Galician Public Foundation of Genomic Medicine (FPGMX), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Genomics Medicine Group, Hospital Clínico, Santiago de Compostela, University of Santiago de Compostela, Galicia, Spain.
PLoS One. 2010 Sep 9;5(9):e12673. doi: 10.1371/journal.pone.0012673.
Colorectal cancer (CRC) is considered a complex disease, and thus the majority of the genetic susceptibility is thought to lie in the form of low-penetrance variants following a polygenic model of inheritance. Candidate-gene studies have so far been one of the basic approaches taken to identify these susceptibility variants. The consistent involvement of some signaling routes in carcinogenesis provided support for pathway-based studies as a natural strategy to select genes that could potentially harbour new susceptibility loci.
METHODOLOGY/PRINCIPAL FINDINGS: We selected two main carcinogenesis-related pathways: Wnt and BMP, in order to screen the implicated genes for new risk variants. We then conducted a case-control association study in 933 CRC cases and 969 controls based on coding and regulatory SNPs. We also included rs4444235 and rs9929218, which did not fulfill our selection criteria but belonged to two genes in the BMP pathway and had consistently been linked to CRC in previous studies. Neither allelic, nor genotypic or haplotypic analyses showed any signs of association between the 37 screened variants and CRC risk. Adjustments for sex and age, and stratified analysis between sporadic and control groups did not yield any positive results either.
CONCLUSIONS/SIGNIFICANCE: Despite the relevance of both pathways in the pathogenesis of the disease, and the fact that this is indeed the first study that considers these pathways as a candidate-gene selection approach, our study does not present any evidence of the presence of low-penetrance variants for the selected markers in any of the considered genes in our cohort.
结直肠癌（CRC）被认为是一种复杂的疾病，因此大多数遗传易感性被认为是以多基因遗传模型为形式的低外显率变体。候选基因研究一直是识别这些易感性变体的基本方法之一。一些信号通路在癌变中的一致参与为基于通路的研究提供了支持，这是一种选择可能潜在携带新易感性位点的基因的自然策略。
方法/主要发现：我们选择了两个主要的致癌相关通路：Wnt 和 BMP，以筛选涉及的基因中的新风险变体。然后，我们基于编码和调节 SNP 在 933 例 CRC 病例和 969 例对照中进行了病例对照关联研究。我们还包括 rs4444235 和 rs9929218，它们不符合我们的选择标准，但属于 BMP 通路中的两个基因，并且在以前的研究中一直与 CRC 相关。在筛选的 37 个变体与 CRC 风险之间，既没有等位基因、基因型或单倍型分析显示出任何关联的迹象。对性别和年龄进行调整，以及对散发性和对照组进行分层分析，也没有产生任何阳性结果。
结论/意义：尽管这两个通路在疾病的发病机制中都很重要，而且这确实是第一个将这些通路作为候选基因选择方法的研究，但我们的研究并没有在我们队列中的任何考虑基因中为所选标记的低外显率变体提供任何存在证据。
