Obata M, Nishimori H, Ogawa K, Lee G H
Department of Pathology, Asahikawa Medical College, Nishikagura, Japan.
Oncogene. 1996 Oct 17;13(8):1599-604.
The A/J mouse strain is 14 times more susceptible to urethane-induction of lung carcinogenesis than the BALB/cByJ strain (BALB). The relative resistance of BALB is dominant over the high sensitivity of A/J, since (BALBxA/J)F1 mice are phenotypically similar to the parental BALB mice. BALB mice must thus possess modifier genes suppressing phenotypic expression of the Pas (Pulmonary adenoma susceptibility) genes, which are known to be dominant genetic determinants for lung carcinogenesis in A/J mice. In order to genetically dissect the dominant resistance of the BALB mouse, we performed a linkage analysis to chromosomally map modifier genes by using 130 (A/JxBALB)F1xA/J backcross mice. Each backcross mouse was injected i.p. with urethane (1 mg/g bw) at 6 weeks of age and lung tumors were enumerated after 120 days. When the backcross mice were genotyped at multiple simple sequence repeat marker loci distributed on all the chromosomes, a significant linkage between the presence of a BALB allele and resistance to lung tumor induction was found on distal chromosome 18 (maximum LOD = 12.2). Thus, distal chromosome 18 of the BALB mouse contains a modifier gene for lung carcinogenesis: The locus, designated Par2 (Pulmonary adenoma resistance), accounted for 38% of the phenotypic variance in the backcross population, indicating a major role in protection against lung tumor development.
A/J小鼠品系对氨基甲酸乙酯诱导的肺癌发生的易感性比BALB/cByJ品系（BALB）高14倍。BALB的相对抗性对A/J的高敏感性呈显性，因为（BALB×A/J）F1小鼠的表型与亲代BALB小鼠相似。因此，BALB小鼠必定拥有抑制Pas（肺腺瘤易感性）基因表型表达的修饰基因，已知Pas基因是A/J小鼠肺癌发生的显性遗传决定因素。为了从遗传学角度剖析BALB小鼠的显性抗性，我们利用130只（A/J×BALB）F1×A/J回交小鼠进行连锁分析，以在染色体上定位修饰基因。每只回交小鼠在6周龄时经腹腔注射氨基甲酸乙酯（1毫克/克体重），120天后统计肺部肿瘤数量。当对分布于所有染色体上的多个简单序列重复标记位点进行回交小鼠基因分型时，在18号染色体远端发现BALB等位基因的存在与对肺部肿瘤诱导的抗性之间存在显著连锁（最大对数优势计分=12.2）。因此，BALB小鼠的18号染色体远端含有一个肺癌发生修饰基因：该位点命名为Par2（肺腺瘤抗性），在回交群体的表型变异中占38%，表明其在预防肺部肿瘤发生中起主要作用。
