Department of Predictive and Preventive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Via Amadeo 42, Milan, 20133, Italy.
BMC Genomics. 2013 Mar 6;14:152. doi: 10.1186/1471-2164-14-152.
In an intercross between the SWR/J and BALB/c mouse strains, the pulmonary adenoma progression 1 (Papg1) locus on chromosome 4 modulates lung tumor size, one of several measures of lung tumor progression. This locus has not been fully characterized and defined in its extent and genetic content. Fine mapping of this and other loci affecting lung tumor phenotype is possible using recombinant inbred strains.
A population of 376 mice, obtained by crossing mice of the SWR/J strain with CXBN recombinant inbred mice, was treated with a single dose of urethane and assayed for multiplicity of large lung tumors (N2lung). A genome-wide analysis comparing N2lung with 6364 autosomal SNPs revealed multiple peaks of association. The Papg1 locus had two peaks, at rs3654162 (70.574 Mb, -logP=2.8) and rs6209043 (86.606 Mb, -logP=2.7), joined by an interval of weaker statistical association; these data confirm the presence of Papg1 on chromosome 4 and reduce the mapping region to two stretches of ~6.8 and ~4.2 Mb, in the proximal and distal peaks, respectively. The distal peak included Cdkn2a, a gene already proposed as being involved in Papg1 function. Other loci possibly modulating N2lung were detected on chromosomes 5, 8, 9, 11, 15, and 19, but analysis for linkage disequilibrium of these putative loci with Papg1 locus suggested that only those on chromosomes 11 and 15 were true positives.
These findings suggest that Papg1 consists, most likely, of two distinct, nearby loci, and point to putative additional loci on chromosomes 11 and 15 modulating lung tumor size. Within Papg1, Cdkn2a appears to be a strong candidate gene while additional Papg1 genes await to be identified. Greater knowledge of the genetic and biochemical mechanisms underlying the germ-line modulation of lung tumor size in mice is relevant to other species, including humans, in that it may help identify new therapeutic targets in the fight against tumor progression.
在 SWR/J 和 BALB/c 两种小鼠的杂交实验中，4 号染色体上的肺腺癌进展 1（Papg1）基因座可调节肺肿瘤的大小，这是肺肿瘤进展的几个衡量指标之一。该基因座尚未在其范围和遗传内容上得到充分描述和定义。使用重组近交系，可以对影响肺肿瘤表型的这个基因座和其他基因座进行精细定位。
通过将 SWR/J 系的小鼠与 CXBN 重组近交系小鼠杂交，获得了 376 只小鼠，对这些小鼠进行单次尿嘧啶处理并检测大肺肿瘤（N2lung）的多发性。对 N2lung 与 6364 个常染色体 SNP 进行全基因组分析，发现了多个关联峰。Papg1 基因座有两个峰，位于 rs3654162（70.574Mb，-logP=2.8）和 rs6209043（86.606Mb，-logP=2.7），中间间隔着一个关联较弱的区域；这些数据证实了 Papg1 基因座位于 4 号染色体上，并将图谱区域缩小到近端和远端峰的两个大约 6.8 和 4.2Mb 的延伸区域。远端峰包含 Cdkn2a 基因，该基因已被提议参与 Papg1 功能。还在 5、8、9、11、15 和 19 号染色体上检测到了其他可能调节 N2lung 的基因座，但对这些假定基因座与 Papg1 基因座之间的连锁不平衡分析表明，只有 11 号和 15 号染色体上的基因座是真正的阳性。
这些发现表明，Papg1 很可能由两个不同的、附近的基因座组成，并指出了染色体 11 和 15 上可能调节肺肿瘤大小的其他基因座。在 Papg1 内部，Cdkn2a 似乎是一个强有力的候选基因，而其他 Papg1 基因有待进一步鉴定。进一步了解小鼠中肺肿瘤大小的种系调节的遗传和生化机制，与其他物种（包括人类）相关，因为它可能有助于确定肿瘤进展治疗的新靶点。
