Malignant Potential of Gastrointestinal Cancers Assessed by Structural Equation Modeling

<div><p>Background</p><p>Parameters reported in pathologic reviews have been failing to assess exactly the malignant potential of gastrointestinal cancers. We hypothesized that malignant potential could be defined by common latent variables (hypothesis I), but there are substantial differences in the associations between malignant potential and pathologic parameters according to the origin of gastrointestinal cancers (hypothesis II). We shed light on these issues by structural equation modeling.</p><p>Materials and Methods</p><p>We conducted a cross-sectional survey of 217 esophageal, 192 gastric, and 175 colorectal cancer patients who consecutively underwent curative surgery for their pathologic stage I cancers at Keiyukai Sapporo Hospital. Latent variables identified by factor analysis and seven conventional pathologic parameters were introduced in the structural equation modeling analysis.</p><p>Results</p><p>Because latent variables were disparate except for their number, 'three' in the examined gastrointestinal cancers, the first hypothesis was rejected. Because configural invariance across gastrointestinal cancers was not approved, the second hypothesis was verified. We could trace the three significant paths on the causal graph from latent variables to lymph node metastasis, which were mediated through depth, lymphatic invasion, and matrilysin expression in esophageal cancer, whereas only one significant path could be traced in both gastric and colorectal cancer. Two of the three latent variables were exogenous in esophageal cancer, whereas one factor was exogenous in the other gastrointestinal cancers. Cancer stemness promoted viability in esophageal cancer, but it was suppressed in others.</p><p>Conclusion</p><p>These results reflect the malignant potential of esophageal cancer is higher than that of the other gastrointestinal cancers. Such information might contribute to refining clinical treatments for gastrointestinal cancers.</p></div

The segregation pattern of rs76418789 in the pedigree.

<p>The results from PCR sequencing of rs76418789 were placed on each member in the pedigree. The arrowheads indicated the SNV portion. Red colored variants were derived from the mother’s risk allele, whereas green colored ones were derived from father’s reference allele. The pedigree comprised healthy parents (father is indicated as ‘1’ and mother as ‘2’), a healthy second son (4), and older (3) and younger sons (5) affected by Crohn’s disease. Age is indicated in years (y) in the right margin.</p

Malignant potential of each GI cancer type.

<p>Malignant potential of each GI cancer type.</p

Characteristics of the study population.

<p>Characteristics of the study population.</p

Case-control association study of susceptibility to Crohn’s disease.

<p>Abbreviations: HC, healthy control; CD, Crohn’s disease; NA, not available</p><p>Case-control association study of susceptibility to Crohn’s disease.</p

Low-Frequency <i>IL23R</i> Coding Variant Associated with Crohn’s Disease Susceptibility in Japanese Subjects Identified by Personal Genomics Analysis

<div><p>Background</p><p>The common disease-common variant hypothesis is insufficient to explain the complexities of Crohn’s disease (CD) genetics; therefore, rare variants are expected to be important in the disease. We explored rare variants associated with susceptibility to CD in Japanese individuals by personal genomic analysis.</p><p>Methods</p><p>Two-step analyses were performed. The first step was a trio analysis with whole-exome sequence (WES) analysis and the second was a follow-up case-control association study. The WES analysis pipeline comprised Burrows-Wheeler Aligner, Picard, Genome Analysis Toolkit, and SAMTOOLS. Single nucleotide variants (SNVs)/indels were annotated and filtered by using programs implemented in ANNOVAR in combination with identity-by-descent (IBD), subsequently were subjected to the linkage based, and <i>de novo</i> based strategies. Finally, we conducted an association study that included 176 unrelated subjects with CD and 358 healthy control subjects.</p><p>Results</p><p>In family members, 234,067–297,523 SNVs/indels were detected and they were educed to 106–146 by annotation based filtering. Fifty-four CD variants common to both individuals of the affected sib pair were identified. The linkage based strategy detected five candidate variants whereas the <i>de novo</i> based strategy identified no variants. Consequently, five candidates were analyzed in the case-control association study. CD showed a significant association with one variant in exon 4 of <i>IL23R</i>, G149R [rs76418789, <i>P</i> = 3.9E-5, odds ratio (OR) 0.21, 95% confidence interval (CI) 0.09–0.47 for the dominant model (AA + AG versus GG), and <i>P</i> = 7.3E-5, OR 0.21, 95% CI 0.10–0.48 for AG versus GG, and <i>P</i> = 7.2E-5, OR 0.23, 95% CI 0.10–0.50 for the allele model].</p><p>Conclusions</p><p>The present study, using personal genomics analysis of a small CD pedigree, is the first to show that the low-frequency non-synonymous variant of <i>IL23R</i>, rs76418789, protects against CD development in Japanese subjects.</p></div

SEM of esophageal cancer.

<p>Circles indicate unobserved latent variables, while rectangles represent observed variables. Yellow indicates a dependent endogenous variable and grey indicates an independent exogenous variable. Significant paths with their estimated parameter are shown by solid lines, while insignificant paths are shown by broken lines (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149327#pone.0149327.g002" target="_blank">Fig 2</a>). Rred arrows represent either a negative causal effect or measurement errors within the model. The blue triangle in the center suggests that the malignant potential includes three latent variables. Coefficient of determination is written as R². Abbreviations: v, vascular invasion; ly, lymphatic invasion; n, lymph node metastasis; hist, histological grade.</p

SEM of gastric cancer.

<p>Circles indicate unobserved latent variables, while rectangles represent observed variables. Yellow indicates a dependent endogenous variable and grey indicates an independent exogenous variable. Significant paths with their estimated parameter are shown by solid lines, while insignificant paths are shown by broken lines (Fig 2). Rred arrows represent either a negative causal effect or measurement errors within the model. The blue triangle in the center suggests that the malignant potential includes three latent variables. Coefficient of determination is written as R². Abbreviations: v, vascular invasion; ly, lymphatic invasion; n, lymph node metastasis; hist, histological grade.</p

The study pedigree.

<p>The pedigree comprised healthy parents (father is indicated as ‘1’ and mother as ‘2’), a healthy second son (4), and older (3) and younger sons (5) affected by Crohn’s disease. Age is indicated in years (y) in the right margin.</p

Workflow of whole-exome sequence.

<p>Orange rounded rectangles indicate unaffected members, while blue round rectangles indicate affected members. The pedigree numbers, 1, 2, 3, 5, 4, above the round rectangles indicate father, mother, the first, second, and third son, respectively. Numbers inside the rectangles indicate the number of variants. Dashed ellipsoids indicate variants from affected members whereas solid line ellipsoids indicate variants from unaffected members. See text for details. </p