HMGIC, a high-mobility-group protein gene encoding an architectural transcription factor, was recently identified as the target of gene fusion in a variety of human benign mesenchymal tumors; some of these events were chromosomal translocations involving 12q13-15. HMGIC consists of three DNA-binding domains (encoded by exons 1-3), a spacer, and an acidic carboxyl-terminal regulatory domain (exons 4-5). To determine the spectrum and nature of the aberrations in uterine myomas in Japanese patients, we systematically examined the tumors of 45 patients for all possible types of gene fusions involving HMGIC, by means of 3Ј-rapid amplification of cDNA ends (RACE) and reverse transcriptase-polymerase chain reaction (RT-PCR) experiments. HMGIC gene fusions were found in 16 (36%) of the tumors; aberrant splicings to five cryptic sequences located in introns of the HMGIC gene were found in 11 of these cases, and translocations causing juxtaposition to other genes, such as COX6C and RAD51B, were found in 5. In all fusion transcripts, the first two or three exons of HMGIC were fused to ectopic sequences. Our results suggest that a fusion event, resulting in the separation of the DNA-binding domains of HMGIC from the spacer and the acidic carboxyl-terminal regulatory domain, is a common tumorigenic mechanism in the development of uterine myomas.

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Uterine leiomyoma, a benign smooth-muscle tumor of the myometrium, is the most commonly encountered neoplasm in women of reproductive age. Band q15 of chromosome 12 is often rearranged in benign mesenchymal tumors such as uterine leiomyomas, and the HMGIC gene, encoding a protein of the high-mobility-group (HMG), is present in that region. Using 3′ ′ ′ ′ rapid amplification of cDNA ends (3′ ′ ′ ′RACE) experiments, we isolated an ectopic sequence that was fused to HMGIC in a uterine leiomyoma. Cloning of the fusion cDNA identified a gene termed "homo sapiens enhancer of invasion 10" (HEI10) as the fusion partner. Radiation hybrid mapping revealed that the normal location of HEI10 is at 14q11. In the fusion transcript the first two exons of the HMGIC gene, which encode DNA-binding domains, were fused to the 3′ ′ ′ ′ portion of the HEI10 gene. This rearrangement implicates HMGIC in the tumorigenesis of uterine leiomyoma, and suggests that its fusion HMGIC product may play a role in mesenchymal differentiation.

Cytogenetic analyses have shown that aberrations involving 12q13–15 are frequent chromosomal changes in a variety of human benign mesenchymal tumors, e.g., pleomorphic adenomas of the parotid gland, pulmonary chondroid hamartomas, lipomas, and uterine leiomyomas. Recently, the high‐mobility group protein gene HMGIC was identified as the target gene affected by the 12q13–15 aberrations. Using 3′ rapid amplification of cDNA ends experiments, we isolated novel ectopic sequences fused to HMGIC in a uterine leiomyoma. Cloning of the fusion cDNA identified the human cytochrome c oxidase subunit VIc (COX6C) gene on 8q22–23 as the fusion partner of HMGIC. Nucleotide sequences of the fusion transcript revealed that the first 3 exons of the HMGIC gene, encoding the 3 DNA binding domains, was fused to the exon 2 of the COX6C gene. The identification of a gene rearrangement suggests a role for HMGIC in tumorigenesis of uterine leiomyoma and suggests a possible involvement of HMGIC in mesenchymal differentiation. Genes Chromosomes Cancer 27:303–307, 2000. © 2000 Wiley‐Liss, Inc.

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We present here a case of uterine perforation following manual removal of the placenta during the third stage of normal labor. Total abdominal hysterectomy was performed, and the 4x3-cm perforation of the uterus and placenta accreta were confirmed. In this case, the round ligament covering the hematoma prevented bleeding into the peritoneal cavity and peritonitis. Manual removal of the placenta should be performed carefully following ultrasonographic assessment for placental abnormalities such as placenta accreta.

Cytogenetic aberrations involving chromosome region 12q13-15 occur frequently among benign mesenchymal tumors in humans, e.g., pleomorphic adenomas of the parotid gland, pulmonary chondroid hamartomas, lipomas, or uterine leiomyomas. HMGIC, a gene encoding a protein of the high-mobility group, has been identified as a target of those events. Using the 3' rapid amplification of cDNA ends (RACE) technique, we identified six different fusion transcripts of the HMGIC gene among 13 uterine leiomyomas; three of these variants had not been described before. Radiation-hybrid mapping located all three of the novel fusion transcripts in the same chromosomal region as the HMGIC gene. Cloning of the entire HMGIC gene in a genomic contig of P1-derived artificial chromosomes and cosmids revealed that the 3' portion of each novel fusion transcript contained cryptic exonic sequences (designated a, b, and c) present in intron 3 of the HMGIC gene. Thus, aberrant alternative splicing was responsible for abnormal HMGIC isoforms in those myomas. Identification of these novel variants suggested that aberrant splicing can join chromosomal translocation and inversion as a mechanism for producing abnormal HMGIC transcripts, and that separation of the DNA binding domains of HMGIC from its acidic carboxyl-terminal regulatory domain can lead to development of benign mesenchymal tumors.

Human cancers derived from breast, esophageal, or ovarian tissues frequently show allelic losses on chromosome band 17q25. Moreover, a locus responsible for hereditary focal nonepidermolytic palmoplantar keratoderma, a condition associated with esophageal cancer (TOC; tylosis with oesophageal cancer), has been mapped to the same band. During efforts to sequence, by shotgun methods, a 1-Mb target region that we had defined as the DNA segment harboring the putative tumor suppressor gene(s) involved in these events, we identified a novel cDNA. The full-length cDNA is 2495 bp long and is expressed predominantly in skeletal muscle, heart, kidney, and placenta. The predicted product, a 627-amino-acid protein, exhibited significant sequence homology to the canine 68-kd subunit of the signal recognition particle that has been implicated in the transport of secreted and membrane proteins to the endoplasmic reticulum for proper processing. We confirmed the location of this gene at chromosome 17q25.1 by radiationhybrid mapping and by fluorescence in situ hybridization.