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The Influence of Screening for Precancerous Lesions on Family-Based Genetic Association Tests: An Example of Colorectal Polyps and Cancer.

ABSTRACT: Unintended consequences of secondary prevention include potential introduction of bias into epidemiologic studies estimating genotype-disease associations. To better understand such bias, we simulated a family-based study of colorectal cancer (CRC), which can be prevented by resecting screen-detected polyps. We simulated genes related to CRC development through risk of polyps (G1), risk of CRC but not polyps (G2), and progression from polyp to CRC (G3). Then, we examined 4 analytical strategies for studying diseases subject to secondary prevention, comparing the following: 1) CRC cases with all controls, without adjusting for polyp history; 2) CRC cases with controls, adjusting for polyp history; 3) CRC cases with only polyp-free controls; and 4) cases with either CRC or polyps with controls having neither. Strategy 1 yielded estimates of association between CRC and each G that were not substantially biased. Strategies 2-4 yielded biased estimates varying in direction according to analysis strategy and gene type. Type I errors were correct, but strategy 1 provided greater power for estimating associations with G2 and G3. We also applied each strategy to case-control data from the Colon Cancer Family Registry (1997-2007). Generally, the best analytical option balancing bias and power is to compare all CRC cases with all controls, ignoring polyps.

SUBMITTER: Schmit SL

PROVIDER: S-EPMC4597802 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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The Influence of Screening for Precancerous Lesions on Family-Based Genetic Association Tests: An Example of Colorectal Polyps and Cancer.

Schmit Stephanie L SL Figueiredo Jane C JC Cortessis Victoria K VK Thomas Duncan C DC

American journal of epidemiology 20150824 8

Unintended consequences of secondary prevention include potential introduction of bias into epidemiologic studies estimating genotype-disease associations. To better understand such bias, we simulated a family-based study of colorectal cancer (CRC), which can be prevented by resecting screen-detected polyps. We simulated genes related to CRC development through risk of polyps (G1), risk of CRC but not polyps (G2), and progression from polyp to CRC (G3). Then, we examined 4 analytical strategies ...[more]

PMID: 26306664

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Project description:Little is known about the immunoediting process in precancerous lesions. We explored this aspect of benign colorectal adenomas with a descriptive analysis of the immune pathways and immune cells whose regulation is linked to the morphology and size of these lesions. Two series of polypoid and nonpolypoid colorectal adenomas were used in this study: 1) 84 samples (42 lesions, each with matched samples of normal mucosa) whose gene expression data were used to quantify the tumor morphology- and size-related dysregulation of immune pathways collected in the Molecular Signature Database, using Gene Set Enrichment Analysis; 2) 40 other lesions examined with immunohistochemistry to quantify the presence of immune cells in the stromal compartment. In the analysis of transcriptomic data, 429 immune pathways displayed significant differential regulation in neoplasms of different morphology and size. Most pathways were significantly upregulated or downregulated in polypoid lesions versus nonpolypoid lesions (regardless of size). Differential pathway regulation associated with lesion size was observed only in polypoid neoplasms. These findings were mirrored by tissue immunostaining with CD4, CD8, FOXP3, MHC-I, CD68, and CD163 antibodies: stromal immune cell counts (mainly T lymphocytes and macrophages) were significantly higher in polypoid lesions. Certain markers displayed significant size-related differences regardless of lesion morphology. Multivariate analysis of variance showed that the marker panel clearly discriminated between precancerous lesions of different morphologies and sizes. Statistical analysis of immunostained cell counts fully support the results of the transcriptomic data analysis: the density of infiltration of most immune cells in the stroma of polypoid precancerous lesions was significantly higher than that observed in nonpolypoid lesions. Large neoplasms also have more immune cells in their stroma than small lesions. Immunoediting in precancerous colorectal tumors may vary with lesion morphology and stage of development, and this variability could influence a given lesion's trajectory to cancer.

Project description:Epigenetic silencing of protein-encoding genes is common in early-stage colorectal tumorigenesis. Less is known about the methylation-mediated silencing of genes encoding microRNAs (miRNAs), which are also important epigenetic modulators of gene expression. Using quantitative PCR, we identified 56 miRNAs that were expressed in normal colorectal mucosa and in HT29 colorectal cancer cells treated with demethylating agents but not in untreated HT29 cells, suggesting that they probably undergo methylation-induced silencing during colorectal tumorigenesis. One of these, miR-195, had recently been reported to be underexpressed in colorectal cancers and to exert tumor-suppressor effects in colorectal cancer cells. We identified the transcription start site (TSS) for primary miRNA (pri-miR)-497/195, the primary precursor that yields miR-195 and another candidate on our list, miR-497, and a single CpG island upstream to the TSS, which controls expression of both miRNAs. Combined bisulfite restriction analysis and bisulfite genomic sequencing studies revealed monoallelic methylation of this island in normal colorectal mucosa (50/50 samples) and full methylation in most colorectal adenomas (38/50; 76%). The hypermethylated precancerous lesions displayed significantly downregulated expression of both miRNAs. Similar methylation patterns were observed at two known imprinted genes, MEG3 and GNAS-AS1, which encode several of the 56 miRNAs on our list. Imprinting at these loci was lost in over half the adenomas (62% at MEG3 and 52% at GNAS-AS1). Copy-number alterations at MEG3, GNAS-AS1 and pri-miR-497/195, which are frequent in colorectal cancers, were less common in adenomas and confined to tumors displaying differential methylation at the involved locus. Our data show that somatically acquired, epigenetic changes at monoallelically methylated regions encoding miRNAs are relatively frequent in sporadic colorectal adenomas and might contribute to the onset and progression of these tumors.

Dataset Information

The Influence of Screening for Precancerous Lesions on Family-Based Genetic Association Tests: An Example of Colorectal Polyps and Cancer.

Publications

The Influence of Screening for Precancerous Lesions on Family-Based Genetic Association Tests: An Example of Colorectal Polyps and Cancer.

Similar Datasets

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