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Journal ArticleDOI

Focus on genetic and epigenetic events of colorectal cancer pathogenesis: implications for molecular diagnosis

28 Mar 2014-Tumor Biology (Springer Netherlands)-Vol. 35, Iss: 7, pp 6195-6206
TL;DR: This review summarizes the most investigated biomolecular pathways involved in CRC pathogenesis, their role as biomarkers for early CRC diagnosis and their possible use to stratify susceptible patients into appropriate screening or surveillance programs.
Abstract: Originally, colorectal cancer (CRC) tumorigenesis was understood as a multistep process that involved accumulation of tumor suppressor genes and oncogenes mutations, such as APC, TP53 and KRAS. However, this assumption proposed a relatively limited repertoire of genetic alterations. In the last decade, there have been major advances in knowledge of multiple molecular pathways involved in CRC pathogenesis, particularly regarding cytogenetic and epigenetic events. Microsatellite instability, chromosomal instability and CpG island methylator phenotype are the most analyzed cytogenetic changes, while DNA methylation, modifications in histone proteins and microRNAs (miRNAs) were analyzed in the field of epigenetic alterations. Therefore, CRC development results from interactions at many levels between genetic and epigenetic amendments. Furthermore, hereditary cancer syndrome and individual or environmental risk factors should not be ignored. The difficulties in this setting are addressed to understand the molecular basis of individual susceptibility to CRC and to determine the roles of genetic and epigenetic alterations, in order to yield more effective prevention strategies in CRC patients and directing their treatment. This review summarizes the most investigated biomolecular pathways involved in CRC pathogenesis, their role as biomarkers for early CRC diagnosis and their possible use to stratify susceptible patients into appropriate screening or surveillance programs.
Citations
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Journal ArticleDOI
16 Sep 2014-Genes
TL;DR: The current state of play for DNA methylation biomarkers is reviewed, the barriers that must be crossed on the way to implementation in a clinical setting are discussed, and their future use for human disease is predicted.
Abstract: Biomarkers are naturally-occurring characteristics by which a particular pathological process or disease can be identified or monitored. They can reflect past environmental exposures, predict disease onset or course, or determine a patient's response to therapy. Epigenetic changes are such characteristics, with most epigenetic biomarkers discovered to date based on the epigenetic mark of DNA methylation. Many tissue types are suitable for the discovery of DNA methylation biomarkers including cell-based samples such as blood and tumor material and cell-free DNA samples such as plasma. DNA methylation biomarkers with diagnostic, prognostic and predictive power are already in clinical trials or in a clinical setting for cancer. Outside cancer, strong evidence that complex disease originates in early life is opening up exciting new avenues for the detection of DNA methylation biomarkers for adverse early life environment and for estimation of future disease risk. However, there are a number of limitations to overcome before such biomarkers reach the clinic. Nevertheless, DNA methylation biomarkers have great potential to contribute to personalized medicine throughout life. We review the current state of play for DNA methylation biomarkers, discuss the barriers that must be crossed on the way to implementation in a clinical setting, and predict their future use for human disease.

242 citations


Cites background from "Focus on genetic and epigenetic eve..."

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Journal ArticleDOI
TL;DR: DNA methylation represents one of the largest bodies of literature in epigenetics, and hence has the highest potential for minimally invasive biomarker development.
Abstract: Colorectal cancer (CRC) is a common malignancy and the fourth leading cause of cancer deaths worldwide. It results from the accumulation of multiple genetic and epigenetic changes leading to the transformation of colon epithelial cells into invasive adenocarcinomas. In CRC, epigenetic changes, in particular promoter CpG island methylation, occur more frequently than genetic mutations. Hypermethylation contributes to carcinogenesis by inducing transcriptional silencing or downregulation of tumour suppressor genes and currently, over 600 candidate hypermethylated genes have been identified. Over the past decade, a deeper understanding of epigenetics coupled with technological advances have hinted at the potential of translating benchtop research into biomarkers for clinical use. DNA methylation represents one of the largest bodies of literature in epigenetics, and hence has the highest potential for minimally invasive biomarker development. Most progress has been made in the development of diagnostic markers and there are currently two, one stool-based and one blood-based, biomarkers that are commercially available for diagnostics. Prognostic and predictive methylation markers are still at their infantile stages.

