Dorward Ann M, Shultz Kathryn L, Horton Lindsay G, Li Renhua, Churchill Gary A, Beamer Wesley G
The Jackson Laboratory, Bar Harbor, Maine, USA.
Cancer Res. 2005 Feb 15;65(4):1259-64. doi: 10.1158/0008-5472.CAN-04-2992.
The spontaneous development of juvenile-onset ovarian granulosa cell tumors in mice of the SWXJ-9 recombinant inbred strain is a model for juvenile-type granulosa cell tumors that appear in very young girls. To expedite gene discovery in this mouse model of childhood cancer, we did a gene mapping study with the SWXJ-9 recombinant inbred strain and the evolutionarily divergent Mus musculus castaneus (CAST/Ei) strain as a mapping partner. Our mapping strategy focused on autosomal determinants of susceptibility with a backcross scheme that exploited a paternal, parent-of-origin effect for a X-linked gene (Gct4) that strongly supports granulosa cell tumor development. Of 1,968 backcross females examined, we detected 81 granulosa cell tumor-bearing animals and compared their allelic inheritance patterns to non-tumor-bearing siblings in a case-control analysis. The results of our study have confirmed an important locus on mouse chromosome (Chr) 4 (Gct1) and have revealed new loci for granulosa cell tumor susceptibility (Gct7-Gct9) on Chrs 1, 2, and 13 with susceptibility alleles contributed by the SWXJ-9 progenitor. Two novel gene-gene interactions supportive for granulosa cell tumor development were also observed between loci on Chrs 17 and 18 and loci on Chrs 2 and 10. Our data substantiate the evidence that Gct1 on Chr 4 is a fundamental oncogene for granulosa cell tumorigenesis in mice and has identified additional interacting autosomal loci that support tumor development.
SWXJ - 9重组近交系小鼠自发发生的青少年型卵巢颗粒细胞瘤，是非常年幼女孩中出现的青少年型颗粒细胞瘤的一个模型。为了在这个儿童癌症小鼠模型中加快基因发现，我们用SWXJ - 9重组近交系和进化上不同的小家鼠栗色品系（CAST/Ei）作为定位伙伴进行了基因定位研究。我们的定位策略聚焦于易感性的常染色体决定因素，采用了一种回交方案，该方案利用了一个对颗粒细胞瘤发展有强烈支持作用的X连锁基因（Gct4）的父本、亲本来源效应。在检查的1968只回交雌性小鼠中，我们检测到81只患有颗粒细胞瘤的动物，并在病例对照分析中将它们的等位基因遗传模式与无肿瘤的同胞进行了比较。我们的研究结果证实了小鼠4号染色体（Chr）上的一个重要位点（Gct1），并揭示了1号、2号和13号染色体上颗粒细胞瘤易感性的新位点（Gct7 - Gct9），其易感等位基因由SWXJ - 9祖系提供。在17号和18号染色体上的位点与2号和10号染色体上的位点之间还观察到了两个支持颗粒细胞瘤发展的新型基因 - 基因相互作用。我们的数据证实了4号染色体上的Gct1是小鼠颗粒细胞瘤发生的一个基本癌基因的证据，并确定了其他支持肿瘤发展的相互作用常染色体位点。
