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Early identification of individuals with colorectal cancer who are at high risk of metastasis might help guide treatment choice and improve outcome. Stein et al . now report that MACC1 , a previously undescribed gene, is a prognostic indicator of colorectal cancer and describe its role as a transcriptional regulator of MET , which encodes the hepatocyte growth factor receptor and promotes metastasis of a variety of cancers. We identified a previously undescribed gene associated with colon cancer by genome-wide expression analysis in primary and metastatic carcinomas: metastasis-associated in colon cancer-1, MACC1 . MACC1 expression in tumor specimens is an independent prognostic indicator of metastasis formation and metastasis-free survival. We show that the gene encoding the hepatocyte growth factor (HGF) receptor, MET , is a transcriptional target of MACC1. MACC1 promotes proliferation, invasion and HGF-induced scattering of colon cancer cells in cell culture and tumor growth and metastasis in mouse models. These phenotypes are lost in cells expressing MACC1 mutants lacking the SH3 domain or the proline-rich motif. For clinical practice, MACC1 will be useful for the identification of poor prognosis subjects with colorectal cancer and is a promising new target for intervention in metastasis formation.

Key Points The term metastasis encompasses specific biological traits that together enable the spread of aggressive tumour cells. Different tumour types metastasize to distinct secondary organs, reflecting the influence of: the malignant cell of origin, aggressiveness of the primary tumour, the direction of circulation, and the capacity to co-opt supporting components of the microenvironment. Underlying each of these factors are genetic determinants that are largely distinct from those that mediate malignant transformation. Mediators of metastasis can be classified as metastasis initiation, metastasis progression and metastasis virulence genes, on the basis of the tumour stage, location in the body where they act, and their biological function. By combining genome-wide technologies, functional experimentation in model systems and clinical validation, it is becoming possible to identify genetic alterations that are relevant to human metastatic disease. These integrative approaches have uncovered genetic, epigenetic, somatic and inherited alterations, and serve as precedents for future metastasis gene discovery, prognosis and therapy. Genome-wide technologies, functional experimentation in model systems and clinical validation are beginning to identify genetic and epigenetic alterations that underlie metastatic disease. These genetic determinants are distinct from those that mediate malignant transformation and can be classified into metastasis initiation, metastasis progression and metastasis virulence genes. Metastasis can be viewed as an evolutionary process, culminating in the prevalence of rare tumour cells that overcame stringent physiological barriers as they separated from their original environment and developmental fate. This phenomenon brings into focus long-standing questions about the stage at which cancer cells acquire metastatic abilities, the relationship of metastatic cells to their tumour of origin, the basis for metastatic tissue tropism, the nature of metastasis predisposition factors and, importantly, the identity of genes that mediate these processes. With knowledge cemented in decades of research into tumour-initiating events, current experimental and conceptual models are beginning to address the genetic basis for cancer colonization of distant organs.

The effects of sarcosine on the processes driving prostate cancer (PCa) development remain still unclear. Herein, we show that a supplementation of metastatic PCa cells (androgen independent PC-3 and androgen dependent LNCaP) with sarcosine stimulates cells proliferation in vitro. Similar stimulatory effects were observed also in PCa murine xenografts, in which sarcosine treatment induced a tumor growth and significantly reduced weight of treated mice (p < 0.05). Determination of sarcosine metabolism-related amino acids and enzymes within tumor mass revealed significantly increased glycine, serine and sarcosine concentrations after treatment accompanied with the increased amount of sarcosine dehydrogenase. In both tumor types, dimethylglycine and glycine-N-methyltransferase were affected slightly, only. To identify the effects of sarcosine treatment on the expression of genes involved in any aspect of cancer development, we further investigated expression profiles of excised tumors using cDNA electrochemical microarray followed by validation using the semi-quantitative PCR. We found 25 differentially expressed genes in PC-3, 32 in LNCaP tumors and 18 overlapping genes. Bioinformatical processing revealed strong sarcosine-related induction of genes involved particularly in a cell cycle progression. Our exploratory study demonstrates that sarcosine stimulates PCa metastatic cells irrespectively of androgen dependence. Overall, the obtained data provides valuable information towards understanding the role of sarcosine in PCa progression and adds another piece of puzzle into a picture of sarcosine oncometabolic potential.