141 citations

Journal ArticleDOI
06 Feb 2018-Gut
TL;DR: The integrated immunology-MPE model can contribute to better understanding of environment-tumour-immune interactions, and effective immunoprevention and immunotherapy strategies for precision medicine.
Abstract: Immunotherapy strategies targeting immune checkpoints such as the CTLA4 and CD274 (programmed cell death 1 ligand 1, PD-L1)/PDCD1 (programmed cell death 1, PD-1) T-cell coreceptor pathways are revolutionising oncology. The approval of pembrolizumab use for solid tumours with high-level microsatellite instability or mismatch repair deficiency by the US Food and Drug Administration highlights promise of precision immuno-oncology. However, despite evidence indicating influences of exogenous and endogenous factors such as diet, nutrients, alcohol, smoking, obesity, lifestyle, environmental exposures and microbiome on tumour-immune interactions, integrative analyses of those factors and immunity lag behind. Immune cell analyses in the tumour microenvironment have not adequately been integrated into large-scale studies. Addressing this gap, the transdisciplinary field of molecular pathological epidemiology (MPE) offers research frameworks to integrate tumour immunology into population health sciences, and link the exposures and germline genetics (eg, HLA genotypes) to tumour and immune characteristics. Multilevel research using bioinformatics, in vivo pathology and omics (genomics, epigenomics, transcriptomics, proteomics and metabolomics) technologies is possible with use of tissue, peripheral blood circulating cells, cell-free plasma, stool, sputum, urine and other body fluids. This immunology-MPE model can synergise with experimental immunology, microbiology and systems biology. GI neoplasms represent exemplary diseases for the immunology-MPE model, given rich microbiota and immune tissues of intestines, and the well-established carcinogenic role of intestinal inflammation. Proof-of-principle studies on colorectal cancer provided insights into immunomodulating effects of aspirin, vitamin D, inflammatory diets and omega-3 polyunsaturated fatty acids. The integrated immunology-MPE model can contribute to better understanding of environment-tumour-immune interactions, and effective immunoprevention and immunotherapy strategies for precision medicine.

135 citations

Journal ArticleDOI
TL;DR: This study highlights an oncomiR role for miR-19a in regulating TIA1 in CRC and suggests that miR -19a may be a novel molecular therapeutic target for CRC.
Abstract: Colorectal cancer (CRC) is a major worldwide health problem due to its high prevalence and mortality rate. T-cell intracellular antigen 1 (TIA1) is an important tumor suppressor involved in many aspects of carcinogenesis and cancer development. How TIA1 expression is regulated during CRC development remains to be carefully elucidated. In CRC tissue sample pairs, TIA1 protein and mRNA levels were monitored by Western blot and qRT-PCR, respectively. Combining meta-analysis and miRNA target prediction software, we could predict microRNAs that targeted TIA1. Next, three CRC cell lines (SW480, Caco2 and HT29) were used to demonstrate the direct targeting of TIA1 by miR-19a. In addition, we investigated the biological effects of TIA1 inhibition by miR-19a both in vitro by CCK-8, EdU, Transwell, Ki67 immunofluorescence and Colony formation assays and in vivo by a xenograft mice model. In colorectal cancer (CRC), we found that TIA1 protein, but not its mRNA, was downregulated. We predicted that TIA1 was a target of miR-19a and validated that miR-19a binded directly to the 3’-UTR of TIA1 mRNA. miR-19a could promote cell proliferation and migration in CRC cells and accelerated tumor growth in xenograft mice by targeting TIA1. This study highlights an oncomiR role for miR-19a in regulating TIA1 in CRC and suggests that miR-19a may be a novel molecular therapeutic target for CRC.

134 citations

Journal ArticleDOI
TL;DR: F. nucleatum was enriched in CRC tissues and associated with CRC development and metastasis and its association with CRC invasiveness in Chinese patients was observed.
Abstract: Association of Fusobacterium nucleatum infection with colorectal cancer in Chinese patients

131 citations

References
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Journal ArticleDOI
04 Mar 2011-Cell
TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

51,099 citations

Journal ArticleDOI
01 Jun 1990-Cell
TL;DR: A model for the genetic basis of colorectal neoplasia that includes the following salient features is presented, which may be applicable to other common epithelial neoplasms, in which tumors of varying stage are more difficult to study.

11,576 citations


"Focus on genetic and epigenetic eve..." refers background or methods in this paper

  • ...18q called “deleted in colorectal carcinoma” gene (DCC) [12]....

