子宮筋腫とMED12突然変異：続報（３）

この10年で一番驚いた報告の一つは子宮筋腫とMED12突然変異であった。通常このような論文はあとが続かないのだが、このテーマに関しては派手ではないが続報が続いている。良性腫瘍と突然変異でこれほど再現性のあるストーリーは他にはないと思われる。そこで面白いものをいくつか・・・

１）国立がん研究センターの金井さんのところから・・・・

1. 日本の子宮筋腫でも80%にMED12突然変異があるという報告。
2. 12例の平滑筋肉腫には2例しか認めない。
3.  興味深いのは
   
   「子宮外の平滑筋腫瘍には一切の MED12突然変異を認めない」ということ。
   
   小生は3年前からこのことがが知りたかった。

Histopathology. 2013 Mar;62(4):657-61.

Prevalence of MED12 mutations in uterine and extrauterine smooth muscle tumours

Akiko Matsubara, Shigeki Sekine, Masayuki Yoshida, Akihiko Yoshida, Hirokazu Taniguchi, Ryoji Kushima, Hitoshi Tsuda and Yae Kanai

Aims

To determine the prevalence of MED12 mutations in smooth muscle tumours of different organs.

Methods and results

A total of 142 smooth muscle tumours of the uterus, gastrointestinal tract, retroperitoneum and soft tissue were analysed for MED12 mutations using Sanger sequencing. Among the uterine tumours that were examined, MED12 mutations were identified in 36 of 45 conventional leiomyomas (80%), two of six cellular leiomyomas (33%), one of four bizarre leiomyomas (25%), none of four lipoleiomyomas (0%), and two of 12 leiomyosarcomas (17%). The two MED12-mutated leiomyosarcomas were associated with benign leiomyomatous components that also harboured MED12 mutations identical to those in the respective leiomyosarcomatous components. None of the extrauterine smooth muscle tumours, including the leiomyomas, leiomyosarcomas, and angioleiomyomas, had MED12 mutations.

Conclusions

Among uterine smooth muscle tumours, MED12 mutations are frequently present in conventional leiomyomas, but are significantly less common in histological variants of leiomyoma and leiomyosarcoma. In contrast to uterine lesions, none of the extrauterine smooth muscle tumours had MED12 mutations.

２）もうひとつ面白いのが子宮筋腫のin vitroモデルであり、これはドイツからの報告。 MED1２変異のある子宮筋腫細胞を培養系に移すと、変異細胞は直ちに消失してしまうというのだという。一パッセージも保たないのだという。面白いはなしだなあ。

Genes Chromosomes Cancer. 
2014 Apr;53(4):317-23. Jan 21.

Cell cultures in uterine leiomyomas: Rapid disappearance of cells carrying MED12 mutations.

Nadine Markowski D¹, Tadayyon M, Bartnitzke S, Belge G, Maria Helmke B, Bullerdiek J.
Center for Human Genetics, University of Bremen, Leobener Str. ZHG, 28359, Bremen, Germany.

Abstract

Uterine leiomyomas (UL) are the most frequent symptomatic human tumors. Nevertheless, their molecular pathogenesis is not yet fully understood. To learn more about the biology of these common neoplasms and their response to treatment, cell cultures derived from UL are a frequently used model system, but until recently appropriate genetic markers confirming their origin from the tumor cell population were lacking for most UL, i.e., those not displaying karyotypic abnormalities. The identification of MED12 mutations in the majority of UL makes it possible to trace the tumor cell population during in vitro passaging in the absence of cytogenetic abnormalities. The present study is addressing the in vitro survival of cells carrying MED12 mutations and its association with karyotypic alterations. The results challenge numerous in vitro studies into the biology and behavior of leiomyomas. Cells of one genetic subtype of UL, i.e., those with rearrangements of the high mobility AT-hook 2 protein gene (HMGA2), seem to be able to proliferate in vitro for many passages whereas tumor cells from the much more frequent MED12-mutated lesions barely survive even the first passages. Apparently, for the most frequent type of human UL no good in vitro model seems to exist because cells do not survive culturing. On the other hand, this inability may point to an Achilles' heel of this type of UL.