Chromosomal translocations affecting 12q14-15 but not deletions of the long arm of chromosome 7 associated with a growth advantage of uterine smooth muscle cells

Abstract

Cytogenetically, uterine leiomyomata are the best investigated human tumours. The most frequent clonal abnormalities are structural rearrangements involving 12q14-15 and deletions of part of the long arm of chromosome 7. The present study investigated a possible growth advantage conferred by these abnormalities, when compared with myomata having an apparently normal karyotype. A total of 155 myomata were included in the study. All samples were obtained after hysterectomy enabling karyotype analysis of all detectable tumours. Myomata with clonal chromosome abnormalities were significantly larger than those with a normal karyotype (6.8 +/- 5.3 versus 3.4 +/- 2.1 cm; P < 0.001). However, when differentiating between the two main aberrations, this was found to be true for the myomata with 12q14-15 changes affecting the high mobility group protein IC (HMGIC) gene (8.9 +/- 5.6 cm), but not for the group of tumours characterized by deletions of chromosome 7 (3.5 +/- 2.0 cm). The results are compatible with the hypothesis that myomata develop due to an unknown event, whereas the chromosomal abnormalities act as secondary changes, with those affecting the HMGIC gene increasing the growth potential of the corresponding tumours.

Overexpression of HMGA2 in uterine leiomyomas points to its general role for the pathogenesis of the disease

“…Mutations of the gene encoding the high mobility group protein HMGA2 have been suggested to cause a subset of uterine leiomyomas (Schoenmakers et al, 1995;Hennig et al, 1999). As a Percentage of nuclei either with two colocalized signals (2RG) or with one colocalized, one single red and one single green signal (1RG1R1G) indicating a HMGA2 rearrangement.…”

“…Thus, overexpression of HMGA2 seems to be sufficient to trigger tumorigenesis. It is obvious that an enhanced level of HMGA2 is pathogenetically relevant in a subset of some 10-20% of uterine leiomyomas (Hennig et al, 1999), but it remains an open question whether or not an increased level of HMGA2, compared to normal myometrium, may characterize also leiomyomas that do not have HMGA2 rearrangements. A recent study by Peng et al, (2008) suggests that upregulation of HMGA2 may be a more general phenomenon in UL but the analyzed tumors were not genetically classified and no matched samples were analyzed individually by quantitative RT-PCR.…”

HMGA2 and the p19Arf‐TP53‐CDKN1A axis: A delicate balance in the growth of uterine leiomyomas

“…A large subgroup of UL is characterized by clonal translocations affecting chromosomal region 12q14$15, leading to upregulation of HMGA2 (Schoenmakers et al, 1995;Gross et al, 2003;Klemke et al, 2009). Interestingly, ULs with 12q14$15 rearrangements are larger than those without detectable cytogenetic deviations (Rein et al, 1998;Hennig et al, 1999). Although it is tempting to speculate that the overexpression of HMGA2, a protein abundantly expressed in stem cells and linked to their self-renewal (Li et al, 2006(Li et al, , 2007Nishino et al, 2008), accounts for that enhanced growth potential, the exact mechanisms by which HMGA2 can influence UL growth still remain to be resolved.…”

Zur Genetik und Pathogenese des Uterus myomatosus

“…Deutlich sind in der Arbeit von Tsibris et al [28] unter den 67 Genen, die in den Leiomyomen im Vergleich zum Kontrollmyometrium überexprimiert sind, sdlk oder Pref-1, doublecotin, JM27, ionotopic glutamate receptor subunit 2,apolipoproteien E3,IGFII,semaphorin F,myelin proteolipid protein, MEST, frizzled, CRABP II, stromelysin-3 und TBFbeta3 aufregu-| Gynäkologische Endokrinologie 1 · 2004 30 normalerweise in einem Leiomyom zu erkennen sind [9].…”

“…Das als Tumorsuppressor agierende Enzym besitzt nur eine geringe oder gänzlich fehlende Aktivität in den Tumoren der untersuchten Familien.Keimzellmutationen in diesem Gen prädisponieren zu dominant vererbten uterinen Leiomyomen, aber auch Hautleiomyomen und Nierenzellkarzinomen.Der Mechanismus jedoch,durch den das Enzym die Tumorbildung unterdrückt,und sein Einfluss auf den Zellzyklus sind noch ungeklärt[27]. Von Martinez-Mir et al[15] wurden gegenwärtig 5 neue Mutationen des Gens gefunden, die die Struktur des Fumarathydratase-Proteins verändern.Leiomyome des Uterus sind zytogenetisch die am besten untersuchten Tumoren des Menschen[9]. Zu unterscheiden ist zwischen solchen Neoplasien,die chromosomale Aberrationen aufweisen,und solchen, die einen normalen weiblichen Karyotyp 46,XX enthalten.Nur in etwa 1/3 aller Myome finden sich Aberrationen der Chromosomen.Die Angaben hierzu schwanken jedoch je nach Autor (20-60%) und sollen hier lediglich als Anhaltspunkt dienen.…”