近日,，刊登在國際雜志Nature Genetics上的一篇研究報(bào)告中，科學(xué)家們發(fā)現(xiàn)餓了和黑色素瘤發(fā)展相關(guān)的新的基因突變,。在皮膚癌患者死亡病例中,，黑色素瘤占據(jù)了絕大多數(shù)。促使黑色素瘤的主要原因是過度暴露在太陽紫外線照射下,。
來自耶魯癌癥研究中心的研究者使用DNA序列分析技術(shù)分析了147個(gè)黑色素瘤患者身體暴露于太陽光下和隔離的身體部位,，通過研究，研究者在太陽光暴露部位發(fā)現(xiàn)了紫外線誘導(dǎo)的基因突變,，但是大部分的突變對(duì)疾病的發(fā)展并不重要,。
研究者M(jìn)ichael表示，我們?cè)O(shè)計(jì)了一個(gè)數(shù)學(xué)模型,，用以將來自25,，000個(gè)突變的相關(guān)DNA修飾進(jìn)行分類，研究者發(fā)現(xiàn)在RAC1基因上的突變可以加速正常皮膚色素細(xì)胞的生長和移動(dòng),，這就預(yù)示著黑色素瘤的開始,。這種突變?cè)诤谏亓霭l(fā)展早期開始發(fā)生，并且可以促進(jìn)癌癥細(xì)胞的生長以及機(jī)體的全身擴(kuò)散,。
RAC1的突變?cè)诖蠹s9%的日光暴露黑色素瘤患者身上發(fā)現(xiàn),，由于RAC1突變?nèi)绱祟l繁，因此研究者指出,，以該基因?yàn)榘悬c(diǎn)可以開發(fā)出新的治療藥物,。
目前在美國大約每年有76，000個(gè)人被診斷患有黑色素瘤,，每年會(huì)有9000人死于該疾病,，因此研究者希望盡快開發(fā)出新的治療手段以應(yīng)對(duì)該疾病。（生物谷Bioon.com）
編譯自：Scientists uncover gene variation linked to melanoma
doi:10.1038/ng.2359
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PMID:
Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma
Michael Krauthammer, Yong Kong, Byung Hak Ha, Perry Evans, Antonella Bacchiocchi, James P McCusker, Elaine Cheng, Matthew J Davis, Gerald Goh, Murim Choi, Stephan Ariyan, Deepak Narayan, Ken Dutton-Regester, Ana Capatana, Edna C Holman, Marcus Bosenberg, Mario Sznol, Harriet M Kluger, Douglas E Brash, David F Stern, Miguel A Materin, Roger S Lo, Shrikant Mane, Shuangge Ma, Kenneth K Kidd et al.
We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1P29S) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1P29S showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.
