Molecular portraits of colorectal cancer morphological regions.

Heterogeneity of colorectal carcinoma (CRC) represents a major hurdle towards personalized medicine. Efforts based on whole tumor profiling demonstrated that the CRC molecular subtypes were associated with specific tumor morphological patterns representing tumor subregions. We hypothesize that whole-tumor molecular descriptors depend on the morphological heterogeneity with significant impact on current molecular predictors. We investigated intra-tumor heterogeneity by morphology-guided transcriptomics to better understand the links between gene expression and tumor morphology represented by six morphological patterns (morphotypes): complex tubular, desmoplastic, mucinous, papillary, serrated, and solid/trabecular. Whole-transcriptome profiling by microarrays of 202 tumor regions (morphotypes, tumor-adjacent normal tissue, supportive stroma, and matched whole tumors) from 111 stage II-IV CRCs identified morphotype-specific gene expression profiles and molecular programs and differences in their cellular buildup. The proportion of cell types (fibroblasts, epithelial and immune cells) and differentiation of epithelial cells were the main drivers of the observed disparities with activation of EMT and TNF-α signaling in contrast to MYC and E2F targets signaling, defining major gradients of changes at molecular level. Several gene expression-based (including single-cell) classifiers, prognostic and predictive signatures were examined to study their behavior across morphotypes. Most exhibited important morphotype-dependent variability within same tumor sections, with regional predictions often contradicting the whole-tumor classification. The results show that morphotype-based tumor sampling allows the detection of molecular features that would otherwise be distilled in whole tumor profile, while maintaining histopathology context for their interpretation. This represents a practical approach at improving the reproducibility of expression profiling and, by consequence, of gene-based classifiers.

Colorectal Tumour Mucosa Microbiome Is Enriched in Oral Pathogens and Defines Three Subtypes That Correlate with Markers of Tumour Progression.

Long-term dysbiosis of the gut microbiome has a significant impact on colorectal cancer (CRC) progression and explains part of the observed heterogeneity of the disease. Even though the shifts in gut microbiome in the normal-adenoma-carcinoma sequence were described, the landscape of the microbiome within CRC and its associations with clinical variables remain under-explored. We performed 16S rRNA gene sequencing of paired tumour tissue, adjacent visually normal mucosa and stool swabs of 178 patients with stage 0-IV CRC to describe the tumour microbiome and its association with clinical variables. We identified new genera associated either with CRC tumour mucosa or CRC in general. The tumour mucosa was dominated by genera belonging to oral pathogens. Based on the tumour microbiome, we stratified CRC patients into three subtypes, significantly associated with prognostic factors such as tumour grade, sidedness and TNM staging, BRAF mutation and MSI status. We found that the CRC microbiome is strongly correlated with the grade, location and stage, but these associations are dependent on the microbial environment. Our study opens new research avenues in the microbiome CRC biomarker detection of disease progression while identifying its limitations, suggesting the need for combining several sampling sites (e.g., stool and tumour swabs).

Role of the Microbiome in the Formation and Development of Colorectal Cancer.

BACKGROUND: The clinical, histopathological, and molecular characteristics of colorectal cancer vary considerably. Factors associated with the heterogeneity of this disease and with understanding the effects of heterogeneity on disease progression and response to therapy are critical for the better stratification of patients and the development of new therapeutic methods. Although studies have focused mainly on tumor molecular profiling, current molecular predictive and prognostic factors are relevant to specific groups of colorectal cancer patients and are mostly used to predict the applicability of targeted biological agents rather than to predict their benefits. Molecular profiling fails to capture aspects important for tumor growth and aggressiveness, including the tumor microenvironment. The gut microbiome, consisting of specific communities of all commensal, symbiotic, and pathogenic microorganisms, has been shown to have a significant impact on the development of many diseases, including Crohns disease, type II diabetes, and obesity. Recent studies have indicated that long-term dysbiosis of the intestinal microflora can influence the development and progression of colorectal cancer, as well as tumor aggressiveness and response to treatment. CONCLUSION: This review article summarizes current knowledge of the gut microbiome in colorectal cancer, including the various mechanisms by which the gut microbiome affects the intestinal wall, thereby contributing to the development and progression of colorectal cancer. This work was supported by Ministry of Health of the Czech Republic (project AZV 16-31966A), project of Ministry of Education, Youth and Sports of the Czech Republic - NPU I - LO1413 a Ministry of Health of the Czech Republic - RVO (MMCI, 00209805). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 15. 4. 2019 Accepted: 17. 6. 2019.