Key Points Hepatocellular carcinoma (HCC) is one of the most lethal cancers, and affects many of the world's populations. Various aetiologies have been linked to HCC development, the most prominent of which include chronic hepatitis B (HBV) and C (HCV) viral infection, chronic alcohol consumption and aflatoxin-B1-contaminated food. Virtually all cirrhosis-inducing conditions can cause HCC, pointing to important interactions with the host microenvironment. HBV-induced hepatocarcinogenesis can involve an array of processes, including host–viral interactions, sustained cycles of necrosis–inflammation–regeneration, viral–endoplasmic-reticulum interactions (induction of oxidative stress), viral integration into the host genome (and associated host DNA deletions) and the targeted activation of oncogenic pathways by various viral proteins. HCV-induced hepatocarcinogenesis also provokes similar biological processes, but is associated with a propensity of HCV to evade the host's immune responses and to promote cirrhosis. Alcohol-induced hepatocarcinogenesis is associated with the induction of inflammation and, consequently, cycles of hepatocyte necrosis and regeneration, oxidative stress and cirrhosis. Aflatoxin-B1-induced hepatocarcinogenesis is mostly associated with carcinogenic mutations. Various genetic events have been associated with the development of HCC, such as the inactivation of the tumour suppressor p53, mutations in β-catenin, overexpression of various ErbB receptor family members and overexpression of the Met receptor. In addition, various cancer-relevant genes seem to be targeted on the epigenetic level (methylation) in human HCC. Genomic instability is a common feature of human HCC. Various mechanisms are thought to contribute, including telomere erosion, chromosome segregation defects and alterations in the DNA-damage-response pathways. There are many genomic alterations in HCC. Comparative genomic hybridization studies so far have pointed to frequent chromosomal gains in 1q, 6p, 8q, 11q and 17q, and losses in 1p, 4q, 8p, 13q and 17p. Attempts have also been made to relate particular genomic alterations to aetiology and tumour-stage, albeit to a limited extent. Gene-expression analyses of human HCCs have led to the successful molecular classification of HCCs on the basis of prognosis, aetiology and intrahepatic recurrence. Many challenges and opportunities exist in this field, including the need for a more detailed and clinically grounded genomic characterization of human HCCs, deeper understanding of the mechanisms of genomic instability, host–viral interactions, microenvironmental processes (inflammation and cirrhosis), cell of origin in hepatocarcinogenesis and the identification of biomarkers to identify early stage disease as well as those at greatest risk of developing HCC. Hepatocellular carcinoma (HCC) is highly lethal and has a high incidence worldwide. However, at present there is only a basic understanding of the genetic, cellular and environmental mechanisms that drive HCC pathogenesis. What is known, and what are the challenges and opportunities? Hepatocellular carcinoma is among the most lethal and prevalent cancers in the human population. Despite its significance, there is only an elemental understanding of the molecular, cellular and environmental mechanisms that drive disease pathogenesis, and there are only limited therapeutic options, many with negligible clinical benefit. This Review summarizes the current state of knowledge of this, the most common and dreaded liver neoplasm, and highlights the principal challenges and scientific opportunities that are relevant to controlling this accelerating global health crisis.

Eric Rahrmann and colleagues performed a transposon-based somatic mutagenesis screen for genes involved in malignant peripheral nerve sheath tumors (MPNSTs). They identified many recurrent transposon insertions and nominate Foxr2 as a new oncogene in MPNSTs. Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas of Schwann cell lineage origin that occur sporadically or in association with the inherited syndrome neurofibromatosis type 1. To identify genetic drivers of MPNST development, we used the Sleeping Beauty ( SB ) transposon-based somatic mutagenesis system in mice with somatic loss of transformation-related protein p53 ( Trp53 ) function and/or overexpression of human epidermal growth factor receptor ( EGFR ). Common insertion site (CIS) analysis of 269 neurofibromas and 106 MPNSTs identified 695 and 87 sites with a statistically significant number of recurrent transposon insertions, respectively. Comparison to human data sets identified new and known driver genes for MPNST formation at these sites. Pairwise co-occurrence analysis of CIS-associated genes identified many cooperating mutations that are enriched in Wnt/β-catenin, PI3K-AKT-mTOR and growth factor receptor signaling pathways. Lastly, we identified several new proto-oncogenes, including Foxr2 (encoding forkhead box R2), which we functionally validated as a proto-oncogene involved in MPNST maintenance.

