Metabolomics provides a comprehensive assessment of numerous small molecules in biological samples. As it integrates the effects of exogenous exposures, endogenous metabolism, and genetic variation, ...metabolomics is well-suited for studies examining metabolic profiles associated with a variety of chronic diseases. In this review, we summarize the studies that have characterized the effects of various pre-analytical factors on both targeted and untargeted metabolomic studies involving human plasma, serum, and urine and were published through 14 January 2019. A standardized protocol was used for extracting data from full-text articles identified by searching PubMed and EMBASE. For plasma and serum samples, metabolomic profiles were affected by fasting status, hemolysis, collection time, processing delays, particularly at room temperature, and repeated freeze/thaw cycles. For urine samples, collection time and fasting, centrifugation conditions, filtration and the use of additives, normalization procedures and multiple freeze/thaw cycles were found to alter metabolomic findings. Consideration of the effects of pre-analytical factors is a particularly important issue for epidemiological studies where samples are often collected in nonclinical settings and various locations and are subjected to time and temperature delays prior being to processed and frozen for storage.
In recent years, metabolomic analyses have been increasingly performed in studies with an epidemiological design. Since 2012, the National Cancer Institute has recognized the importance of supporting ...these efforts by strategically building resources and infrastructure to move this area forward. This review outlines those efforts, including building infrastructure, leveraging existing resources, establishing the COnsortium of METabolomics Studies (COMETS), and improving rigor and reproducibility.
MicroRNAs (miRNAs) have been used as cancer‐related biomarkers. Hepatocellular carcinoma (HCC) is an aggressive cancer with a dismal outcome largely due to metastasis and postsurgical recurrence. We ...investigated whether the expression of certain miRNAs are associated with HCC metastasis. We examined the miRNA expression profiles of 482 cancerous and noncancerous specimens from radical resection of 241 patients with HCC. Using a supervised algorithm and a clinically well‐defined cohort of 131 cases, we built a unique 20‐miRNA metastasis signature that could significantly predict (P < 0.001) primary HCC tissues with venous metastases from metastasis‐free solitary tumors with 10‐fold cross‐validation. However, significant miRNAs could not be identified from the corresponding noncancerous hepatic tissues. A survival risk prediction analysis revealed that a majority of the metastasis‐related miRNAs were associated with survival. Furthermore, the 20‐miRNA tumor signature was validated in 110 additional cases as a significant independent predictor of survival (P = 0.009) and was significantly associated with both survival and relapse in 89 cases of early stage HCC (P = 0.022 and 0.002, respectively). These 20 miRNAs may provide a simple profiling method to assist in identifying patients with HCC who are likely to develop metastases/recurrence. In addition, functional analysis of these miRNAs may enhance our biological understanding of HCC metastasis. (HEPATOLOGY 2008.)
Hepatocellular carcinoma (HCC) is an aggressive malignancy mainly due to metastases or postsurgical recurrence. We postulate that metastases are influenced by the liver microenvironment. Here, we ...show that a unique inflammation/immune response-related signature is associated with noncancerous hepatic tissues from metastatic HCC patients. This signature is principally different from that of the tumor. A global Th1/Th2-like cytokine shift in the venous metastasis-associated liver microenvironment coincides with elevated expression of macrophage colony-stimulating factor (CSF1). Moreover, a refined 17 gene signature was validated as a superior predictor of HCC venous metastases in an independent cohort, when compared to other clinical prognostic parameters. We suggest that a predominant humoral cytokine profile occurs in the metastatic liver milieu and that a shift toward anti-inflammatory/immune-suppressive responses may promote HCC metastases.
The heterogeneous nature of hepatocellular carcinoma (HCC) and the lack of appropriate biomarkers have hampered patient prognosis and treatment stratification. Recently, we have identified that a ...hepatic stem cell marker, epithelial cell adhesion molecule (EpCAM), may serve as an early biomarker of HCC because its expression is highly elevated in premalignant hepatic tissues and in a subset of HCC. In this study, we aimed to identify novel HCC subtypes that resemble certain stages of liver lineages by searching for EpCAM-coexpressed genes. A unique signature of EpCAM-positive HCCs was identified by cDNA microarray analysis of 40 HCC cases and validated by oligonucleotide microarray analysis of 238 independent HCC cases, which was further confirmed by immunohistochemical analysis of an additional 101 HCC cases. EpCAM-positive HCC displayed a distinct molecular signature with features of hepatic progenitor cells including the presence of known stem/progenitor markers such as cytokeratin 19, c-Kit, EpCAM, and activated Wnt-beta-catenin signaling, whereas EpCAM-negative HCC displayed genes with features of mature hepatocytes. Moreover, EpCAM-positive and EpCAM-negative HCC could be further subclassified into four groups with prognostic implication by determining the level of alpha-fetoprotein (AFP). These four subtypes displayed distinct gene expression patterns with features resembling certain stages of hepatic lineages. Taken together, we proposed an easy classification system defined by EpCAM and AFP to reveal HCC subtypes similar to hepatic cell maturation lineages, which may enable prognostic stratification and assessment of HCC patients with adjuvant therapy and provide new insights into the potential cellular origin of HCC and its activated molecular pathways.
