伦敦大学国王学院与日本广岛大学的研究人员通过对一个家庭中10成员患有咽喉癌的遗传研究，已经鉴定出一个特定的基因与咽喉癌有关。
发表在3月8日The American Journal of Human Genetics上的研究揭示ATR基因突变，首次证实ATR基因的异常与遗传类型的癌症有关。研究人员说这一发现提示咽喉癌与遗传因素有关，并为探索ATR在癌症生物学的作用提供一个平台（奠定了基础）。
科学家对一个不寻常遗传因素影响超过5代24个家庭成员的美国家庭进行了全基因组连锁分析。这些遗传特征包括：头发、牙齿和指甲以及扩张型皮肤血管发育异常。值得注意的是，参与研究的几乎每个有上述症状的人在20??多岁或30岁时都患上了咽喉癌（口咽部鳞状细胞癌）。
该小组收集了家庭中受遗传因素影响的13名成员以及13名未受影响的成员血液样本。分析这些样品后，他们发现具有遗传特征的人ATR都发生了单基因突变，而正常人的ATR都没有突变。具有遗传特征的13人中有10人患上了咽喉癌。
以盖伊医院圣约翰皮肤科为基础的国王学院伦敦遗传皮肤研究所的John McGrath教授说：“这一耐人寻味的研究不仅为不寻常综合征提供了遗传解释，同时也提出了ATR基因可能与某种具体类型的癌症有关的新见解。这项研究是一个我们如何使用罕见情况分析研究更多常见疾病的典型例子。
“引发咽喉癌的关键危险因素包括酒精和烟草以及病毒感染如HPV（人乳头瘤病毒）。由于是首次发现ATR基因异常与这种易感性癌症类型有关的相关证据。我们知道ATR编码的蛋白质对细胞修复其DNA非常关键，因此ATR编码的蛋白质是一个重要的机制。现在，我们计划更详细的研究癌症中该条途径，试图找到新的肿瘤治疗方法。(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.
