Dorward Ann M, Shultz Kathryn L, Ackert-Bicknell Cheryl L, Eicher Eva M, Beamer Wesley G
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Cancer Res. 2003 Dec 1;63(23):8197-202.
SWR/Bm (SWR) female mice spontaneously develop early-onset ovarian granulosa cell (GC) tumors that can progress to metastatic carcinoma and thus provide a model system for human, juvenile-type GC tumors. In SWR mice, GC tumor susceptibility is an inherited, polygenic trait that appears at a low frequency. A dramatic increase in tumor frequency occurs when the autosomal SWR genetic complement is combined with the X-linked Gct4 allele of the mouse strain SJL/Bm (SJL). The modifier effect of the SJL Gct4 allele (Gct4(J)) also shows a strong parent-of-origin effect, occurring only when the Gct4(J) allele is paternally inherited. To genetically localize Gct4, we generated seven congenic mouse strains (SWR.SJL-X1 through -X7) that contained a defined segment of the SJL X chromosome (Chr) on the SWR autosomal strain background and mapped Gct4 to a 3 cM region. To better define the location of Gct4, we created an additional congenic strain (SWR.CAST-X) that contains most of the genetically polymorphic Chr X from the strain CAST/Ei. From crosses of the SWR.CAST-X and SWR.SJL-X congenic strains, we derived males carrying unique combinations of SJL-X and CAST-X segments. Progeny testing subsequently revealed a second SJL-derived, GC tumor frequency modifier gene, Gct6, located 6.5 cM distal to Gct4 on Chr X. In summary, we have mapped two modifier genes on the mouse Chr X that cause high-frequency, juvenile-type GC tumor development in female mice. The identity of these genes will provide a solid foundation for determination of tumor susceptibility genes in human cases of juvenile-type GC tumors.
SWR/Bm（SWR）雌性小鼠会自发发生早发性卵巢颗粒细胞瘤（GC），这种肿瘤可进展为转移性癌，因此为人类青少年型GC肿瘤提供了一个模型系统。在SWR小鼠中，GC肿瘤易感性是一种遗传性多基因性状，出现频率较低。当常染色体SWR遗传背景与小鼠品系SJL/Bm（SJL）的X连锁Gct4等位基因结合时，肿瘤发生频率会急剧增加。SJL Gct4等位基因（Gct4(J)）的修饰作用也表现出强烈的亲本来源效应，仅当Gct4(J)等位基因是父系遗传时才会出现。为了对Gct4进行基因定位，我们构建了7个近交系小鼠（SWR.SJL-X1至-X7），它们在SWR常染色体品系背景上含有SJL X染色体（Chr）的一个特定片段，并将Gct4定位到一个3 cM的区域。为了更好地确定Gct4的位置，我们创建了另一个近交系（SWR.CAST-X），它包含来自CAST/Ei品系的大部分具有遗传多态性的Chr X。通过SWR.CAST-X和SWR.SJL-X近交系的杂交，我们获得了携带SJL-X和CAST-X片段独特组合的雄性小鼠。随后的子代检测揭示了第二个源自SJL的GC肿瘤频率修饰基因Gct6，它位于Chr X上Gct4远端6.5 cM处。总之，我们在小鼠Chr X上定位了两个修饰基因，它们导致雌性小鼠发生高频青少年型GC肿瘤。这些基因的鉴定将为确定人类青少年型GC肿瘤病例中的肿瘤易感基因提供坚实基础。
