Variants in KITLG predispose to testicular germ cell cancer independently from spermatogenic function
Variants in KITLG predispose to testicular germ cell cancer independently from spermatogenic function
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DOI：
10.1530/erc-11-0340
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发表时间：
2012-02-01
影响因子：
3.9
通讯作者：
Foresta, Carlo
中科院分区：
文献类型：
--
作者：
Ferlin, Alberto;Pengo, Manuel;Foresta, Carlo
流行病学数据表明，男性不育和睾丸生殖细胞肿瘤（TGCT）的发展之间的关联和共同的发病机制。全基因组研究发现，TGCT易感性与KITLG（c-KIT配体）相关，KITLG调节原始生殖细胞的形成，据信TGCT从原始生殖细胞中产生，精子发生也从原始生殖细胞中发育。在这项研究中，我们分析了KITLG，TGCT和生精障碍之间的联系，通过进行KITLG标记rs 995030和rs 4471514和426例TGCT病例和614例正常和异常精子计数对照之间的关联研究。我们发现KITLG rs 995030和rs 4471514中主要G等位基因和A等位基因的每一个拷贝，TGCT风险增加两倍以上。（OR =2.38，95%可信区间（95% CI）=1.81-3.12; OR=2.43，95% CI=1.86-3.17），危险等位基因纯合子的TGCT发病风险增加7倍。KITLG标记物与腺瘤亚型密切相关（每个等位基因的风险增加超过3倍，纯合子风险增加13- 16倍），与非腺瘤弱相关。KITLG标记物与精子生成无关，因为在正常精子症和无-少精子症男性中，无论是对照组还是TGCT病例中，均未观察到差异。总之，本研究提供的证据表明，KITLG变异体参与TGCT的发展，他们代表了一个独立的和强大的TGCT的特异性风险因素，独立于生精功能。从这项研究来看，TGCT发展和精子发生障碍之间的共同遗传原因和共同发病联系并不明显。内分泌相关癌症（2012）19 101-108
Epidemiological data suggest an association and a common pathogenetic link between male infertility and testicular germ cell tumor (TGCT) development. Genome-wide studies identified that TGCT susceptibility is associated with KITLG (c-KIT ligand), which regulates the formation of primordial germ cells, from which TGCT is believed to arise and spermatogenesis develops. In this study, we analyzed the link between KITLG, TGCT, and spermatogenic disruption by performing an association study between the KITLG markers rs995030 and rs4471514 and 426 TGCT cases and 614 controls with normal and abnormal sperm count. We found that TGCT risk was increased more than twofold per copy of the major G allele and A allele in KITLG rs995030 and rs4471514 (odds ratio (OR)=2.38, 95% confidence interval (95% CI)=1.81-3.12; OR=2.43, 95% CI=1.86-3.17 respectively), and homozygotes for the risk allele had a sevenfold increased risk of TGCT. KITLG markers were strongly associated with seminoma subtype (per allele risk increased more than threefold, homozygote risk increased by 13- to 16-fold) and weakly with nonseminoma. KITLG markers were not associated with sperm production, as no difference was observed in men with normozoospermia and azoo-oligozoospermia, both in controls and in TGCT cases. In conclusion, this study provides evidence that KITLG variants are involved in TGCT development and they represent an independent and strong specific risk factor for TGCT independently from spermatogenic function. A shared genetic cause and a common pathogenetic link between TGCT development and impairment of spermatogenesis are not evident from this study. Endocrine-Related Cancer (2012) 19 101-108