对5号染色体p15区域的TERT-CLPTM1L癌症风险区域进行候选基因座分析，确定了多个与子宫内膜癌风险相关的独立变异。
Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk.
作者信息
Carvajal-Carmona Luis G, O'Mara Tracy A, Painter Jodie N, Lose Felicity A, Dennis Joe, Michailidou Kyriaki, Tyrer Jonathan P, Ahmed Shahana, Ferguson Kaltin, Healey Catherine S, Pooley Karen, Beesley Jonathan, Cheng Timothy, Jones Angela, Howarth Kimberley, Martin Lynn, Gorman Maggie, Hodgson Shirley, Wentzensen Nicholas, Fasching Peter A, Hein Alexander, Beckmann Matthias W, Renner Stefan P, Dörk Thilo, Hillemanns Peter, Dürst Matthias, Runnebaum Ingo, Lambrechts Diether, Coenegrachts Lieve, Schrauwen Stefanie, Amant Frederic, Winterhoff Boris, Dowdy Sean C, Goode Ellen L, Teoman Attila, Salvesen Helga B, Trovik Jone, Njolstad Tormund S, Werner Henrica M J, Scott Rodney J, Ashton Katie, Proietto Tony, Otton Geoffrey, Wersäll Ofra, Mints Miriam, Tham Emma, Hall Per, Czene Kamila, Liu Jianjun, Li Jingmei, Hopper John L, Southey Melissa C, Ekici Arif B, Ruebner Matthias, Johnson Nichola, Peto Julian, Burwinkel Barbara, Marme Frederik, Brenner Hermann, Dieffenbach Aida K, Meindl Alfons, Brauch Hiltrud, Lindblom Annika, Depreeuw Jeroen, Moisse Matthieu, Chang-Claude Jenny, Rudolph Anja, Couch Fergus J, Olson Janet E, Giles Graham G, Bruinsma Fiona, Cunningham Julie M, Fridley Brooke L, Børresen-Dale Anne-Lise, Kristensen Vessela N, Cox Angela, Swerdlow Anthony J, Orr Nicholas, Bolla Manjeet K, Wang Qin, Weber Rachel Palmieri, Chen Zhihua, Shah Mitul, Pharoah Paul D P, Dunning Alison M, Tomlinson Ian, Easton Douglas F, Spurdle Amanda B, Thompson Deborah J
机构信息
Genome Center and Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, 95616, USA,
出版信息
Hum Genet. 2015 Feb;134(2):231-45. doi: 10.1007/s00439-014-1515-4. Epub 2014 Dec 9.
Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.
多项研究报告了多种癌症类型与5号染色体p15区域的单核苷酸多态性（SNP）之间的关联，该区域包含端粒酶逆转录酶（TERT）和类克拉通样跨膜蛋白1样蛋白（CLPTM1L），但尚未有关于子宫内膜癌的此类关联报道。为了评估TERT-CLPTM1L区域的基因变异在子宫内膜癌风险中的作用，我们使用定制的Illumina iSelect芯片对基因分型和推算的SNP进行了全面的精细定位分析，该芯片对该区域具有密集的SNP覆盖。我们在4401例子宫内膜癌病例和28758例对照中检测了396个SNP（113个基因分型，283个推算）。单SNP以及向前/向后逻辑回归模型表明，有证据显示三个变异与子宫内膜癌风险独立相关（P = 4.9×10⁻⁶至P = 7.7×10⁻⁵）。只有一个属于先前与其他癌症类型相关的单倍型（rs7705526，位于TERT内含子1），并且该SNP已被证明会改变TERT启动子活性。其中一个新关联（rs13174814）定位于TERT启动子中的第二个区域，另一个（rs62329728）位于CLPTM1L的启动子区域；两者均与先前报道的癌症相关SNP不相关。使用癌症基因组图谱（TCGA）RNA测序数据，我们发现与正常组织相比，子宫内膜癌组织中TERT和CLPTM1L的表达均显著增加（TERT，P = 1.5×10⁻¹⁸；CLPTM1L，P = 1.5×10⁻¹⁹）。因此，我们的研究报告了一个新的子宫内膜癌风险位点，并扩展了与5p15基因变异相关的癌症类型谱，进一步凸显了该区域对癌症易感性的重要性。
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