Post GWA Studies in Testicular Germ Cell Tumors

描述（由申请人提供）：睾丸生殖细胞肿瘤（TGCT）是年轻男性中最常见的癌症。TGCT的流行病学特征有几个显著特点：发病率增加、风险的种族差异和高家族相对风险。然而，对TGCT危险因素和原因的了解远远落后于其他恶性肿瘤。最近，全基因组关联（GWA）研究已经确定了6个与TGCT易感性相关的基因座，最引人注目的是KITLG，每个等位基因的风险超过3倍。然而，这六个基因座仅解释了TGCT男性兄弟11%的风险。结合我们的初步数据，我们假设可以确定其他TGCT风险位点。在具体目标1中，我们提出了一个汇总分析所有现有的TGCT全基因组关联（GWA）研究，包括2227例和6762对照，发现新的遗传标记的风险没有确定在个别研究。前2000个SNP沿着来自已知风险基因座重测序的500个SNP将被复制到来自代表8个国家21个位点的新的国际TGCT联盟的5491个TGCT病例和8190个对照中。在具体目标2中，我们将通过深度重测序进一步表征包含复制中注意到的风险标记的基因组区域。还将检测通过重测序鉴定并代表推定因果变异体的SNP标记在复制样本中的关联性。在具体目标3中，我们将研究复制的TGCT风险等位基因是否通过母体和/或起源父母效应影响TGCT风险。由于TGCT的发展始于子宫内，它可能涉及来自妊娠环境的因素。此外，来自TGCT易感性小鼠模型的证据和我们的初步数据支持亲本效应。为了实现这一目标，将使用对数线性方法分析1878例病例-父母三联体和895例病例-父母二联体的基因型数据，以评估与母体基因型和母体与父母等位基因传递相关的独立相对风险，并对后代基因型进行调整。最后，目标4侧重于建立一个TGCT联盟，并正式确定了为此应用而建立的研究联盟。总之，这些目标将大大推进我们目前对TGCT的遗传基础和生物学基础的理解。

DESCRIPTION (provided by applicant): Testicular germ cell tumors (TGCT) are the most common cancers in young men. Several striking features characterize the epidemiology of TGCT: increasing incidence, racial disparity in risk and high familial relative risks. However, knowledge of TGCT risk factors and causes lags far behind that of other malignancies. Recently, genome-wide association (GWA) studies have identified six loci associated with TGCT susceptibility, the most striking being KITLG with a per allele risk surpassing 3- fold. However, these six loci only explain 11% of the risk to brothers of men with TGCT. In conjunction with our preliminary data, we hypothesize that additional TGCT risk loci can be identified. In Specific Aim 1, we propose a pooled analysis of all existing genome-wide association (GWA) studies of TGCT, including 2227 cases and 6762 controls, to discover novel genetic markers of risk not identified in the individual studies. The top 2000 SNPs along with 500 from resequencing of known risk loci will be taken into replication into 5491 TGCT cases and 8190 controls from a new international TGCT consortium representing 21 sites in eight countries. In Specific Aim 2, we will further characterize genomic regions containing risk markers noted in replication through deep resequencing. SNP markers identified by resequencing and representing putative causal variant(s) also will be tested for association in the replication samples. In Specific Aim 3, we will examine whether replicated TGCT risk alleles affect risk of TGCT through maternal and/or parent-of-origin effects. As the development of TGCT begins in utero, it may involve factors derived from the pregnancy environment. In addition, evidence from mouse models of TGCT susceptibility and our preliminary data support parent-of-origin effects. To address this aim, genotype data on 1878 case-parent triads and 895 case-parent dyads will be analyzed using a log-linear method to assess the independent relative risks associated with maternal genotypes and maternal vs. parental allele transmission, adjusted for offspring genotype. Finally, Aim 4 focuses on the establishment of a TGCT consortium and formalizes the research alliance brought together for this application. Together, these aims will significantly advance our current understanding of the genetic basis and biological underpinnings of TGCT.