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Metabolomic Markers of Colorectal Tumor With Different Clinicopathological Features.

ABSTRACT: Background: Colorectal cancer (CRC) is the result of complex interactions between the tumor's molecular profile and metabolites produced by its microenvironment. Despite recent studies identifying CRC molecular subtypes, a metabolite classification system is still lacking. We aimed to explore the distinct phenotypes and subtypes of CRC at the metabolite level. Methods: We conducted an untargeted metabolomics analysis of 51 paired tumor tissues and adjacent mucosa using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. Multivariate analysis including principal component analysis, orthogonal partial least squares discriminant analysis and heat maps, univariate analysis, and pathway analysis were used to identify potential metabolite phenotypes of CRC. Unsupervised consensus clustering was used to identify robust metabolite subtypes, and evaluated their clinical relevance. Results: A total of 173 metabolites (including nucleotides, carbohydrates, free fatty acids, and choline) were identified between CRC tumor tissue and adjacent mucosa. We found that lipid metabolism was closely related to the occurrence and progression of CRC. In particular, CRC tissues could be divided into three subtypes, and statistically significant correlations between different subtypes and clinical prognosis were observed. Conclusions: CRC tumor tissue exhibits distinct metabolite phenotypes. Metabolite differences between subtypes may provide a basis and direction for further clinical individualized treatment planning.

SUBMITTER: Long Z

PROVIDER: S-EPMC7311671 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Metabolomic Markers of Colorectal Tumor With Different Clinicopathological Features.

Long Zhiping Z Zhou Junde J Xie Kun K Wu Zhen Z Yin Huihui H Daria Volontovich V Tian Jingshen J Zhang Nannan N Li Liangliang L Zhao Yashuang Y Wang Fan F Wang Maoqing M Cui Yunfu Y

Frontiers in oncology 20200617

<b>Background:</b> Colorectal cancer (CRC) is the result of complex interactions between the tumor's molecular profile and metabolites produced by its microenvironment. Despite recent studies identifying CRC molecular subtypes, a metabolite classification system is still lacking. We aimed to explore the distinct phenotypes and subtypes of CRC at the metabolite level. <b>Methods:</b> We conducted an untargeted metabolomics analysis of 51 paired tumor tissues and adjacent mucosa using ultra-perfor ...[more]

PMID: 32626659

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Project description:BackgroundIt remains unknown to what extent consensus molecular subtype (CMS) groups and immune-stromal infiltration patterns improve our ability to predict outcomes over tumor-node-metastasis (TNM) staging and microsatellite instability (MSI) status in early-stage colorectal cancer (CRC).Patients and methodsWe carried out a comprehensive retrospective biomarker analysis of prognostic markers in adjuvant chemotherapy-untreated (N = 1656) and treated (N = 980), stage II (N = 1799) and III (N = 837) CRCs. We defined CMS scores and estimated CD8+ cytotoxic lymphocytes (CytoLym) and cancer-associated fibroblasts (CAF) infiltration scores from bulk tumor tissue transcriptomes (CMSclassifier and MCPcounter R packages); constructed a stratified multivariable Cox model for disease-free survival (DFS); and calculated the relative proportion of explained variation by each marker (clinicopathological [ClinPath], genomics [Gen: MSI, BRAF and KRAS mutations], CMS scores [CMS] and microenvironment cells [MicroCells: CytoLym+CAF]).ResultsIn multivariable models, only ClinPath and MicroCells remained significant prognostic factors, with both CytoLym and CAF infiltration scores improving survival prediction beyond other markers. The explained variation for DFS models of ClinPath, MicroCells, Gen markers and CMS4 scores was 77%, 14%, 5.3% and 3.7%, respectively, in stage II; and 55.9%, 35.1%, 4.1% and 0.9%, respectively, in stage III. Patients whose tumors were CytoLym high/CAF low had better DFS than other strata [HR=0.71 (0.6-0.9); P = 0.004]. Microsatellite stable tumors had the strongest signal for improved outcomes with CytoLym high scores (interaction P = 0.04) and the poor prognosis linked to high CAF scores was limited to stage III disease (interaction P = 0.04).ConclusionsOur results confirm that tumor microenvironment infiltration patterns represent potent determinants of the risk for distant dissemination in early-stage CRC. Multivariable models suggest that the prognostic value of MSI and CMS groups is largely explained by CytoLym and CAF infiltration patterns.

