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Cytogenetically normal uterine leiomyomas without MED12-mutations - a source to identify unknown mechanisms of the development of uterine smooth muscle tumors.

Holzmann C, Markowski DN, Koczan D, Küpker W, Helmke BM, Bullerdiek J - Mol Cytogenet (2014)

Bottom Line: The other three tumors did not show relevant copy number alterations at all.While chromothripsis was initially described as a hallmark of malignancy, the etiology and significance of this phenomenon in benign tumors still remain obscure.In uterine smooth muscle tumors, these changes per se do not indicate malignancy.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Genetics, University Rostock Medical Center, Ernst-Heydemann-Strasse 8, D-18057 Rostock, Germany.

ABSTRACT

Background: Recent findings on genetic changes in uterine leiomyomas suggest these benign tumors being a heterogeneous group of diseases in terms of molecular pathogenesis with those showing karyotype alterations as well as those characterized only by cytogenetically invisible mutations of mediator subcomplex 12 (MED12). Herein, five uterine leiomyomas (UL) with an apparently normal karyotype that lacked MED12-mutations were investigated by copy number variation arrays along with their matching myometrium to search for small genomic imbalances.

Results: Of five tumors one showed chromothripsis-like phenomena with numerous gains and losses of small segments mainly clustered to five chromosomal regions i.e. 2p14-2pter, 2q33.1-2q37.3, 5q31.3-5qter,11q14.1-11qter, and 18p11.21-18q2.3. Apparently, these cells had escaped detection by classical cytogenetics. Histologically, the tumor presented as a cellular leiomyoma with extended hyalinization. Of the remaining four tumors, one had a small intragenic deletion of the HMGA2 gene that was lacking in the corresponding myometrium. The other three tumors did not show relevant copy number alterations at all.

Conclusions: Overall, the results suggest that leiomyomas with an apparently normal karyotype based on classical cytogenetics and lacking MED12 mutations represent a heterogeneous group of diseases. While the HMGA2 deletion detected in one of the tumors likely represents the driver mutation and, due to its size, has escaped detection by classical cytogenetics, the extended genomic imbalances detected in one of the other cases cannot be overlooked by this method suggesting an inability of the affected cells to divide in vitro. Of particular interest in that case is the occurrence of so-called "chromothripsis" or "firestorms" without involvement of the loci of common chromosomal rearrangements in UL, as e.g. 12q14 ~ 15 and 6p21. While chromothripsis was initially described as a hallmark of malignancy, the etiology and significance of this phenomenon in benign tumors still remain obscure. In uterine smooth muscle tumors, these changes per se do not indicate malignancy.

No MeSH data available.


Related in: MedlinePlus

Leiomyoma (#708) with extended copy number alterations confined to four distinct chromosomal regions and the whole chromosome 18, respectively. A: Genomic view of the case showing for each chromosome the ideogram, the myometrial tissue (light blue line), and the leiomyomas (dark blue line). Red blocks represent deletions. B-F: Detailed view of the five parts of the genome showing numerous losses, i.e. 2p14 → 2pter, 2q33.1→2qter, 5q31.3→5qter, 11q14.1→11qter, and 18p11.21→18q22.3. Within each diagram the two lines above the ideogram represent myometrial tissue (light blue) and the leiomyoma (dark blue), respectively. Dashed lines and numbers represent the map positions according to Hg19 (NCBI Build 37 reference sequence). In the top line, the positions of deletions are shown as red blocks.
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Fig2: Leiomyoma (#708) with extended copy number alterations confined to four distinct chromosomal regions and the whole chromosome 18, respectively. A: Genomic view of the case showing for each chromosome the ideogram, the myometrial tissue (light blue line), and the leiomyomas (dark blue line). Red blocks represent deletions. B-F: Detailed view of the five parts of the genome showing numerous losses, i.e. 2p14 → 2pter, 2q33.1→2qter, 5q31.3→5qter, 11q14.1→11qter, and 18p11.21→18q22.3. Within each diagram the two lines above the ideogram represent myometrial tissue (light blue) and the leiomyoma (dark blue), respectively. Dashed lines and numbers represent the map positions according to Hg19 (NCBI Build 37 reference sequence). In the top line, the positions of deletions are shown as red blocks.

Mentions: Accordingly, four of the tumors did not reveal gross copy number alterations after CNV-analysis (Figure 1A, B). In contrast, in one tumor (My 708-2) numerous deletions were seen while the myometrial tissue did not show these deletions (Figures 1C and 2A). Interestingly, these copy number alterations were mainly restricted to a total of five chromosomal regions i.e. 2p14 → 2pter, 2q33.1 → 2q37.3, 5q31.3 → 5qter, 11q14.1 → 11qter, and 18p11.21 → 18q2.3 (Figure 2B-F). Across these five parts of the genome it was possible to detect at least 145 distinct regions of copy number alterations ranging in size between 43 and 13,647,027 kbp. On the other hand, in that case classical cytogenetics on a 275 to 550 bands/haploid set-level revealed an apparently normal karyotype 46,XX in all 20 metaphases examined (Figure 3A). Histologically, the tumor presented as a cellular leiomyoma with large areas of hyalinization (Figure 3B, C).Figure 1


Cytogenetically normal uterine leiomyomas without MED12-mutations - a source to identify unknown mechanisms of the development of uterine smooth muscle tumors.

