Dataset Information

Genome-Wide Association Study of Metachronous Colorectal Adenoma Risk among Participants in the Selenium Trial.

ABSTRACT: Genetic variants related to colorectal adenoma may help identify those who are at highest risk of colorectal cancer development or illuminate potential chemopreventive strategies. The purpose of this genome-wide association study was to identify genetic variants that are associated with risk of developing a metachronous colorectal adenoma among 1,215 study participants of European descent from the Selenium Trial. Associations of variants were assessed with logistic regression analyses and validated in an independent case-control study population of 1,491 participants from the Colorectal Cancer Study of Austria (CORSA). No statistically significant genome-wide associations between any variant and metachronous adenoma were identified after correction for multiple comparisons. However, an intron variant of FAT3 gene, rs61901554, showed a suggestive association (P = 1.10 × 10^-6) and was associated with advanced adenomas in CORSA (P = 0.04). Two intronic variants, rs12728998 and rs6699944 in NLRP3 were also observed to have suggestive associations with metachronous lesions (P = 2.00 × 10^-6) in the Selenium Trial and were associated with advanced adenoma in CORSA (P = 0.03). Our results provide new areas of investigation for the genetic basis of the development of metachronous colorectal adenoma and support a role for FAT3 involvement in the Wnt/β-catenin pathway leading to colorectal neoplasia.Trial Registration number: NCT00078897 (ClinicalTrials.gov).

SUBMITTER: Trejo MJ

PROVIDER: S-EPMC10120393 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Genome-Wide Association Study of Metachronous Colorectal Adenoma Risk among Participants in the Selenium Trial.

Trejo Mario Jesus MJ Batai Ken K Chen Yuliang Y Brezina Stefanie S Chow H-H Sherry HS Ellis Nathan N Lance Peter P Hsu Chiu-Hsieh CH Pogreba-Brown Kristen K Bishop Maria M Gsur Andrea A Jacobs Elizabeth T ET

Nutrition and cancer 20220709 1

Genetic variants related to colorectal adenoma may help identify those who are at highest risk of colorectal cancer development or illuminate potential chemopreventive strategies. The purpose of this genome-wide association study was to identify genetic variants that are associated with risk of developing a metachronous colorectal adenoma among 1,215 study participants of European descent from the Selenium Trial. Associations of variants were assessed with logistic regression analyses and valida ...[more]

PMID: 35815403

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Project description:Dietary selenium (Se) intake is essential for synthesizing selenoproteins that are important in countering oxidative and inflammatory processes linked to colorectal carcinogenesis. However, there is limited knowledge on the selenoprotein expression in colorectal adenoma (CRA) and colorectal cancer (CRC) patients, or the interaction with Se status levels. We studied the expression of seventeen Se pathway genes (including fifteen of the twenty-five human selenoproteins) in RNA extracted from disease-normal colorectal tissue pairs, in the discovery phase of sixty-two CRA/CRC patients from Ireland and a validation cohort of a hundred and five CRC patients from the Czech Republic. Differences in transcript levels between the disease and paired control mucosa were assessed by the Mann-Whitney U-test. GPX2 and TXNRD3 showed a higher expression and GPX3, SELENOP, SELENOS, and SEPHS2 exhibited a lower expression in the disease tissue from adenomas and both cancer groups (p-values from 0.023 to <0.001). In the Czech cohort, up-regulation of GPX1, SELENOH, and SOD2 and down-regulation of SELENBP1, SELENON, and SELENOK (p-values 0.036 to <0.001) was also observed. We further examined the correlation of gene expression with serum Se status (assessed by Se and selenoprotein P, SELENOP) in the Irish patients. While there were no significant correlations with both Se status markers, SELENOF, SELENOK, and TXNRD1 tumor tissue expression positively correlated with Se, while TXNRD2 and TXNRD3 negatively correlated with SELENOP. In an analysis restricted to the larger Czech CRC patient cohort, Cox regression showed no major association of transcript levels with patient survival, except for an association of higher SELENOF gene expression with both a lower disease-free and overall survival. Several selenoproteins were differentially expressed in the disease tissue compared to the normal tissue of both CRA and CRC patients. Altered selenoprotein expression may serve as a marker of functional Se status and colorectal adenoma to cancer progression.

Project description:Background: Sessile serrated adenomas are important precursors to colorectal cancers and account for 30% of colorectal cancers. The United States Multi-Society Task Force recommends that patients with sessile serrated adenomas undergo surveillance similar to tubular adenomas. However, the risk of metachronous neoplasia when the high-risk adenoma co-exists with sessile serrated adenomas is poorly defined. Objective: To examine the risk of metachronous neoplasia in the presence of high-risk adenoma and synchronous sessile serrated adenomas compared with isolated high-risk adenoma. Data sources: PubMed, Embase, Scopus, Cochrane Library. Study selection: A literature search for studies evaluating the risk of metachronous neoplasia in patients with high-risk adenoma alone and those with synchronous high-risk adenoma and sessile serrated adenomas during surveillance colonoscopy was conducted on online databases. Main outcome measures: The primary outcome of interest was the presence of metachronous neoplasia. Results: Of the 1164 records reviewed, six (four retrospective and two prospective) studies met inclusion criteria with 2490 patients (1607 males, mean age 59.98 ± 3.23 years). Average follow-up was 47.5 ± 12.5 months. There were 2068 patients with high-risk adenoma on index colonoscopy and 422 patients with high-risk adenoma and synchronous sessile serrated adenomas. Pooled estimates showed a significantly elevated risk for metachronous neoplasia in patients with high-risk adenoma and synchronous sessile serrated adenomas (pooled odds ratio 2.21; 95% confidence intervals 1.65-2.96; p < 0.01). There was low heterogeneity (I2 = 11%) among the studies. Sensitivity analysis of the prospective studies alone also showed elevated risk of metachronous neoplasm (pooled odds ratio 2.56; 95%, confidence intervals 1.05-6.23; p = 0.04). Limitations: Inclusion of a small number of retrospective studies. Conclusions: The presence of high-risk adenomas and synchronous sessile serrated adenomas is associated with an increased risk of metachronous neoplasia. Therefore, shorter surveillance intervals may be considered in patients with high-risk adenoma and synchronous sessile serrated adenomas compared to those with high-risk adenoma alone.

Dataset Information

Genome-Wide Association Study of Metachronous Colorectal Adenoma Risk among Participants in the Selenium Trial.

Publications

Genome-Wide Association Study of Metachronous Colorectal Adenoma Risk among Participants in the Selenium Trial.

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