评估卵巢癌促性腺激素假说：一项候选基因研究。
Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study.
作者信息
Lee Alice W, Tyrer Jonathan P, Doherty Jennifer A, Stram Douglas A, Kupryjanczyk Jolanta, Dansonka-Mieszkowska Agnieszka, Plisiecka-Halasa Joanna, Spiewankiewicz Beata, Myers Emily J, Chenevix-Trench Georgia, Fasching Peter A, Beckmann Matthias W, Ekici Arif B, Hein Alexander, Vergote Ignace, Van Nieuwenhuysen Els, Lambrechts Diether, Wicklund Kristine G, Eilber Ursula, Wang-Gohrke Shan, Chang-Claude Jenny, Rudolph Anja, Sucheston-Campbell Lara, Odunsi Kunle, Moysich Kirsten B, Shvetsov Yurii B, Thompson Pamela J, Goodman Marc T, Wilkens Lynne R, Dörk Thilo, Hillemanns Peter, Dürst Matthias, Runnebaum Ingo B, Bogdanova Natalia, Pelttari Liisa M, Nevanlinna Heli, Leminen Arto, Edwards Robert P, Kelley Joseph L, Harter Philipp, Schwaab Ira, Heitz Florian, du Bois Andreas, Orsulic Sandra, Lester Jenny, Walsh Christine, Karlan Beth Y, Hogdall Estrid, Kjaer Susanne K, Jensen Allan, Vierkant Robert A, Cunningham Julie M, Goode Ellen L, Fridley Brooke L, Southey Melissa C, Giles Graham G, Bruinsma Fiona, Wu Xifeng, Hildebrandt Michelle A T, Lu Karen, Liang Dong, Bisogna Maria, Levine Douglas A, Weber Rachel Palmieri, Schildkraut Joellen M, Iversen Edwin S, Berchuck Andrew, Terry Kathryn L, Cramer Daniel W, Tworoger Shelley S, Poole Elizabeth M, Olson Sara H, Orlow Irene, Bandera Elisa V, Bjorge Line, Tangen Ingvild L, Salvesen Helga B, Krakstad Camilla, Massuger Leon F A G, Kiemeney Lambertus A, Aben Katja K H, van Altena Anne M, Bean Yukie, Pejovic Tanja, Kellar Melissa, Le Nhu D, Cook Linda S, Kelemen Linda E, Brooks-Wilson Angela, Lubinski Jan, Gronwald Jacek, Cybulski Cezary, Jakubowska Anna, Wentzensen Nicolas, Brinton Louise A, Lissowska Jolanta, Yang Hannah, Nedergaard Lotte, Lundvall Lene, Hogdall Claus, Song Honglin, Campbell Ian G, Eccles Diana, Glasspool Rosalind, Siddiqui Nadeem, Carty Karen, Paul James, McNeish Iain A, Sieh Weiva, McGuire Valerie, Rothstein Joseph H, Whittemore Alice S, McLaughlin John R, Risch Harvey A, Phelan Catherine M, Anton-Culver Hoda, Ziogas Argyrios, Menon Usha, Ramus Susan J, Gentry-Maharaj Aleksandra, Harrington Patricia, Pike Malcolm C, Modugno Francesmary, Rossing Mary Anne, Ness Roberta B, Pharoah Paul D P, Stram Daniel O, Wu Anna H, Pearce Celeste Leigh
机构信息
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
出版信息
Gynecol Oncol. 2015 Mar;136(3):542-8. doi: 10.1016/j.ygyno.2014.12.017. Epub 2014 Dec 17.
OBJECTIVE
Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted.
METHODS
Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations.
RESULTS
We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive).
CONCLUSIONS
Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.
目的
卵巢癌是一种具有强大遗传基础的激素相关疾病。然而，迄今为止，其高 penetrance 易感基因和全基因组关联研究（GWAS）确定的变异均未被发现参与激素途径。鉴于促性腺激素的假定病因学作用，有必要评估促性腺激素信号通路相关基因的变异性如何影响疾病风险。
方法
汇总来自 41 个卵巢癌研究地点的遗传数据，并使用无条件逻辑回归来评估来自 11 个促性腺激素信号通路基因的 2185 个单核苷酸多态性（SNP）中的任何一个是否与卵巢癌风险相关。还使用基于混合似然（AML）方法的负担检验来评估基因水平的关联。
结果
我们未发现个体 SNP 与卵巢癌风险之间存在任何全基因组显著关联。然而，有一些迹象表明四个促性腺激素信号通路基因存在基因水平的关联：抑制素βB（INHBB，p = 0.045，黏液性）、促黄体生成素/绒毛膜促性腺激素受体（LHCGR，p = 0.046，高级别浆液性）、促性腺激素释放激素（GNRH，p = 0.041，高级别浆液性）和促卵泡激素β（FSHB，p = 0.036，总体浸润性）。对于抑制素α（INHA，p = 0.060，总体浸润性）也有提示性证据。
结论
卵巢癌研究的样本数量有限，因此相对于乳腺癌和前列腺癌，已鉴定出的全基因组易感等位基因较少，且关联程度适中。据我们所知，我们已经评估了大多数有生物样本的卵巢癌研究，没有留下重复验证的机会。利用我们对生物学的理解和强大的基因水平检验，我们在 INHBB、LHCGR、GNRH 和 FSHB 附近鉴定出四个假定的卵巢癌基因座，如果有更大的样本量和更密集的基因型芯片，值得进一步研究。
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