美国辛辛那提州大学癌细胞生物学家发现一个与肺癌敏感有关的基因。这个叫RGS17的基因与有明显肺癌家族史的人潜在发生肺癌的危险有关。随着研究的深入科学家相信，这个基因可用来识别高危险患者，通过筛查早期发现疾病，从而使患者受益。研究人员马歇尔﹒安德森和同事在4月15日的《临床癌症研究》杂志上报道了这一发现。
“了解RGS17基因如何影响癌症发生，将改善临床诊断和治疗效果，就像发现乳腺癌基因BRCA1和BRCA2 一样。”安德森解释说。“一个遗传实验就能帮助我们在发生疾病以前识别出处于危险的人。”
根据美国癌症学会的报道，肺癌是癌症相关疾病和死亡的主要原因。尽管吸烟是引起肺癌的主要环境因素，但科学家证明，导致该病的还有明显的遗传因素。
“这项研究有助于我们对肺癌敏感性的了解，也是向预防医学迈出的一步。”哈佛大学公共卫生学院职业病学和环境卫生学教授大卫﹒克里斯提尼博士说。“研究人员在努力寻找发病基因中所进行的家族性研究是一个无所畏惧的挑战。”
基因位于细胞染色体的固定位置上，它携带了决定遗传特性的DNA编码，其中也包括某些疾病的发病危险。研究人员收集了许多患肺癌5人以上家族的多代人的生物样本。结合将遗传信息剖开分析的“精确定位”和遗传相关研究，研究人员发现RGS17是家族性肺癌的主要候选敏感基因。研究证明，肺癌可以在没有危险因素和家族史的人中零星发病，也可以在同一家族多成员中遗传性发病。2004年，安德森研究小组报道了首个肺癌的遗传证据：在6号染色体上的一个“敏感基因座”，以及其它3条染色体上存在一个敏感区域。早期发现的染色体肺癌标记物区域里含有大约100个基因，包括数个怀疑与肿瘤抑制和细胞生长有关的基因。
通过遗传改良小鼠模型研究发现，当RGS17 被抑制后肿瘤会缩小，证明这个基因与癌症发生有关，而且癌症发生必须有这个基因存在。
“更有意思的是，在60%非遗传性肺癌的样本中，这个基因处于超表达。”安德森说。“这说明可能有外部外因素在影响着遗传性肺癌发病。”
研究小组将对环境因素如何会影响家族性癌症发病作进一步研究。（生物谷Bioon.com）
生物谷推荐原始出处：
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.