Glioblastoma (GBM) is a highly malignant glioma, which has the propensity to infiltrate throughout the brain in contrast to pilocytic astrocytoma (PA) of the posterior fossa, which does not spread and can be cured by surgery. We have used Suppression Subtractive Hybridization to define markers that better delineate the molecular basis of brain invasion and distinguish these tumor groups. We have identified 106 genes expressed in PA versus GBM and 80 genes expressed in GBM versus PA. Subsequent analysis identified a subset of 20 transcripts showing a common differential expression pattern for the two groups. GBM differs from PA by the expression of five genes involved in invasion and angiogenesis: fibronectin, osteopontin, chitinase-3-like-1 (YKL-40), keratoepithelin and fibromodulin. PA differs from GBM by the expression of genes related to metabolism (apolipoprotein D), proteolysis (protease-serine-11), receptor and signal transduction (PLEKHB1 for Pleckstrin-Homology-domain-containing-protein-family-B-member-1), transcription/translation (eukaryotic-translation-elongation-factor-1- α 1) processes and cell adhesion (SPOCK1 for SPARC/Osteonectin-CWCV-kazal-like-domains-proteoglycan). The expression of these genes was confirmed by real-time quantitative RT-PCR and immunohistochemistry. This study highlights the crucial role of brain invasion in GBM and identifies specific molecules involved in this process. In addition, it offers a restricted list of markers that accurately distinguish PA from GBM.

Background:Epithelial ovarian cancer (EOC) is the commonest cause of gynecological cancer-related mortality. Although the prognosis for patients with advanced cancer is poor, there is a wide range of outcomes for individual patients.Objective:The aim of this study was to review molecular factors predictive of poor prognosis of women with EOC by reviewing microarray research identifying gene expression profiles.Methods:A systematic search was performed in the electronic databases PubMed and ScienceDirect up to July 2008, combining the keywords \"genome-wide,\" \"microarray,\" \"epithelial ovarian cancer\" \"prognosis,\" and \"epithelial-mesenchymal transition\" with specific expression profiles of genes.Results:Many genes that participated in cell signaling, growth factors, transcription factors, proteinases, metabolism, cell adhesion, extracellular matrix component, cell proliferation, and anti-apoptosis were overexpressed in patients with poor prognosis. Several important prognosis-related genes overlap with those known to be regulated by epithelial-mesenchymal transition (EMT). This signaling pathway of EMT (E-cadherin, β-catenin, receptor tyrosine kinases, NF-κB, TGF-β, or Wnt signalings) will be discussed, as it provides new insights into a new treatment strategy.Conclusions:This review summarizes recent advances in prognosis-related molecular biology. Collectively, molecular changes possibly through EMT are considered to be a major contributor to the poor prognosis of EOC.

The possibility of predicting clinical outcome of cancer patients through the analysis of gene expression profiles in the primary tumor is a kind of ideological revolution as the multistep carcinogenesis model postulates that the proportion of cells within the primary tumor that actually acquire metastasis driving mutation(s) is small; too small to leave its imprint on the gene expression profile. The data collected to date have brought a new paradigm to reality in the metastasis field: metastasis must at least in part rely on mutations and/or gene regulation events present in the majority of cells which constitute the primary tumor mass. By analyses of differential expression of primary tumors versus metastases or by functional analyses of putative metastasis genes in experimental metastasis, many metastasis-associated gene expression events have been identified that correlate with the development of metastases. Among genes “favoring” metastasis, we find many molecules that are expressed not by the tumor cell itself but by the cells of the microenvironment, as well as genes over-expressed in the primary tumor that have a principle role in mediating tumor–host interactions. Here we review these concepts and advance hypotheses on how gene expression of the primary tumor and the microenvironment can favor the spread of the metastasis seeds and how this knowledge can provide tools to secondary prevention.