Project description:BackgroundThe aim of this study is to investigate the clinicopathological features of intrinsic and extrinsic subtypes in adenomyosis. In particular, we focused on the early lesions of adenomyosis.MethodsThis is a single-center, prospective study of women who elected surgery for adenomyosis at the Department of Gynecology, Nara Medical University Hospital, Kashihara, Japan, from April 2008 to March 2018. Adenomyosis was histologically classified as intrinsic, extrinsic, and others, depending on the type of intramural growth. Adenomyosis that occurs at the inner and outer myometrium was defined as an intrinsic and extrinsic type, respectively.ResultsOne hundred eighty-nine patients with histologically confirmed adenomyosis were classified into three different types, 74 intrinsic type, 78 extrinsic type, and 37 other type. Compared to the intrinsic type, the extrinsic type was more likely to have endometriosis, including ovarian endometrioma (OMA), superficial peritoneal endometriosis (SUP), or deep infiltrating endometriosis (DIE). To further identify the clinicopathological features of early-stage adenomyosis, we focused only on patients with intrinsic and extrinsic types of adenomyosis with less than one-third of muscular layer infiltration. Patients with early-stage intrinsic adenomyosis were more likely to experience induced abortions. Patients with early-stage extrinsic adenomyosis were more likely to have endometriosis. The coexistence of endometriosis and the lack of induced abortion were independent predictors of extrinsic adenomyosis. Multivariate logistic regression analysis identified coexistence of endometriosis as independent predictors of the early stage extrinsic adenomyosis.ConclusionThe study suggests that there are at least two types of adenomyosis, where the intrinsic type is closely associated with a history of induced abortion, while the extrinsic type is strongly associated with endometriosis. Adenomyosis might be a gynecological disorder with complex pathogenesis implicating both traumatic and endometriotic factors.

Project description:Colorectal cancer (CRC) has become a major health concern in China due to its increasing incidence and mortality. This study aimed to clarify the relationship between tumor locations and the clinicopathological molecular marker features in eastern China CRC patients. We continuously collected data on 2,356 CRC patients who underwent surgical resection from January 2017 to April 2019. Right-sided colorectal cancer (RCC), was located from the cecum to the transverse colon and left-side colorectal cancer (LCRC) was located from the splenic flexure to the rectum. The clinicopathological indices (including age, sex, pTNM stage, mucinous production, and distant metastasis) and frequency of molecular markers such as KRAS, NRAS, BRAF, and microsatellite instability (MSI) were statistically analyzed between the RCC and LCRC groups. The associations between clinicopathological characters and molecular markers were also investigated. LCRC and RCC proportions in eastern China CRC patients were 81.75% and 18.25%, respectively. RCC (vs. LCRC) was more frequently observed with higher frequencies of MSI-high (MSI-H) and BRAF mutations in female and younger patients, and was closely associated with metastasis, poor differentiation, and mucinous tumors. Tumor location also showed significant differences in bowel wall infiltration degree and pTNM stage. Mutation rates of KRAS, NRAS, MSI, and BRAF were 40.15%, 3.85%, 6.31%, and 2.30%, respectively. Patients with a KRAS mutation tended to be female, had mucinous, perineural invasive, and polypoid tumor. Those with NRAS mutation tended to develop well-differentiated ulcerative tumors. The BRAF mutation was more relevant with lymph node involvement, deeper infiltration of the bowel wall, mucinous, poorly-differentiated tumor with thrombus, and perineural invasion. Furthermore, MSI-H was more commonly found in younger patients with deeper bowel wall infiltration and a poorly-differentiated polypoid tumor, whereas MSS patients tended to develop lymph node involvement, and a mucinous and perineural invasive tumor. In our study, we found that LCRC and RCC showed different features on the clinicopathological and molecular markers in eastern China CRC patients. Since our data differ from those of Western countries and other regions in China, further studies are required to clarify the regional differences of the clinicopathological and molecular markers in CRC patients.

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Metabolomic Markers of Colorectal Tumor With Different Clinicopathological Features.

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Metabolomic Markers of Colorectal Tumor With Different Clinicopathological Features.

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