Common Genetic Variants in Wnt Signaling Pathway Genes as Potential Prognostic Biomarkers for Colorectal Cancer

<div><p>Compelling evidence has implicated the Wnt signaling pathway in the pathogenesis of colorectal cancer. We assessed the use of tag single nucleotide polymorphisms (tSNPs) in <em>adenomatous polyposis coli</em> (<em>APC</em>)/<em>β-catenin</em> (<em>CTNNB1</em>) genes to predict outcomes in patients with colorectal cancer. We selected and genotyped 10 tSNP to predict common variants across entire <em>APC</em> and <em>CTNNB1</em> genes in 282 colorectal cancer patients. The associations of these tSNPs with distant metastasis-free survival and overall survival were evaluated by Kaplan-Meier analysis, Cox regression model, and survival tree analysis. The 5-year overall survival rate was 68.3%. Survival tree analysis identified a higher-order genetic interaction profile consisting of the <em>APC</em> rs565453, <em>CTNNB1</em> 2293303, and <em>APC</em> rs1816769 that was significantly associated with overall survival. The 5-year survival overall rates were 89.2%, 66.1%, and 58.8% for the low-, medium-, and high-risk genetic profiles, respectively (log-rank <em>P</em> = 0.001). After adjusting for possible confounders, including age, gender, carcinoembryonic antigen levels, tumor differentiation, stage, lymphovascular invasion, perineural invasion, and lymph node involvement, the genetic interaction profile remained significant. None of the studied SNPs were individually associated with distant metastasis-free survival and overall survival. Our results suggest that the genetic interaction profile among Wnt pathway SNPs might potentially increase the prognostic value in outcome prediction for colorectal cancer.</p> </div

Cox proportional hazards analysis of factors associated with overall survival.

<p>Abbreviations: CEA, carcinoembryonic antigen; HR, hazard ratio; CI, confidence interval.</p>*<p>Age, gender, CEA levels, tumor differentiation, stage, lymphovascular invasion, perineural invasion, lymph node involvement, and genetic risk classification by Wnt pathway gene polymorphisms were included in the multivariate analysis.</p><p><i>P</i><0.05 are in boldface.</p

Potential higher order SNP-SNP interactions among Wnt pathway gene polymorphisms.

<p>(A) Survival tree analysis identifies the interactions among the three polymorphisms. (B) Kaplan-Meier curves of overall survival based on the survival tree analysis. Numbers in parentheses indicate the number of patients.</p

Demographic and clinical characteristics of colorectal cancer patients.

<p>Abbreviations: CEA, carcinoembryonic antigen; IQR, interquartile range.</p>*<p>Column subtotals do not sum to n of patients and n of events due to missing data.</p>†<p><i>P</i> values were calculated using the log-rank test.</p>‡<p>According to the American Joint Committee on Cancer - Cancer Staging Manual (version 6.0).</p><p><i>P</i><0.05 are in boldface.</p

Bioactive 6<i>S</i>‑Styryllactone Constituents of <i>Polyalthia parviflora</i>

Parvistones A–E (<b>1</b>–<b>5</b>), five new styryllactones possessing a rare α,β-lactone moiety and a 6<i>S</i> configuration, were isolated from a methanolic extract of <i>Polyalthia parviflora</i> leaves. The structures and the absolute configuration of the isolates were elucidated using NMR spectroscopy, specific rotation, circular dichroism, and X-ray single-crystal analysis. Compounds <b>8</b>, <b>9</b>, <b>11</b>, and <b>12</b> were isolated for the first time. The results were supported by comparing the data measured to those of 6<i>R</i>-styryllactones. Moreover, a plausible biogenetic pathway of the isolated compounds was proposed. The structure–activity relationship of the compounds in an in vitro anti-inflammatory assay revealed the 6<i>S</i>-styryllactones to be more potent than the 6<i>R</i> derivatives. However, the effect was opposite regarding their cytotoxic activity. In addition, 6<i>S</i>-styrylpyrones isolated showed more potent anti-inflammatory and cytotoxic activity when compared to the 1<i>S</i>-phenylpyranopyrones obtained

Bioactive 6<i>S</i>‑Styryllactone Constituents of <i>Polyalthia parviflora</i>

Parvistones A–E (<b>1</b>–<b>5</b>), five new styryllactones possessing a rare α,β-lactone moiety and a 6<i>S</i> configuration, were isolated from a methanolic extract of <i>Polyalthia parviflora</i> leaves. The structures and the absolute configuration of the isolates were elucidated using NMR spectroscopy, specific rotation, circular dichroism, and X-ray single-crystal analysis. Compounds <b>8</b>, <b>9</b>, <b>11</b>, and <b>12</b> were isolated for the first time. The results were supported by comparing the data measured to those of 6<i>R</i>-styryllactones. Moreover, a plausible biogenetic pathway of the isolated compounds was proposed. The structure–activity relationship of the compounds in an in vitro anti-inflammatory assay revealed the 6<i>S</i>-styryllactones to be more potent than the 6<i>R</i> derivatives. However, the effect was opposite regarding their cytotoxic activity. In addition, 6<i>S</i>-styrylpyrones isolated showed more potent anti-inflammatory and cytotoxic activity when compared to the 1<i>S</i>-phenylpyranopyrones obtained