Dataset Information

APC Promoter Deletion in Classic Familial Adenomatous Polyposis

ABSTRACT:

The ~80% of individuals with classic familial adenomatous polyposis (FAP) have detectable mutations in the coding sequence of the adenomatous polyposis coli (APC) gene. To investigate the 20% of families without detectable causative mutations, we used exome sequencing and second-generation sequencing of the APC locus including non-coding regions. We identified a novel ~11kb deletion 44kb upstream of APC that was present only in affected individuals of three kindreds. SNP analysis showed that this ~11kb deletion was accompanied by silencing of one of the APC alleles in blood-derived RNA of affected individuals.

PROVIDER: phs000904 | dbGaP |

SECONDARY ACCESSION(S): PRJNA282060PRJNA282061

REPOSITORIES: dbGaP

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Dataset's files

Source:

			Action	DRS
	GapExchange_phs000904.v1.p1.xml	Xml
	dbGaPEx2.1.5.xsd	Other
	Study_Report.phs000904.GastrointestinalNeoplasia.v1.p1.MULTI.pdf	Pdf
	manifest_phs000904.GastrointestinalNeoplasia.v1.p1.c1.HMB-IRB.pdf	Pdf
	datadict_v2.xsl	Other

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Project description:Mutation of the adenomatous polyposis coli (APC gene), an early event in the adenoma-carcinoma sequence, is present in 70-80% of sporadic human colorectal adenomas and carcinomas. To test the hypothesis that mutation of the APC gene alters microbial interactions with host intestinal mucosa prior to the development of polyposis, culture-independent methods (targeted qPCR assays and Illumina sequencing of the 16S rRNA gene V1V2 hypervariable region) were used to compare the intestinal microbial composition of 30 six-week old C57BL/6 APCMin/+ and 30 congenic wild type (WT) mice. The results demonstrate that similar to 12-14 week old APCMin/+ mice with intestinal neoplasia, 6 week old APCMin/+ mice with no detectable neoplasia, exhibit an increased relative abundance of Bacteroidetes spp in the colon. Parallel mouse RNA sequence analysis, conducted on a subset of proximal colonic RNA samples (6 APCMin/+, 6 WT) revealed 130 differentially expressed genes (DEGs, fold change ? 2, FDR <0.05). Hierarchical clustering of the DEGs was carried out by using 1-r dissimilarity measurement, where r stands for the Pearson correlation, and Ward minimum variance linkage, in order to reduce the number of input variables. When the cluster centroids (medians) were included along with APC genotype as input variables, analysis of variance and covariance (ANCOVA) with stepwise variable selection, selected two of seven mouse gene clusters, in addition to APC genotype, as significantly associated (p = 0.011 and p = 0.004) with the increased relative abundance of Bacteroidetes spp. One of the two clusters includes several downregulated genes encoding immunoglobulin variable regions and non-protein coding RNAs. These results support the concept that mutation of the APC gene alters colonic-microbial interactions prior to polyposis. It remains to be determined whether interventions directed at ameliorating dysbiosis in APCMin/+mice, such as through probiotics, prebiotics or antibiotics, could reduce tumor formation. Comparing the differential gene expressions in proximal colonic mucosal samples from 6 six-week-old female Apc Min/+ and 6 six-week-old female WT mice

Dataset Information

APC Promoter Deletion in Classic Familial Adenomatous Polyposis

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