Cormier R T, Hong K H, Halberg R B, Hawkins T L, Richardson P, Mulherkar R, Dove W F, Lander E S
McArdle Laboratory for Cancer Research, University of Wisconsin, Madison 53706, USA.
Nat Genet. 1997 Sep;17(1):88-91. doi: 10.1038/ng0997-88.
Individuals inheriting the same mutation predisposing to cancer may show very different outcomes, ranging from early aggressive cancer to disease-free survival. Experimental mouse models can provide a powerful tool to identify factors in the environment and genetic background that account for such modifications. The Min mouse strain, in which the ApcMin mutation disrupts the mouse homologue of the human familial polyposis gene, develops intestinal neoplasms whose multiplicity is strongly affected by genetic background. We previously mapped a strong modifier locus, Mom1 (modifier of Min-1), to a 4-cM region on mouse chromosome 4 containing a candidate gene Pla2g2a encoding a secretory phospholipase. Here, we report that a cosmid transgene overexpressing Pla2g2a caused a reduction in tumour multiplicity and size, comparable to that conferred by a single copy of the resistance allele of Mom1. These results offer strong evidence that this secretory phospholipase can provide active tumour resistance. The association of Pla2g2a with Mom1 thus withstands a strong functional test and is likely to represent the successful identification of a polymorphic quantitative trait locus in mammals.
携带相同癌症易感突变的个体可能会表现出非常不同的结果，从早期侵袭性癌症到无病生存。实验小鼠模型可以提供一个强大的工具，以识别环境和遗传背景中导致这种差异的因素。Min小鼠品系中，ApcMin突变破坏了人类家族性息肉病基因的小鼠同源物，会发展出肠道肿瘤，其肿瘤数量受到遗传背景的强烈影响。我们之前将一个强修饰基因座Mom1（Min-1的修饰基因）定位到小鼠4号染色体上一个4厘摩的区域，该区域包含一个编码分泌型磷脂酶的候选基因Pla2g2a。在此，我们报告一个过表达Pla2g2a的黏粒转基因导致肿瘤数量和大小减少，这与Mom1抗性等位基因单拷贝所产生的效果相当。这些结果提供了强有力的证据，表明这种分泌型磷脂酶可以提供有效的肿瘤抗性。因此，Pla2g2a与Mom1之间的关联经受住了严格的功能测试，并可能代表着在哺乳动物中成功鉴定出一个多态性数量性状基因座。
