耶魯大學醫(yī)學院的研究人員第一次描述了影響數百萬被慢性骨盆痛和不育癥所標志的婦女的子宮內膜異位癥遺傳基礎,。研究人員的這個新基因突變發(fā)現為新篩查方法提供了希望,。
發(fā)表在2月3日版的在線刊EMBO Molecular Medicine的研究探討了位于KRAS基因上的遺傳性突變,，該突變導致異常子宮內膜生長和子宮內膜風險,。在子宮內膜異位癥中,，子宮組織生長在機體其他部分,，如腹腔,、卵巢,、陰道和子宮頸,。這種情況通常是遺傳性的，在5-15%的育齡婦女中發(fā)現，影響著全世界多于7000萬婦女,。
盡管這種疾病已被研究了許多年,，但仍未知它的確切原因和如何發(fā)生的。以前已經指出激活KRAS基因引起小鼠發(fā)生子宮內膜異位癥,。但是,，在患子宮內膜異位癥婦女中，這個基因上沒有鑒定出突變,。
在通訊作者Hugh S. Taylor博士,、產科婦科和生殖科學系的生殖內分泌學與不育癥分部的教授與主管的領導下，作者們研究了132名子宮內膜異位癥患者,，評估了他們在負責調控的KRAS基因區(qū)域內的新鑒定突變,。以前，這種突變與增加的肺癌及卵巢癌風險性相關,，這是此研究的合著者,、放射治療學副教授Joanne Weidhaas博士所報道的。
"我們發(fā)現,，這項研究中31%的子宮內膜異位癥患者攜帶這個突變,，相當于總人口的5.8%"， Taylor說,，"這種突變的存在也與較高的KRAS蛋白水平和這些細胞增加的擴散能力相關,。它也可解釋子宮內膜異位癥婦女的卵巢癌高風險性。"
耶魯大學的研究團隊是第一個確定這種常見且以前了解甚少疾病的原因,。"這種突變潛在地代表了子宮內膜異位癥的一個新治療靶標以及潛在篩選方法的基礎,，這種篩選方法用來確定誰有發(fā)生子宮內膜異位癥的風險性。",，Taylor說,。
此項研究的其他作者包括：Olga Grechukhina、Rafaella Petracco,、Shota Popkhadze,、Trupti Paranjape、 Elcie Chan,、 Idhaliz Flores和Joanne Weidhaas,。（生物谷bioon.com）
doi:10.1002/emmm.201100200
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A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis
Olga Grechukhina, Rafaella Petracco, Shota Popkhadze, Efi Massasa, Trupti Paranjape, Elcie Chan, Idhaliz Flores, Joanne B. Weidhaas, Hugh S. Taylor
Abstract Endometriosis is found in 5-15% of women of reproductive age and is more frequent in relatives of women with the disease. Activation of KRAS results in de novoendometriosis in mice, however, activating KRAS mutations have not been identified in women. We screened 150 women with endometriosis for a polymorphism in a let-7 microRNA (miRNA) binding site in the 3'-UTR of KRAS and detected a KRAS variant allele in 31% of women with endometriosis as opposed to 5% of a large diverse control population. KRAS mRNA and protein expression were increased in cultured endometrial stromal cells of women with the KRAS variant. Increased KRAS protein was due to altered miRNA binding as demonstrated in reporter assays. Endometrial stromal cells from women with the KRAS variant showed increased proliferation and invasion. In a murine model, endometrial xenografts containing the KRAS variant demonstrated increased proliferation and decreased progesterone receptor levels. These findings suggest that an inherited polymorphism of a let-7 miRNA binding site in KRAS leads to abnormal endometrial growth and endometriosis. The LCS6 polymorphism is the first described genetic marker of endometriosis risk.
