Familial adenomatous polyposis (FAP) is an autosomal dominant condition that predisposes patients to colorectal cancer. FAP is the result of a loss of APC function due to germline pathogenic variants disrupting gene expression. Genotype-phenotype correlations are described for FAP. For example attenuated forms of the disease are associated with pathogenic variants at the 5’ and 3’ ends of APC whilst severe forms of the disease appear to be linked to variants occurring in the mutation cluster region (MCR) of the gene. Variants occurring in the MCR are phenotypically associated with hundreds to thousands of adenomas carpeting the colon and rectum and patients harbouring changes in this region have a high propensity to develop colorectal cancer. Not all patients who carry pathogenic variants in this region have severe disease which may be a result of environmental factors. Alternatively, phenotypic variation observed in these patients could be due to modifier genes that either promote or inhibit disease expression. Mouse models of FAP have provided several plausible candidate modifier genes, but very few of these have survived scrutiny. One such genetic modifier that appears to be associated with disease expression is CD36. We previously reported a weak association between a polymorphism in CD36 and a later age of disease onset on a relatively small FAP patient cohort. In the current study, we enlarged the FAP cohort. 395 patients all carrying pathogenic variants in APC were tested against three CD36 Single Nucleotide Polymorphisms (SNP)s (rs1049673, rs1761667 rs1984112), to determine if any of them were associated with differences in the age of disease expression. Overall, there appeared to be a statistically significant difference in the age of disease onset between carriers of the variant rs1984112 and wildtype. Furthermore, test equality of survivor functions for each SNP and mutation group suggested an interaction in the Log Rank, Wilcoxon, and Tarone-Ware methods for rs1049673, rs1761667, and rs1984112, thereby supporting the notion that CD36 modifies disease expression. This study supports and strengthens our previous findings concerning CD36 and an association with disease onset in FAP, AFAP and FAP-MCR affected individuals. Knowledge about the role CD36 in adenoma development may provide greater insight into the development of colorectal cancer.

中文翻译：

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CD36多态性与APC突变簇区域内致病变异患者的发病年龄

家族性腺瘤性息肉病（FAP）是常染色体显性疾病，易使患者罹患大肠癌。FAP是由于种系致病变异破坏基因表达而导致APC功能丧失的结果。描述了FAP的基因型与表型的相关性。例如，该疾病的减毒形式与APC的5'和3'端的致病变异有关，而该疾病的严重形式似乎与该基因的突变簇区域（MCR）中发生的变异有关。MCR中发生的变异与表型相关，覆盖了结肠和直肠的数百至数千个腺瘤，并且在该区域中有变化的患者极有可能发展为大肠癌。并非所有在该区域携带病原体的患者都患有严重的疾病，这可能是环境因素导致的。或者，在这些患者中观察到的表型变异可能是由于促进或抑制疾病表达的修饰基因所致。FAP的小鼠模型提供了一些可能的候选修饰基因，但其中很少有幸存下来的。似乎与疾病表达有关的一种此类遗传修饰物是CD36。我们以前曾报道过，相对较小的FAP患者队列中CD36的多态性与疾病的发病年龄之间存在弱关联。在当前的研究中，我们扩大了FAP队列。对395名均在APC中携带致病性变体的患者进行了3种CD36单核苷酸多态性（SNP）检测（rs1049673，rs1761667 rs1984112），确定它们是否与疾病表达年龄的差异有关。总体而言，变体rs1984112的携带者与野生型之间的发病年龄似乎在统计学上有显着差异。此外，测试每个SNP和突变组的幸存者功能是否相等，提示rs1049673，rs1761667和rs1984112在Log Rank，Wilcoxon和Tarone-Ware方法中存在相互作用，从而支持CD36修饰疾病表达的观点。这项研究支持并加强了我们先前有关CD36的发现，以及与FAP，AFAP和FAP-MCR感染个体中疾病发作的关系。关于CD36在腺瘤发展中的作用的知识可能会为结直肠癌的发展提供更多的见识。