Assessing the genetic architecture of epithelial ovarian cancer histological subtypes.
Assessing the genetic architecture of epithelial ovarian cancer histological subtypes.
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评估上皮性卵巢癌组织学亚型的遗传结构。
DOI：
10.1007/s00439-016-1663-9
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发表时间：
2016-07
期刊：
影响因子：
5.3
通讯作者：
MacGregor S
中科院分区：
文献类型：
--
作者：
Cuellar-Partida G;Lu Y;Dixon SC;Australian Ovarian Cancer Study;Fasching PA;Hein A;Burghaus S;Beckmann MW;Lambrechts D;Van Nieuwenhuysen E;Vergote I;Vanderstichele A;Doherty JA;Rossing MA;Chang-Claude J;Rudolph A;Wang-Gohrke S;Goodman MT;Bogdanova N;Dörk T;Dürst M;Hillemanns P;Runnebaum IB;Antonenkova N;Butzow R;Leminen A;Nevanlinna H;Pelttari LM;Edwards RP;Kelley JL;Modugno F;Moysich KB;Ness RB;Cannioto R;Høgdall E;Høgdall C;Jensen A;Giles GG;Bruinsma F;Kjaer SK;Hildebrandt MA;Liang D;Lu KH;Wu X;Bisogna M;Dao F;Levine DA;Cramer DW;Terry KL;Tworoger SS;Stampfer M;Missmer S;Bjorge L;Salvesen HB;Kopperud RK;Bischof K;Aben KK;Kiemeney LA;Massuger LF;Brooks-Wilson A;Olson SH;McGuire V;Rothstein JH;Sieh W;Whittemore AS;Cook LS;Le ND;Blake Gilks C;Gronwald J;Jakubowska A;Lubiński J;Kluz T;Song H;Tyrer JP;Wentzensen N;Brinton L;Trabert B;Lissowska J;McLaughlin JR;Narod SA;Phelan C;Anton-Culver H;Ziogas A;Eccles D;Campbell I;Gayther SA;Gentry-Maharaj A;Menon U;Ramus SJ;Wu AH;Dansonka-Mieszkowska A;Kupryjanczyk J;Timorek A;Szafron L;Cunningham JM;Fridley BL;Winham SJ;Bandera EV;Poole EM;Morgan TK;Goode EL;Schildkraut JM;Pearce CL;Berchuck A;Pharoah PD;Webb PM;Chenevix-Trench G;Risch HA;MacGregor S
上皮性卵巢癌（EOC）是最致命的常见癌症之一。五种最常见的疾病类型是高级别和低级别浆液性、类浆液性、粘液性和透明细胞癌。这些亚型中的每一种都呈现出不同的分子发病机制和对治疗的敏感性。最近的研究表明，某些遗传变异赋予所有亚型的易感性，而其他变异则具有亚型特异性。在这里，我们进行了广泛的分析EOC亚型的遗传结构。为此，我们使用了来自卵巢癌协会联盟的10，014名侵袭性EOC患者和21，233名对照的数据，在iCOGS阵列中进行基因分型（211，155个SNP）。我们估计了每个亚型的阵列遗传力（归因于阵列上标记的变体）及其遗传相关性。我们还寻找与肥胖、吸烟行为、糖尿病、初潮年龄和身高等因素的遗传重叠。我们估计了高度浆液性疾病（）、类浆液性疾病（）、透明细胞疾病（）和所有卵巢上皮性癌（）的阵列遗传力。已知的相关基因座贡献了每个亚型总阵列遗传力的约40%。每条染色体对总遗传力的贡献与染色体大小不成正比。通过双变量和跨性状LD评分回归，我们发现了三个高级别亚型（浆液性、类浆液性和未分化）之间共享遗传背景的证据。最后，我们使用多基因预测方法发现了所有EOC与糖尿病和肥胖的显着遗传相关性。
Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ( ), endometrioid ( ), clear cell ( ) and all EOC ( ). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.