美國辛辛那提州大學(xué)癌細胞生物學(xué)家發(fā)現(xiàn)一個與肺癌敏感有關(guān)的基因。這個叫RGS17的基因與有明顯肺癌家族史的人潛在發(fā)生肺癌的危險有關(guān),。隨著研究的深入科學(xué)家相信,，這個基因可用來識別高危險患者，通過篩查早期發(fā)現(xiàn)疾病,，從而使患者受益,。研究人員馬歇爾﹒安德森和同事在4月15日的《臨床癌癥研究》雜志上報道了這一發(fā)現(xiàn)。
“了解RGS17基因如何影響癌癥發(fā)生，將改善臨床診斷和治療效果,，就像發(fā)現(xiàn)乳腺癌基因BRCA1和BRCA2 一樣,。”安德森解釋說。“一個遺傳實驗就能幫助我們在發(fā)生疾病以前識別出處于危險的人,。”
根據(jù)美國癌癥學(xué)會的報道,，肺癌是癌癥相關(guān)疾病和死亡的主要原因。盡管吸煙是引起肺癌的主要環(huán)境因素,，但科學(xué)家證明,，導(dǎo)致該病的還有明顯的遺傳因素。
“這項研究有助于我們對肺癌敏感性的了解,，也是向預(yù)防醫(yī)學(xué)邁出的一步,。”哈佛大學(xué)公共衛(wèi)生學(xué)院職業(yè)病學(xué)和環(huán)境衛(wèi)生學(xué)教授大衛(wèi)﹒克里斯提尼博士說。“研究人員在努力尋找發(fā)病基因中所進行的家族性研究是一個無所畏懼的挑戰(zhàn),。”
基因位于細胞染色體的固定位置上,，它攜帶了決定遺傳特性的DNA編碼，其中也包括某些疾病的發(fā)病危險,。研究人員收集了許多患肺癌5人以上家族的多代人的生物樣本,。結(jié)合將遺傳信息剖開分析的“精確定位”和遺傳相關(guān)研究，研究人員發(fā)現(xiàn)RGS17是家族性肺癌的主要候選敏感基因,。研究證明,，肺癌可以在沒有危險因素和家族史的人中零星發(fā)病，也可以在同一家族多成員中遺傳性發(fā)病,。2004年,，安德森研究小組報道了首個肺癌的遺傳證據(jù)：在6號染色體上的一個“敏感基因座”，以及其它3條染色體上存在一個敏感區(qū)域,。早期發(fā)現(xiàn)的染色體肺癌標記物區(qū)域里含有大約100個基因,，包括數(shù)個懷疑與腫瘤抑制和細胞生長有關(guān)的基因。
通過遺傳改良小鼠模型研究發(fā)現(xiàn),，當RGS17 被抑制后腫瘤會縮小,，證明這個基因與癌癥發(fā)生有關(guān)，而且癌癥發(fā)生必須有這個基因存在,。
“更有意思的是,，在60%非遺傳性肺癌的樣本中，這個基因處于超表達,。”安德森說,。“這說明可能有外部外因素在影響著遺傳性肺癌發(fā)病。”
研究小組將對環(huán)境因素如何會影響家族性癌癥發(fā)病作進一步研究,。（生物谷Bioon.com）
生物谷推薦原始出處：
Clinical Cancer Research 15, 2666, April 15, 2009.doi: 10.1158/1078-0432.CCR-08-2335
Fine Mapping of Chromosome 6q23-25 Region in Familial Lung Cancer Families Reveals RGS17 as a Likely Candidate Gene
Ming You1, Daolong Wang1, Pengyuan Liu1, Haris Vikis1, Michael James1, Yan Lu1, Yian Wang1, Min Wang1, Qiong Chen1, Dongmei Jia1, Yan Liu1, Weidong Wen1, Ping Yang2, Zhifu Sun2, Susan M. Pinney3, Wei Zheng4, Xiao-Ou Shu4, Jirong Long4, Yu-Tang Gao5, Yong-Bing Xiang5, Wong-Ho Chow6, Nat Rothman6, Gloria M. Petersen2, Mariza de Andrade2, Yanhong Wu2, Julie M. Cunningham2, Jonathan S. Wiest6, Pamela R. Fain8, Ann G. Schwartz9, Luc Girard10, Adi Gazdar10, Colette Gaba11, Henry Rothschild12, Diptasri Mandal12, Teresa Coons13, Juwon Lee3, Elena Kupert3, Daniela Seminara6, John Minna10, Joan E. Bailey-Wilson7, Christopher I. Amos14 and Marshall W. Anderson3
Authors' Affiliations: 1 Washington University, St. Louis, Missouri; 2 Mayo Clinic, Rochester, Minnesota; 3 University of Cincinnati, Cincinnati, Ohio; 4 Vanderbilt University Medical Center, Nashville, Tennessee; 5 Shanghai Cancer Institute, Shanghai, China; 6 National Cancer Institute, and 7 National Human Genome Research Institute, Bethesda, Maryland; 8 University of Colorado, Denver, Colorado; 9 Karmanos Cancer Institute, Detroit, Michigan; 10 University of Texas Southwestern Medical Center, Dallas, Texas; 11 University of Toledo College of Medicine, Toledo, Ohio; 12 Louisiana State University Health Science Center, New Orleans, Louisiana; 13 Saccomanno Research Institute, Grand Junction, Colorado; and 14 M. D. Anderson Cancer Center, Houston, Texas
Requests for reprints: Ming You, Department of Surgery and The Alvin J. Siteman Cancer Center, Washington University, 660 Euclid Avenue, Box 8109, St. Louis, MO 63110. Phone: 314-362-9294; Fax: 314-362-9366;
Purpose: We have previously mapped a major susceptibility locus influencing familial lung cancer risk to chromosome 6q23-25. However, the causal gene at this locus remains undetermined. In this study, we further refined this locus to identify a single candidate gene, by fine mapping using microsatellite markers and association studies using high-density single nucleotide polymorphisms (SNP).
Experimental Design: Six multigenerational families with five or more affected members were chosen for fine-mapping the 6q linkage region using microsatellite markers. For association mapping, we genotyped 24 6q-linked cases and 72 unrelated noncancer controls from the Genetic Epidemiology of Lung Cancer Consortium resources using the Affymetrix 500K chipset. Significant associations were validated in two independent familial lung cancer populations: 226 familial lung cases and 313 controls from the Genetic Epidemiology of Lung Cancer Consortium, and 154 familial cases and 325 controls from Mayo Clinic. Each familial case was chosen from one high-risk lung cancer family that has three or more affected members.
Results: A region-wide scan across 6q23-25 found significant association between lung cancer susceptibility and three single nucleotide polymorphisms in the first intron of the RGS17 gene. This association was further confirmed in two independent familial lung cancer populations. By quantitative real-time PCR analysis of matched tumor and normal human tissues, we found that RGS17 transcript accumulation is highly and consistently increased in sporadic lung cancers. Human lung tumor cell proliferation and tumorigenesis in nude mice are inhibited upon knockdown of RGS17 levels.
Conclusion: RGS17 is a major candidate for the familial lung cancer susceptibility locus on chromosome 6q23-25.
