倫敦大學(xué)國(guó)王學(xué)院與日本廣島大學(xué)的研究人員通過對(duì)一個(gè)家庭中10成員患有咽喉癌的遺傳研究,，已經(jīng)鑒定出一個(gè)特定的基因與咽喉癌有關(guān),。
發(fā)表在3月8日The American Journal of Human Genetics上的研究揭示ATR基因突變，首次證實(shí)ATR基因的異常與遺傳類型的癌癥有關(guān),。研究人員說這一發(fā)現(xiàn)提示咽喉癌與遺傳因素有關(guān),，并為探索ATR在癌癥生物學(xué)的作用提供一個(gè)平臺(tái)（奠定了基礎(chǔ)）,。
科學(xué)家對(duì)一個(gè)不尋常遺傳因素影響超過5代24個(gè)家庭成員的美國(guó)家庭進(jìn)行了全基因組連鎖分析。這些遺傳特征包括：頭發(fā),、牙齒和指甲以及擴(kuò)張型皮膚血管發(fā)育異常,。值得注意的是，參與研究的幾乎每個(gè)有上述癥狀的人在20??多歲或30歲時(shí)都患上了咽喉癌（口咽部鱗狀細(xì)胞癌）,。
該小組收集了家庭中受遺傳因素影響的13名成員以及13名未受影響的成員血液樣本,。分析這些樣品后,，他們發(fā)現(xiàn)具有遺傳特征的人ATR都發(fā)生了單基因突變,，而正常人的ATR都沒有突變,。具有遺傳特征的13人中有10人患上了咽喉癌,。
以蓋伊醫(yī)院圣約翰皮膚科為基礎(chǔ)的國(guó)王學(xué)院倫敦遺傳皮膚研究所的John McGrath教授說：“這一耐人尋味的研究不僅為不尋常綜合征提供了遺傳解釋,，同時(shí)也提出了ATR基因可能與某種具體類型的癌癥有關(guān)的新見解,。這項(xiàng)研究是一個(gè)我們?nèi)绾问褂煤币娗闆r分析研究更多常見疾病的典型例子,。
“引發(fā)咽喉癌的關(guān)鍵危險(xiǎn)因素包括酒精和煙草以及病毒感染如HPV（人乳頭瘤病毒）,。由于是首次發(fā)現(xiàn)ATR基因異常與這種易感性癌癥類型有關(guān)的相關(guān)證據(jù),。我們知道ATR編碼的蛋白質(zhì)對(duì)細(xì)胞修復(fù)其DNA非常關(guān)鍵，因此ATR編碼的蛋白質(zhì)是一個(gè)重要的機(jī)制?，F(xiàn)在,，我們計(jì)劃更詳細(xì)的研究癌癥中該條途徑,，試圖找到新的腫瘤治療方法,。(生物谷：Bioon)
doi:10.1016/j.ajhg.2012.01.007
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Germline Mutation in ATR in Autosomal- Dominant Oropharyngeal Cancer Syndrome.
Akio Tanaka, Sarah Weinel, Nikoletta Nagy, Mark O'Driscoll, Joey E. Lai-Cheong, Carol L. Kulp-Shorten, Alfred Knable, Gillian Carpenter, Sheila A. Fisher, Makiko Hiragun, Yuhki Yanase, Michihiro Hide, Jeffrey Callen, John A. McGrath.
ATR (ataxia telangiectasia and Rad3 related) is an essential regulator of genome integrity. It controls and coordinates DNA-replication origin firing, replication-fork stability, cell-cycle checkpoints, and DNA repair. Previously, autosomal-recessive loss-of-function mutations in ATR have been demonstrated in Seckel syndrome, a developmental disorder. Here, however, we report on a different kind of genetic disorder that is due to functionally compromised ATR activity, which translates into an autosomal-dominant inherited disease. The condition affects 24 individuals in a five-generation pedigree and comprises oropharyngeal cancer, skin telangiectases, and mild developmental anomalies of the hair, teeth, and nails. We mapped the disorder to a 16.8 cM interval in chromosomal region 3q2224, and by sequencing candidate genes, we found that ATR contained a heterozygous missense mutation (c.6431A>G [p.Gln2144Arg]) that segregated with the disease. The mutation occurs within the FAT (FRAP, ATM, and TRRAP) domainwhich can activate p53of ATR. The mutation did not lead to a reduction in ATR expression, but cultured fibroblasts showed lower p53 levels after activation of ATR with hydroxyurea than did normal control fibroblasts. Moreover, loss of heterozygosity for the ATR locus was noted in oropharyngeal-tumor tissue. Collectively, the clinicopathological and molecular findings point to a cancer syndrome and provide evidence implicating a germline mutation in ATR and susceptibility to malignancy in humans.
