Fancf-deficient mice are prone to develop ovarian tumours
Fancf-deficient mice are prone to develop ovarian tumours
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DOI：
10.1002/path.2992
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发表时间：
2012-01-01
影响因子：
7.3
通讯作者：
Riele, Hein Te
中科院分区：
文献类型：
--
作者：
Bakker, Sietske T.;van de Vrugt, Henri J.;Riele, Hein Te
范可尼贫血（FA）是一种罕见的隐性疾病，其特征是发育异常，骨髓衰竭，以及白血病和实体瘤发展的高风险。FA基因，特别是FANCF的失活，也被记录在散发性肿瘤的非FA患者。为了研究FA通路缺陷和肿瘤发展之间是否存在因果关系，我们产生了一种具有FA核心复合物基因Fancf的靶向破坏的小鼠模型。Fancf缺陷的小鼠胚胎成纤维细胞表现出FA细胞的典型表型：它们对DNA交联剂表现出异常反应，表现为G（2）阻滞、染色体畸变、存活率降低和不能单泛素化FANCD 2。Fancf纯合子小鼠存活，出生时遵循正常孟德尔分布，未显示生长迟缓或发育异常。Fancf突变小鼠的性腺功能异常，表现出受损的卵泡发育和精子发生，如在其他FA小鼠模型和FA患者中观察到的。在一组Fancf缺陷小鼠中，我们观察到总生存率降低和肿瘤发病率增加。值得注意的是，在七只雌性小鼠中，六个卵巢肿瘤发展：五个颗粒细胞瘤和一个黄体瘤。一只老鼠的两个卵巢都长出了肿瘤。对这些肿瘤的高分辨率阵列比较基因组杂交（aCGH）表明，卵巢肿瘤的发病率增加与Fancf缺陷小鼠的不育和FA途径缺陷的基因组不稳定性特征相关。版权所有（C）2011大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
Fanconi anaemia (FA) is a rare recessive disorder marked by developmental abnormalities, bone marrow failure, and a high risk for the development of leukaemia and solid tumours. The inactivation of FA genes, in particular FANCF, has also been documented in sporadic tumours in non-FA patients. To study whether there is a causal relationship between FA pathway defects and tumour development, we have generated a mouse model with a targeted disruption of the FA core complex gene Fancf. Fancf-deficient mouse embryonic fibroblasts displayed a phenotype typical for FA cells: they showed an aberrant response to DNA cross-linking agents as manifested by G(2) arrest, chromosomal aberrations, reduced survival, and an inability to monoubiquitinate FANCD2. Fancf homozygous mice were viable, born following a normal Mendelian distribution, and showed no growth retardation or developmental abnormalities. The gonads of Fancf mutant mice functioned abnormally, showing compromised follicle development and spermatogenesis as has been observed in other FA mouse models and in FA patients. In a cohort of Fancf-deficient mice, we observed decreased overall survival and increased tumour incidence. Notably, in seven female mice, six ovarian tumours developed: five granulosa cell tumours and one luteoma. One mouse had developed tumours in both ovaries. High-resolution array comparative genomic hybridization (aCGH) on these tumours suggests that the increased incidence of ovarian tumours correlates with the infertility in Fancf-deficient mice and the genomic instability characteristic of FA pathway deficiency. Copyright (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.