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  • ...This sequence occurs in 60 % of CRC cases and generally the activation of an oncogene or inactivation of a oncosuppressor gene, involved in this sequence, is associated with clinicopathological tumor features (Table 2) [12]....

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  • ...Up to 70 % of CRC have been shown to carry LOH at chromosome 18q called “deleted in colorectal carcinoma” gene (DCC) [12]....

    [...]

  • ...LOH at chromosome 18q seems caused adenoma progression in CRC tumorigenesis, since genes on this chromosome includes over DCC even SMAD2 and SMAD4 [21]....

    [...]

  • ...Mutations of the DCC gene are also found in 50 % of advanced adenomas of the colon [12]....

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Journal ArticleDOI
TL;DR: The reduction in overall cancer death rates since 1990 in men and 1991 in women translates to the avoidance of about 1,024,400 deaths from cancer, which can be accelerated by applying existing cancer control knowledge across all segments of the population, with an emphasis on those groups in the lowest socioeconomic bracket.
Abstract: Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. A total of 1,638,910 new cancer cases and 577,190 deaths from cancer are projected to occur in the United States in 2012. During the most recent 5 years for which there are data (2004-2008), overall cancer incidence rates declined slightly in men (by 0.6% per year) and were stable in women, while cancer death rates decreased by 1.8% per year in men and by 1.6% per year in women. Over the past 10 years of available data (1999-2008), cancer death rates have declined by more than 1% per year in men and women of every racial/ethnic group with the exception of American Indians/Alaska Natives, among whom rates have remained stable. The most rapid declines in death rates occurred among African American and Hispanic men (2.4% and 2.3% per year, respectively). Death rates continue to decline for all 4 major cancer sites (lung, colorectum, breast, and prostate), with lung cancer accounting for almost 40% of the total decline in men and breast cancer accounting for 34% of the total decline in women. The reduction in overall cancer death rates since 1990 in men and 1991 in women translates to the avoidance of about 1,024,400 deaths from cancer. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population, with an emphasis on those groups in the lowest socioeconomic bracket.

10,630 citations

Journal ArticleDOI
TL;DR: To determine the morbidity and mortality from childhood Haemophilus influenzae type b (Hib) meningitis in a well defined population, a large number of cases are diagnosed with Hib.
Abstract: OBJECTIVE To determine the morbidity and mortality from childhood Haemophilus influenzae type b (Hib) meningitis in a well defined population. DESIGN Retrospective survey 1985-1987 and prospective surveillance of hospital laboratories 1989-1990. Information on outcome of meningitis was obtained from hospital records and attending physicians and, in 1989-1990, from a survey of the children's parents. SETTING Sydney Statistical Division, which had a population of children aged 0-4 years of 229,165 in 1986 and 263,758 in 1990. PATIENTS Eligible children were aged from one month to four years and had clinical and microbiological evidence of Hib meningitis on standard criteria. RESULTS There were 229 eligible children. Twelve were excluded (seven died and five had pre-existing neurological deficits). A neurological deficit was detected at the time of hospital discharge in 45 patients (21%) and persisted for 12 months or longer in 29 patients (13%). Follow-up information was available for 165 (96%) children who were normal at the time of hospital discharge and persistent deficits were recorded in 12 (7%) of these children. Forty-one children (19%) had readily recognisable neurological or hearing problems: nine (4%) had persistent severe neurological deficits and seven (3%) had severe hearing loss requiring hearing aids or a cochlear implant. Age had a significant influence on outcome. The youngest children were significantly more likely to be admitted to intensive care. Severe neurological deficits showed a significant negative trend with increasing age (P = 0.03). Severe unilateral or bilateral sensorineural loss (odds ratio [OR] 8.0, 95% confidence interval [CI] 1.5-81) and ataxia at discharge (OR 13.3, 95% CI 2.8-128) were noticeably more common in children over two years of age, with a significant positive trend (P < or = 0.001) with increasing age. Patients requiring intensive care were much more likely to have an adverse outcome, particularly if positive pressure ventilation was needed. CONCLUSIONS These data provide population-based estimates of the minimum incidence of adverse outcomes from Hib meningitis in an urban community with good access to medical services. This is important in assessing the impact of Hib vaccination, as meningitis is responsible for most of the long-term morbidity from childhood invasive Hib disease. Determination of the relationship between morbidity and age is important for assessing alternative vaccine strategies.

8,476 citations