The incidence of appendiceal cancer (AC) is rising, particularly among individuals younger than 50 years (early-onset AC), with unexplained etiologies. The unique spectrum of somatic cancer gene variations among patients with early-onset AC is largely undetermined. To characterize the frequency of somatic variations and genomic patterns among patients with early-onset (age <50 years) vs late-onset (age ≥50 years) AC. This cohort study included individuals aged 18 years and older diagnosed with pathologically verified AC. Cases with clinical-grade targeted sequencing data from January 1, 2011, to December 31, 2019, were identified from the international clinicogenomic data-sharing consortium American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE). Data analysis was conducted from May to September 2020. Age at disease onset. Somatic variation prevalence and spectrum in AC patients was determined. Variation comparisons between early-onset and late-onset AC were evaluated using multivariable logistic regression with adjustment for sex, race/ethnicity, histological subtype, sequencing center, and sample type. In total 385 individuals (mean [SD] age at diagnosis, 56.0 [12.4] years; 187 [48.6%] men; 306 [79.5%] non-Hispanic White individuals) with AC were included in this study, and 109 patients (28.3%) were diagnosed with early-onset AC. Race/ethnicity differed by age at disease onset; non-Hispanic Black individuals accounted for a larger proportion of early-onset vs late-onset cases (9 of 109 [8.3%] vs 11 of 276 [4.0%]; P = 0.04). Compared with patients aged 50 years or older at diagnosis, patients with early-onset AC had significantly higher odds of presenting with nonsilent variations in PIK3CA, SMAD3, and TSC2 (PIK3CA: odds ratio [OR], 4.58; 95% CI, 1.72-12.21; P = .002; SMAD3: OR, 7.37; 95% CI, 1.24-43.87; P = .03; TSC2: OR, 12.43; 95% CI, 1.03-149.59; P = .047). In contrast, patients with early-onset AC had a 60% decreased odds of presenting with GNAS nonsilent variations compared with patients with late-onset AC (OR, 0.40; 95% CI, 0.21-0.76, P = .006). By histological subtype, young patients with mucinous adenocarcinomas of the appendix had 65% decreased odds of variations in GNAS compared with late-onset cases in adjusted models (OR, 0.35; 95% CI, 0.15-0.79; P = .01). Similarly, patients with early-onset nonmucinous appendiceal adenocarcinomas had 72% decreased odds of presenting with GNAS variations vs late-onset cases, although these findings did not reach significance (OR, 0.28; 95% CI, 0.07-1.14; P = .08). GNAS and TP53 variations were mutually exclusive in ACs among early-onset and late-onset cases (P < .05). In the study, AC diagnosed among younger individuals harbored a distinct genomic landscape compared with AC diagnosed among older individuals. Development of therapeutic modalities that target these unique molecular features may yield clinical implications specifically for younger patients.

Background: Prognosis of ovarian carcinoma is poor, heterogeneous, and not accurately predicted by histoclinical features. We analysed gene expression profiles of ovarian carcinomas to identify a multigene expression model associated with survival after platinum-based therapy. Methods: Data from 401 ovarian carcinoma samples were analysed. The learning set included 35 cases profiled using whole-genome DNA chips. The validation set included 366 cases from five independent public data sets. Results: Whole-genome unsupervised analysis could not distinguish poor from good prognosis samples. By supervised analysis, we built a seven-gene optimal prognostic model (OPM) out of 94 genes identified as associated with progression-free survival. Using the OPM, we could classify patients in two groups with different overall survival (OS) not only in the learning set, but also in the validation set. Five-year OS was 57 and 27% for the predicted ‘Favourable’ and ‘Unfavourable’ classes, respectively. In multivariate analysis, the OPM outperformed the individual current prognostic factors, both in the learning and the validation sets, and added independent prognostic information. Conclusion: We defined a seven-gene model associated with outcome in 401 ovarian carcinomas. Prospective studies are warranted to confirm its prognostic value, and explore its potential ability for better tailoring systemic therapies in advanced-stage tumours.