2008

Int J Oncol

214

243

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Abstract. The 'high mobility group' HMGA protein family consists of four members: HMGA1a, HMGA1b and HMGA1c, which result from translation of alternative spliced forms of one gene and HMGA2, which is encoded for by another gene. HMGA proteins are characterized by three DNA-binding domains, called AT-hooks, and an acidic carboxy-terminal tail. HMGA proteins are architectural transcription factors that both positively and negatively regulate the transcription of a variety of genes. They do not display direct transcriptional activation capacity, but regulate gene expression by changing the DNA conformation by binding to AT-rich regions in the DNA and/or direct interaction with several transcription factors. In this way, they influence a diverse array of normal biological processes including cell growth, proliferation, differentiation and death. Both HMGA1 and HMGA2 are hardly detectable in normal adult tissue but are abundantly and ubiquitously expressed during embryonic development. In malignant epithelial tumors as well as in leukemia, however, expression of HMGA1 is again strongly elevated to embryonic levels thus leading to ectopic expression of (fetal) target genes. HMGA2 overexpression also has a causal role in inducing neoplasia. Besides overexpression of full length HMGA proteins in different tumors, the HMGA genes are often involved in chromosomal rearrangements. Such translocations are mostly detected in benign tumors of mesenchymal origin and are believed to be one of the most common chromosomal rearrangements in human neoplasia. To provide clarity in the abundance of articles on this topic, this review gives a general overview of the nuclear functions and regulation of the HMGA genes and corresponding proteins.

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Gene fusion involving HMGIC is a frequent aberration in uterine leiomyomas

Cited by 38 publications

References 23 publications

A novel truncated form of HMGA2 in tumors of the ovaries

A novel truncated form of HMGA2 in tumors of the ovaries

Value and limitation of immunohistochemical expression of HMGA2 in mesenchymal tumors: about a series of 1052 cases

The HMGA proteins: A myriad of functions (Review)

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