Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot".
Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot".
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DOI：
10.1371/journal.pgen.1001016
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发表时间：
2010-07-08
期刊：
影响因子：
4.5
通讯作者：
Australian Cancer Study (Ovarian Cancer)
中科院分区：
文献类型：
--
作者：
Johnatty SE;Beesley J;Chen X;Macgregor S;Duffy DL;Spurdle AB;deFazio A;Gava N;Webb PM;Rossing MA;Doherty JA;Goodman MT;Lurie G;Thompson PJ;Wilkens LR;Ness RB;Moysich KB;Chang-Claude J;Wang-Gohrke S;Cramer DW;Terry KL;Hankinson SE;Tworoger SS;Garcia-Closas M;Yang H;Lissowska J;Chanock SJ;Pharoah PD;Song H;Whitemore AS;Pearce CL;Stram DO;Wu AH;Pike MC;Gayther SA;Ramus SJ;Menon U;Gentry-Maharaj A;Anton-Culver H;Ziogas A;Hogdall E;Kjaer SK;Hogdall C;Berchuck A;Schildkraut JM;Iversen ES;Moorman PG;Phelan CM;Sellers TA;Cunningham JM;Vierkant RA;Rider DN;Goode EL;Haviv I;Chenevix-Trench G;Ovarian Cancer Association Consortium;Australian Ovarian Cancer Study Group;Australian Cancer Study (Ovarian Cancer)
我们假设，卵巢癌细胞和宿主微环境之间相互作用的结果表达的基因变异可能有助于癌症易感性。因此，我们使用两阶段的方法来评估共同的单核苷酸多态性（SNPs）在卵巢癌协会联盟（OCAC）的173个基因参与间质上皮相互作用。在发现阶段，使用Illumina GoldenGate测定法对上皮性卵巢癌病例（n = 675）和对照组（n = 1，162）在1，536个SNP进行基因分型。 基于阳性预测值估计，从16项OCAC病例对照研究中选择了3个SNP-PODXL rs 1013368、ITGA 6 rs 13027811和MMP 3 rs 522616-用于使用TaqMan基因分型在多达3，059例浆液性浸润性病例和8，905例对照中进行复制。另外18个在发现阶段每个等位基因P <0.05的SNP被选择用于在5个OCAC研究的子集中进行复制（n = 1，233例浆液性浸润性病例; n = 3，364例对照）。 PODXL、ITGA 6和MMP 3的发现阶段相关性在较大的复制集中减弱（adj. P每个等位基因≥0.5）。然而，在较小的五项重复研究中，TERTrs 7726159基因型与卵巢癌风险相关（P每等位基因= 0.03）。 对该TERTSNP的发现集和复制集的联合分析显示，非西班牙裔白人中浆液性卵巢癌的风险增加[adj. OR每等位基因1.14（1.04-1.24）p = 0.003]。 我们的研究增加了越来越多的证据表明，像8 q24基因座，端粒酶逆转录酶基因座在5p15.33，是一个普遍的癌症易感性基因座。在这篇文章中，我们报告了对基因中常见变异的大规模分析结果，这些基因是卵巢癌细胞与其宿主微环境之间相互作用的结果，可能会影响浆液性卵巢癌的风险。我们在卵巢癌协会联盟（OCAC）的两项大型病例对照研究中评估了173个基因内或附近的1,302个常见变异，并在16项OCAC研究中选择了3个变异进行进一步评估，在5项OCAC研究中选择了另外18个变异进行评估。我们观察到浆液性卵巢癌的风险显著增加与端粒酶逆转录酶（TERT）基因的变异有关。虽然以前没有显示TERT变异与卵巢癌风险有关，但最近有几项研究报道了TERT变异与其他形式的癌症之间的关联，包括神经胶质瘤，肺癌，腺癌，基底细胞癌，前列腺癌和多种其他癌症。TERT编码一种蛋白质，该蛋白质对于细胞分裂期间染色体完整性的复制和维持是必需的。在癌细胞中，TERT与基因组不稳定性和肿瘤细胞增殖有关。进一步的研究是必要的，以确认我们的研究结果，并调查所观察到的关联的机制。
We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n = 675) and controls (n = 1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs—PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616—were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with P per-allele<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n = 1,233 serous invasive cases; n = 3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. P per-allele≥0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (P per-allele = 0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04–1.24) p = 0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus. In this article, we report the findings from a large-scale analysis of common variation in genes that are expressed as a consequence of interactions between ovarian cancer cells and their host micro-environment that could influence serous ovarian cancer risk. We evaluated 1,302 common variants within or near 173 genes in two large case-control studies from the Ovarian Cancer Association Consortium (OCAC) and selected three variants for further evaluation in sixteen OCAC studies and an additional 18 for evaluation in five OCAC studies. We observed a significantly increased risk of serous ovarian cancer associated with a variant in the telomerase reverse transcriptase (TERT) gene. Although TERT variants have not been previously shown to contribute to ovarian cancer risk, several studies have recently reported associations between TERT variants and other forms of cancer, including gliomas, lung cancer, adenocarcinoma, basal cell carcinoma, prostate cancer, and multiple other cancers. TERT encodes a protein that is essential for the replication and maintenance of chromosomal integrity during cell division. In cancer cells, TERT has been linked to genomic instability and tumour cell proliferation. Further studies are necessary to confirm our findings and to investigate the mechanisms for the observed association.
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影响因子：
30.8
作者：
McKay, James D.;Hung, Rayjean J.;Gaborieau, Valerie;Boffetta, Paolo;Chabrier, Amelie;Byrnes, Graham;Zaridze, David;Mukeria, Anush;Szeszenia-Dabrowska, Neonilia;Lissowska, Jolanta;Rudnai, Peter;Fabianova, Eleonora;Mates, Dana;Bencko, Vladimir;Foretova, Lenka;Janout, Vladimir;McLaughlin, John;Shepherd, Frances;Montpetit, Alexandre;Narod, Steven;Krokan, Hans E.;Skorpen, Frank;Elvestad, Maiken Bratt;Vatten, Lars;Njolstad, Inger;Axelsson, Tomas;Chen, Chu;Goodman, Gary;Barnett, Matt;Loomis, Melissa M.;Lubinski, Jan;Matyjasik, Joanna;Lener, Marcin;Oszutowska, Dorota;Field, John;Liloglou, Triantafillos;Xinarianos, George;Cassidy, Adrian;Zelenika, Diana;Boland, Anne;Delepine, Marc;Foglio, Mario;Lechner, Doris;Matsuda, Fumihiko;Blanche, Helene;Gut, Ivo;Heath, Simon;Lathrop, Mark;Brennan, Paul
通讯作者：
Brennan, Paul
DOI：
10.1158/1055-9965.epi-07-2849
发表时间：
2008-07
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
--
作者：
Cunningham JM;Sellers TA;Schildkraut JM;Fredericksen ZS;Vierkant RA;Kelemen LE;Gadre M;Phelan CM;Huang Y;Meyer JG;Pankratz VS;Goode EL
通讯作者：
Goode EL
影响因子：
8
作者：
Donninger, H;Bonome, T;Birrer, MJ
通讯作者：
Birrer, MJ
影响因子：
30.8
作者：
de Bakker, PIW;Yelensky, R;Altshuler, D
通讯作者：
Altshuler, D
影响因子：
56.9
作者：
Hinds, DA;Stuve, LL;Cox, DR
通讯作者：
Cox, DR