Evidence that obesity is associated with cancer incidence and mortality is compelling. By contrast, the role of obesity in cancer survival is less well understood. There is inconsistent support for ...the role of obesity in breast cancer survival, and evidence for other tumor sites is scant. The variability in findings may be due in part to comorbidities associated with obesity itself rather than with cancer, but it is also possible that obesity creates a physiological setting that meaningfully alters cancer treatment efficacy. In addition, the effects of obesity at diagnosis may be distinct from the effects of weight change after diagnosis. Obesity and related comorbid conditions may also increase risk for common adverse treatment effects, including breast cancer-related lymphedema, fatigue, poor health-related quality of life, and worse functional health. Racial and ethnic groups with worse cancer survival outcomes are also the groups for whom obesity and related comorbidities are more prevalent, but findings from the few studies that have addressed these complexities are inconsistent. We outline a broad theoretical framework for future research to clarify the specifics of the biological-social-environmental feedback loop for the combined and independent contributions of race, comorbid conditions, and obesity on cancer survival and adverse treatment effects. If upstream issues related to comorbidities, race, and ethnicity partly explain the purported link between obesity and cancer survival outcomes, these factors should be among those on which interventions are focused to reduce the burden of cancer.
MicroRNAs have potential as diagnostic biomarkers and therapeutic targets in cancer. No study has evaluated the association between microRNA expression patterns and colon cancer prognosis or ...therapeutic outcome.
To identify microRNA expression patterns associated with colon adenocarcinomas, prognosis, or therapeutic outcome.
MicroRNA microarray expression profiling of tumors and paired nontumorous tissues was performed on a US test cohort of 84 patients with incident colon adenocarcinoma, recruited between 1993 and 2002. We evaluated associations with tumor status, TNM staging, survival prognosis, and response to adjuvant chemotherapy. Associations were validated in a second, independent Chinese cohort of 113 patients recruited between 1991 and 2000, using quantitative reverse transcription polymerase chain reaction assays. The final date of follow-up was December 31, 2005, for the Maryland cohort and August 16, 2004, for the Hong Kong cohort.
MicroRNAs that were differentially expressed in tumors and microRNA expression patterns associated with survival using cancer-specific death as the end point. RESULTS Thirty-seven microRNAs were differentially expressed in tumors from the test cohort. Selected for validation were miR-20a, miR-21, miR-106a, miR-181b, and miR-203, and all 5 were enriched in tumors from the validation cohort (P < .001). Higher miR-21 expression was present in adenomas (P = .006) and in tumors with more advanced TNM staging (P < .001). In situ hybridization demonstrated miR-21 to be expressed at high levels in colonic carcinoma cells. The 5-year cancer-specific survival rate was 57.5% for the Maryland cohort and was 49.5% for the Hong Kong cohort. High miR-21 expression was associated with poor survival in both the training (hazard ratio, 2.5; 95% confidence interval, 1.2-5.2) and validation cohorts (hazard ratio, 2.4; 95% confidence interval, 1.4-3.9), independent of clinical covariates, including TNM staging, and was associated with a poor therapeutic outcome.
Expression patterns of microRNAs are systematically altered in colon adenocarcinomas. High miR-21 expression is associated with poor survival and poor therapeutic outcome.
We describe here the agreed upon first development steps and priority objectives of a community engagement effort to address current challenges in quality assurance (QA) and quality control (QC) in ...untargeted metabolomic studies. This has included (1) a QA and QC questionnaire responded to by the metabolomics community in 2015 which recommended education of the metabolomics community, development of appropriate standard reference materials and providing incentives for laboratories to apply QA and QC; (2) a 2-day ‘Think Tank on Quality Assurance and Quality Control for Untargeted Metabolomic Studies’ held at the National Cancer Institute’s Shady Grove Campus and (3) establishment of the Metabolomics Quality Assurance and Quality Control Consortium (mQACC) to drive forward developments in a coordinated manner.
Introduction
The Metabolomics Quality Assurance and Quality Control Consortium (mQACC) organized a workshop during the Metabolomics 2022 conference.
Objectives
The goal of the workshop was to ...disseminate recent findings from mQACC community-engagement efforts and to solicit feedback about a living guidance document of QA/QC best practices for untargeted LC–MS metabolomics.
Methods
Four QC-related topics were presented.
Results
During the discussion, participants expressed the need for detailed guidance on a broad range of QA/QC-related topics accompanied by use-cases.
Conclusions
Ongoing efforts will continue to identify, catalog, harmonize, and disseminate QA/QC best practices, including outreach activities, to establish and continually update QA/QC guidelines.
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