Dataset Information

Tumor markers and rectal cancer: support for an inflammation-related pathway.

ABSTRACT: Inflammation may be a key element in the etiology of colorectal cancer. In our study, we examine associations between factors related to inflammation and specific rectal cancer mutations. A population-based study of 750 rectal cancer cases with interview and tumor DNA were compared to 1,205 population-based controls. Study participants were from Utah and the Northern California Kaiser Permanente Medical Care Program. Tumor DNA was analyzed for TP53 and KRAS2 mutations and CpG Island methylator phenotype. We assessed how these tumor markers were associated with use of anti-inflammatory drugs, polymorphisms in the IL6 genes (rs1800795 and rs1800796) and dietary antioxidants. Ibuprofen-type drugs, IL6 polymorphisms (rs1800796) and dietary alpha-tocopherol and lycopene significantly altered likelihood of having a TP53 mutation. This was especially true for TP53 transversion mutations and dietary antioxidants (OR for beta-carotene 0.51 95% CI 0.27, 0.97, p trend 0.03; alpha-tocopherol 0.41 95% CI 0.20, 0.84, p trend 0.02) Beta-carotene and ibuprofen significantly altered risk of KRAS2 tumors. The associations between lutein and tocopherol and TP53 and KRAS2 mutations were modified by IL6 genotype. These results suggest that inflammation-related factors may have unique associations with various rectal tumor markers. Many factors involved in an inflammation-related pathway were associated with TP53 mutations and some dietary factors appeared to be modified by IL6 genotype.

SUBMITTER: Slattery ML

PROVIDER: S-EPMC2768342 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Tumor markers and rectal cancer: support for an inflammation-related pathway.

Slattery Martha L ML Wolff Roger K RK Herrick Jennifer J Caan Bette J BJ Samowitz Wade W

International journal of cancer 20091001 7

Inflammation may be a key element in the etiology of colorectal cancer. In our study, we examine associations between factors related to inflammation and specific rectal cancer mutations. A population-based study of 750 rectal cancer cases with interview and tumor DNA were compared to 1,205 population-based controls. Study participants were from Utah and the Northern California Kaiser Permanente Medical Care Program. Tumor DNA was analyzed for TP53 and KRAS2 mutations and CpG Island methylator p ...[more]

PMID: 19452524

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Project description:Background:Cancer associated fibroblasts are activated in the tumor microenvironment and contribute to tumor progression, angiogenesis, extracellular matrix remodeling, and inflammation. Methods:To identify proteins characteristic for fibroblasts in colorectal cancer we used liquid chromatography-tandem mass spectrometry to derive protein abundance from whole-tissue homogenates of human colorectal cancer/normal mucosa pairs. Alterations of protein levels were determined by two-sided t test with greater than threefold difference and an FDR of < 0.05. Public available datasets were used to predict proteins of stromal origin and link protein with mRNA regulation. Immunohistochemistry confirmed the localization of selected proteins. Results:We identified a set of 24 proteins associated with inflammation, matrix organization, TGF? receptor signaling and angiogenesis mainly originating from the stroma. Most prominent were increased abundance of SerpinB5 in the parenchyme and latent transforming growth factor ?-binding protein, thrombospondin-B2, and secreted protein acidic-and-cysteine-rich in the stroma. Extracellular matrix remodeling involved collagens type VIII, XII, XIV, and VI as well as lysyl-oxidase-2. In silico analysis of mRNA levels demonstrated altered expression in the tumor and the adjacent normal tissue as compared to mucosa of healthy individuals indicating that inflammatory activation affected the surrounding tissue. Immunohistochemistry of 26 tumor specimen confirmed upregulation of SerpinB5, thrombospondin B2 and secreted protein acidic-and-cysteine-rich. Conclusions:This study demonstrates the feasibility of detecting tumor- and compartment-specific protein-signatures that are functionally meaningful by proteomic profiling of whole-tissue extracts together with mining of RNA expression datasets. The results provide the basis for further exploration of inflammation-related stromal markers in larger patient cohorts and experimental models.

Project description:Colorectal cancer arises in part from the cumulative effects of multiple gene lesions. Recent studies in selected cancer types have revealed significant intra-tumor genetic heterogeneity and highlighted its potential role in disease progression and resistance to therapy. We hypothesized the existence of significant intra-tumor genetic heterogeneity in rectal cancers involving variations in localized somatic mutations and copy number abnormalities. Two or three spatially disparate regions from each of six rectal tumors were dissected and subjected to the next-generation whole-exome DNA sequencing, Oncoscan SNP arrays, and targeted confirmatory sequencing and analysis. The resulting data were integrated to define subclones using SciClone. Mutant-allele tumor heterogeneity (MATH) scores, mutant allele frequency correlation, and mutation percent concordance were calculated, and copy number analysis including measurement of correlation between samples was performed. Somatic mutations profiles in individual cancers were similar to prior studies, with some variants found in previously reported significantly mutated genes and many patient-specific mutations in each tumor. Significant intra-tumor heterogeneity was identified in the spatially disparate regions of individual cancers. All tumors had some heterogeneity but the degree of heterogeneity was quite variable in the samples studied. We found that 67-97% of exonic somatic mutations were shared among all regions of an individual's tumor. The SciClone computational method identified 2-8 shared and unshared subclones in the spatially disparate areas in each tumor. MATH scores ranged from 7 to 41. Allele frequency correlation scores ranged from R(2)=0.69-0.96. Measurements of correlation between samples for copy number changes varied from R(2)=0.74-0.93. All tumors had some heterogeneity, but the degree was highly variable in the samples studied. The occurrence of significant intra-tumor heterogeneity may allow selected tumors to have a genetic reservoir to draw from in their evolutionary response to therapy and other challenges.

Dataset Information

Tumor markers and rectal cancer: support for an inflammation-related pathway.

Publications

Tumor markers and rectal cancer: support for an inflammation-related pathway.

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