Holzmann C, Markowski DN, Koczan D, Küpker W, Helmke BM, Bullerdiek J - Mol Cytogenet (2014)

Leiomyoma (#708) with extended copy number alterations confined to four distinct chromosomal regions and the whole chromosome 18, respectively. A: Genomic view of the case showing for each chromosome the ideogram, the myometrial tissue (light blue line), and the leiomyomas (dark blue line). Red blocks represent deletions. B-F: Detailed view of the five parts of the genome showing numerous losses, i.e. 2p14 → 2pter, 2q33.1→2qter, 5q31.3→5qter, 11q14.1→11qter, and 18p11.21→18q22.3. Within each diagram the two lines above the ideogram represent myometrial tissue (light blue) and the leiomyoma (dark blue), respectively. Dashed lines and numbers represent the map positions according to Hg19 (NCBI Build 37 reference sequence). In the top line, the positions of deletions are shown as red blocks.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4264251&req=5

Fig2: Leiomyoma (#708) with extended copy number alterations confined to four distinct chromosomal regions and the whole chromosome 18, respectively. A: Genomic view of the case showing for each chromosome the ideogram, the myometrial tissue (light blue line), and the leiomyomas (dark blue line). Red blocks represent deletions. B-F: Detailed view of the five parts of the genome showing numerous losses, i.e. 2p14 → 2pter, 2q33.1→2qter, 5q31.3→5qter, 11q14.1→11qter, and 18p11.21→18q22.3. Within each diagram the two lines above the ideogram represent myometrial tissue (light blue) and the leiomyoma (dark blue), respectively. Dashed lines and numbers represent the map positions according to Hg19 (NCBI Build 37 reference sequence). In the top line, the positions of deletions are shown as red blocks.
Mentions: Accordingly, four of the tumors did not reveal gross copy number alterations after CNV-analysis (Figure 1A, B). In contrast, in one tumor (My 708-2) numerous deletions were seen while the myometrial tissue did not show these deletions (Figures 1C and 2A). Interestingly, these copy number alterations were mainly restricted to a total of five chromosomal regions i.e. 2p14 → 2pter, 2q33.1 → 2q37.3, 5q31.3 → 5qter, 11q14.1 → 11qter, and 18p11.21 → 18q2.3 (Figure 2B-F). Across these five parts of the genome it was possible to detect at least 145 distinct regions of copy number alterations ranging in size between 43 and 13,647,027 kbp. On the other hand, in that case classical cytogenetics on a 275 to 550 bands/haploid set-level revealed an apparently normal karyotype 46,XX in all 20 metaphases examined (Figure 3A). Histologically, the tumor presented as a cellular leiomyoma with large areas of hyalinization (Figure 3B, C).Figure 1

Bottom Line: The other three tumors did not show relevant copy number alterations at all.While chromothripsis was initially described as a hallmark of malignancy, the etiology and significance of this phenomenon in benign tumors still remain obscure.In uterine smooth muscle tumors, these changes per se do not indicate malignancy.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Genetics, University Rostock Medical Center, Ernst-Heydemann-Strasse 8, D-18057 Rostock, Germany.

ABSTRACT

Background: Recent findings on genetic changes in uterine leiomyomas suggest these benign tumors being a heterogeneous group of diseases in terms of molecular pathogenesis with those showing karyotype alterations as well as those characterized only by cytogenetically invisible mutations of mediator subcomplex 12 (MED12). Herein, five uterine leiomyomas (UL) with an apparently normal karyotype that lacked MED12-mutations were investigated by copy number variation arrays along with their matching myometrium to search for small genomic imbalances.

Results: Of five tumors one showed chromothripsis-like phenomena with numerous gains and losses of small segments mainly clustered to five chromosomal regions i.e. 2p14-2pter, 2q33.1-2q37.3, 5q31.3-5qter,11q14.1-11qter, and 18p11.21-18q2.3. Apparently, these cells had escaped detection by classical cytogenetics. Histologically, the tumor presented as a cellular leiomyoma with extended hyalinization. Of the remaining four tumors, one had a small intragenic deletion of the HMGA2 gene that was lacking in the corresponding myometrium. The other three tumors did not show relevant copy number alterations at all.

Conclusions: Overall, the results suggest that leiomyomas with an apparently normal karyotype based on classical cytogenetics and lacking MED12 mutations represent a heterogeneous group of diseases. While the HMGA2 deletion detected in one of the tumors likely represents the driver mutation and, due to its size, has escaped detection by classical cytogenetics, the extended genomic imbalances detected in one of the other cases cannot be overlooked by this method suggesting an inability of the affected cells to divide in vitro. Of particular interest in that case is the occurrence of so-called "chromothripsis" or "firestorms" without involvement of the loci of common chromosomal rearrangements in UL, as e.g. 12q14 ~ 15 and 6p21. While chromothripsis was initially described as a hallmark of malignancy, the etiology and significance of this phenomenon in benign tumors still remain obscure. In uterine smooth muscle tumors, these changes per se do not indicate malignancy.

No MeSH data available.


Related in: MedlinePlus