Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers

Okugawa, Yoshinaga; Grady, William M.; Goel, Ajay

doi:10.1053/j.gastro.2015.07.011

Cited by 613 publications

(529 citation statements)

References 339 publications

(241 reference statements)

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“…1 The carcinogenesis of colorectum is driven by genetic and epigenetic alterations and also closely regulated by tumour-host interactions. 2,3 Accumulating evidence has revealed immune microenvironment could help tumor cells to evade immune destruction by the infiltrating immune cells. 4 Immunotherapy, especially checkpoint antibodies targeting the PDCD1 (programmed cell death 1, PD-1) and B7-H1 (programmed death-ligand 1 (PD-L1)) protein, has been emerged as a promising strategy to treat a number of cancer types.…”

Section: Introductionmentioning

confidence: 99%

The comprehensive molecular landscape of the immunologic co-stimulator B7 and TNFR ligand receptor families in colorectal cancer: immunotherapeutic implications with microsatellite instability

Tang

Liu

et al. 2018

OncoImmunology

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Immunotherapy is reportedly effective in a subset of colorectal cancers (CRCs) with high microsatellite instability (MSI-H). Exploring the expression patterns and clinical values of immunologic molecules is critical in defining the specific responsive candidates. Here, we performed comprehensive molecular profiling of the B7 and TNFR family genes across 6 CRC datasets with over 1,000 patients’ details using cBioPortal TCGA data. About 20% of patients had B7 and TNFR family gene alterations. The frequency of B7 gene mutations (2.2%–5%) were similar to copy number alterations (0.53%–5.46%). TNFR amplifications were relatively more common (5.45–11.32%) than that of B7 (0.09–2.73%). B7 and TNFR gene mRNAs were upregulated in 26% of cases (102/379) and 16% of cases (61/379), respectively. The mRNA levels of B7 and TNFR genes were inversely correlated with promoter methylation status. Clinically, both B7-H3 and TNFSF7 mRNA overexpression were associated with unfavorable clinical outcomes, and the B7-H3 expression was increased gradually in cases with gene amplifications. Moreover, patients with MSI-H had significantly higher PD-L1 or PD-1 expression. Most importantly, in MSI-H group, patients with PD-L1 or PD-1 upregulation had poorer survivals than those with PD-L1/PD-1 downregulation. This is the first study drawing the immune landscapes of the co-stimulator B7 and TNFR families in CRC and showing that MSI-H patients with PD-1/PD-L1 upregulation are associated with poor clinical outcomes, providing potential markers to stratify patients responsive to immune checkpoint therapy.

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Section: Introductionmentioning

confidence: 99%

The comprehensive molecular landscape of the immunologic co-stimulator B7 and TNFR ligand receptor families in colorectal cancer: immunotherapeutic implications with microsatellite instability

Tang

Liu

et al. 2018

OncoImmunology

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“…Few such studies have reported speciic variations among the mutations observed in chromosomal instability and microsatellite instability tumors. Most of the microsatellite instability tumors have 30% more mutations in β-catenin when compared to Adenomatous polyposis coli protein (APC), while β-catenin mutations are exceptionally rare in nonmicrosatellite instability cancers [40]. This is an indirect conirmation recommending that the microsatellite instability occurs prior to the inactivation of the Adenomatous polyposis coli protein Adenomatous polyposis coli protein (APC) pathway.…”

Section: Genomic Instabilitymentioning

confidence: 97%

Microsatellite Instability in Colorectal Cancer

Parine¹,

Varsha²,

SaudAlanazi³

2016

Microsatellite Markers

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Cancer is a genetic disease. Cancer cells contain various mutations, which includes SNPs to chromosomal aberrations. Together, these changes are referred to as genome instability. Genetic instability is one of the common characteristics of colorectal cancer. In colorectal cancer three major types of genetic instability have been reported. They are chromosomal translocations, microsatellite instability (MSI), and chromosome instability (CIN). Microsatellite instability occurs due to variations in DNA mismatch repair genes, while chromosomal instability is distinguished by major chromosomal alterations occurring at cell division and usually involves -catenin and Adenomatous polyposis coli protein (APC) mutations. This chapter summarizes the major molecular mechanisms leading to genomic and microsatellite instability and tumorigenesis.

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“…[30][31][32] Colorectal cancer represents a heterogeneous group of neoplasms resulting from genomic and epigenomic alterations, which influence and are influenced by tumor-host interactions. [33][34][35][36] A strong immune response to colorectal cancer manifested as high density of CD3 C , CD8…”

Section: Introductionmentioning

confidence: 99%

Tumor SQSTM1 (p62) expression and T cells in colorectal cancer

et al. 2017

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Evidence suggests that activation of autophagy in neoplastic cells potentiates antitumor immunity through cross-presentation of tumor-associated antigens to T cells and release of immune mediators. The SQSTM1 (sequestosome 1, p62) protein is degraded by activated autophagy, and might enhance immune response to tumor cells. We hypothesized that tumor SQSTM1 expression level might be inversely associated with T-cell densities in colorectal carcinoma tissue. We evaluated tumor SQSTM1 expression by immunohistochemistry in 601 rectal and colon cancer cases within the Nurses' Health Study and Health Professionals Follow-up Study. Ordinal logistic regression analyses were conducted to assess the association of tumor SQSTM1 expression with CD3, or FOXP3 C cell density in tumor tissue, controlling for potential confounders, including tumor status of microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation level, and KRAS, BRAF, and PIK3CA mutations. Tumor SQSTM1 expression level was inversely associated with FOXP3 C cell density (p trend D 0.006), but not with CD3C , CD8 C , or CD45RO C cell density (with the adjusted a level of 0.01 for multiple hypothesis testing). For a unit increase in quartile categories of FOXP3 C cell density, multivariable odds ratios were 0.66 [95% confidence interval (CI), 0.45-0.98] for intermediate-level SQSTM1 expression, and 0.55 (95% CI, 0.36-0.83) for high-level SQSTM1 expression, compared with low-level SQSTM1 expression. Tumor SQSTM1 expression is inversely associated with FOXP3 C cell density in colorectal cancer tissue, suggesting a possible role of SQSTM1-expressing carcinoma cells on regulatory T cells in the tumor microenvironment.Abbreviations: ATP, adenosine triphosphate; CI, confidence interval; CIMP, CpG island methylator phenotype; FFPE, formalin-fixed paraffin-embedded; LINE-1, long interspersed nucleotide element-1; MSI, microsatellite instability;

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Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers

Cited by 613 publications

References 339 publications

The comprehensive molecular landscape of the immunologic co-stimulator B7 and TNFR ligand receptor families in colorectal cancer: immunotherapeutic implications with microsatellite instability

The comprehensive molecular landscape of the immunologic co-stimulator B7 and TNFR ligand receptor families in colorectal cancer: immunotherapeutic implications with microsatellite instability

Microsatellite Instability in Colorectal Cancer

Tumor SQSTM1 (p62) expression and T cells in colorectal cancer

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