CD36 – a plausible modifier of disease phenotype in familial adenomatous polyposis

Abstract

BackgroundFamilial adenomatous polyposis (FAP) is a well characterised genetic predisposition to early onset colorectal cancer (CRC) that is characterised by polyposis of the colon and rectum. Animal models have consistently suggested the role of modifier genes in determining disease phenotype, yet none have been substantiated in the human population. The mouse homologue of cluster of differentiation 36 (CD36) has been proposed as a modifier of disease in the MIN mouse model of FAP.MethodsThree single nucleotide polymorphisms (SNPs); rs1049673, rs1761667 and rs1984112 in CD36, have been investigated in 275 FAP patients to determine if they were associated with age of polyposis or risk of developing disease.ResultsThe results revealed a substantially lower age of polyposis diagnosis for patients belonging to the severe FAP group (harbouring adenomatous polyposis coli (APC) variants in the mutation cluster region (MCR)) and high age for patients in the attenuated familial adenomatous polyposis (AFAP) group for SNPs rs1761667 and rs1984112.ConclusionsThis study provides evidence for patients belonging to the MCR and AFAP groups harbouring specific genotypes for SNPs in CD36 to initiate screening/treatment for FAP at much earlier (MCR) and much later (AFAP) ages than the norm in today’s clinical practice. The findings need to be verified in an independent FAP patient cohort.

CD36 polymorphisms and the age of disease onset in patients with pathogenic variants within the mutation cluster region of APC

“…The number of patients in the study by Holmes et al [25] was too small to interrogate further the relationship between rs1984112 and patients diagnosed with AFAP, FAP, and MCR-FAP. In the current study, it became evident that rs1984112 did not influence the age of disease diagnosis in patients deemed to be AFAP or "standard" FAP.…”

“…A relatively recent modifier of Fap, known as Mom-5, was reported in 2015 [24], which seemed to affect adenoma multiplicity. We have previously reported on the role of CD36 in a relatively small group of FAP patients, which revealed a potential association of the wildtype allele of rs1984112 with an earlier age of disease onset compared to heterozygous and homozygous variant carriers [25]. The link between colorectal cancer risk and CD36 has been explored in that variants in rs1984112 have been associated with hypercholesterolemia [34], a known risk factor colorectal cancer [35].…”

“…Recently, the Mom5 locus, which encompassed Cd36, was identified as a potential modifier of disease expression in a mouse model of FAP [24]. We have previously reported tentative evidence that polymorphisms in CD36 influence the age at which polyposis expression occurs [25], based on a relatively small population of patients with confirmed APC pathogenic variants.…”

Advances in Identification of Susceptibility Gene Defects of Hereditary Colorectal Cancer

“…CD36 encodes a scavenger receptor involved in fatty acid processing in the intestine. A recent study found a substantially lower age of polyposis diagnosis for patients in the severe FAP group and higher age for patients in the attenuated FAP group with CD36 rs1761667 and rs1984112 SNPs, respectively 106. However, whether different CD36 mutations have distinct consequences on FAP need to be further investigated.…”

“…In addition, some rare cases of dominant polyposis have also been associated with genetic mutations; for example, mutations in SMAD4 and BMPR1A were detected in juvenile polyposis patients 106-108. Moreover, mutations in LKB1/SKT11 were associated with Peutz-Jeghers syndrome; GREM1 mutations were detected in mixed-type (serrated type and juvenile type) polyposis patients 109; and Cowden/PTEN hamartoma syndrome was associated with mutations at the G129E site of PTEN 110.…”