Genetic Prognostic And Predictive Markers In Colorectal Cancer Pdf

genetic prognostic and predictive markers in colorectal cancer pdf

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In this review, we will discuss adjuvant chemotherapy in non-metastatic colon cancer, the existing prognostic and predictive molecular biomarkers in the field, and how to integrate these molecular biomarkers into the decision about whether to administer adjuvant therapy. The decision about who may derive benefit from adjuvant chemotherapy in colon cancer is often a difficult one for clinicians.

Javascript is currently disabled in your browser. Several features of this site will not function whilst javascript is disabled. Authors Jelski W , Mroczko B.

Genetic prognostic and predictive markers in colorectal cancer

Javascript is currently disabled in your browser. Several features of this site will not function whilst javascript is disabled. Authors Jelski W , Mroczko B. Received 10 March Published 22 June Volume Pages — Review by Single anonymous peer review. Editor who approved publication: Dr Eileen O'Reilly. CRC is often recognized too late for successful therapy. Tumor markers have been sought for a number of years to detect the transformation of malignant cells at the earliest possible stage.

They are usually proteins associated with a malignancy and might be clinically useful in patients with cancer. Several classical markers have been used to recognize colorectal cancer, including carcinoembryonic antigen CEA , carbohydrate antigen CA None of these tests, however, have excellent diagnostic accuracy.

Recent studies have been conducted on the use of hematopoietic growth factors HGFs and various enzymes in the diagnosis and prognosis of colorectal cancer. These include macrophage-colony stimulating factor M-CSF and granulocyte-macrophage-colony stimulating factor GM-CSF , interleukin-3, interleukin-6 and enzymes alcohol dehydrogenase and lysosomal exoglycosidases. Significantly, most cancer deaths are not caused by the primary tumor itself but by its spread.

Analysis of circulating cancer cells CTCs , ie, factors responsible for metastasis, may be a source of information useful in the treatment of patients with colorectal cancer.

Currently available markers have significant limitations. Keywords: tumor markers, colorectal cancer. Colorectal cancer CRC is one of the most common cancers worldwide, with over one million new cases per year. CRC is the second leading cause of cancer deaths in the United States. Beginning in the early s, incidence rates increased among younger adults from 8.

In China, due to changes in diet and lifestyle, morbidity associated with CRC is on the rise, and CRC has recently begun to affect younger people. One of the primary risk factors for colorectal cancer is obesity, a condition typically assessed using a scale known as the body mass index BMI. It has been suggested that the interplay between genetic variants and environmental risk factors, known as gene—environment interaction, may also contribute to an increase of CRC risk.

Other gastrointestinal disorders, such as inflammatory bowel disease characterized by chronic inflammation, mucosa disruption, and the excessive production of reactive oxygen species, act as risk factors in the onset of cancer. In recent years, a new and remarkable factor in the development of cancer and other related intestinal diseases has emerged; the gastrointestinal tract microbiota.

The prognosis for patients with colon cancer is correlated with the pathological stage at the time of detection and it is very important to find markers that would detect a malignant tumor as early as possible.

Colorectal cancer is a serious disease that is characterized by rapid progression, invasiveness and high resistance to treatment. Diagnosing CRC at an early stage is not easy, as cancer is often asymptomatic. Screening requires tools and methods that are both highly sensitive and specific when diagnosing the early stages of cancer.

They must be safe, cheap and widely accepted. A tumor marker can be detected in a solid tumor tissue, in a lymph node, bone marrow, peripheral blood, or other biological materials urine, ascites, and stool.

However, fecal blood is a nonspecific indicator of colorectal cancer, as it can not only come from cancerous lesions but also from polyps. Distal endoscopy, which is the gold standard in diagnosing CRC, allows the diagnosis of changes in real time and enables physicians to perform a target biopsy and histopathological analysis.

Endoscopic ultrasound, computed tomography and magnetic resonance imaging MRI with full clinical assessment make the choice of therapeutic treatment possible. Figure 1 Division of colorectal cancer markers. Recent technological and analytic advances have boosted scientific biomarker research. In the near future, the advent of novel urinary assays with high efficacy that would reduce CRC mortality is expected.

Molecular markers in colorectal cancer can be divided into somatic mutations and microsatellite instability MSI. Carcinoembryonic antigen CEA is a glycoprotein oncofetal antigen that is expressed in many epithelial tumors. This relatively inexpensive blood test, first described by Gold and Freedman in , was part of most recommended surveillance strategies. Seventy percent of patients with CRC have high CEA levels during diagnosis, which makes it a very good marker for the treatment and monitoring of the disease after resection.

Although CEA is usually considered a cancer marker, its concentrations may also be elevated in a variety of benign conditions, including hepatitis, pancreatitis, obstructive pulmonary disease and inflammatory bowel disease.

Tan et al conducted a quantitative meta-analysis of 20 studies involving patients and investigated CEA performance characteristics when used to detect recurrence of colorectal cancer.

Overall sensitivity was found to be 0. About three-quarters of these patients had recurrence detected by other means at the same time as the first increase in CEA. This mostly happens in the advanced stages of cancer. An increased concentration of CEA prior to operation may correlate with an adverse prognosis. CA This marker is used in the diagnostics of pancreatic, colorectal and gastric cancers.

Like CEA, it is not specific to a particular histological type of carcinoma and the organ which it comes from. Vukobrat-Bijedic et al showed that CA Moreover, the determination of both of these markers is used as a postoperative prognostic factor in the evaluation of the stage of the disease and survival rate.

Both CA Tissue polypeptide specific antigen TPS has been described as a useful tumor marker in many malignant cancers and as a response factor in monitoring chemotherapy in different advanced gastrointestinal carcinomas. Tissue-polypeptide-specific antigen TPS is a soluble fragment derived from the carboxy-terminal end of cytokeratin High TPS concentration is a marker of tumor activity, but not necessarily mass of tumor.

The level of TPS in blood, strongly associated with proliferation of cancer cells, is a function of the cell division rate. Estimation of tissue polypeptide specific antigen may be applicable in the early stages of cancers. Repeated determination of TPS concentration during therapy may be of clinical importance, especially as a marker of non-response.

Tumor-associated glycoprotein TAG is a glycoprotein formed in bile duct endothelial cells, gastric epithelium or renal pelvis cells. It is a mucin-like molecule with a molar mass of over kDa.

TAG is found on the surface of many cancer cells, including colon, ovary, breast, and pancreatic cells. Sixty-one percent of patients had at least one marker with elevated levels when measuring these three markers. Analysis of ctDNA in peripheral blood samples, so-called liquid biopsies, has the potential to discern early-stage detection of CRC and serve as a prognostic, monitoring and predictive tool.

A number of studies describe the use of ctDNA methylation markers for the diagnosis and prognosis of colorectal cancer. IGFBP-2 plays an important role in heat shock protein mediated cancer progression and metastasis.

IGFBP-2 serum levels were reported to be significantly elevated in patients with colon cancer in three studies. Recently, several inflammatory markers including pretreatment neutrophil to lymphocyte ratio NLR have been used as prognostic factors, since host inflammatory response to cancer is believed to determine disease progression. The concentration of IGFBP-2 appears to be a prognostic factor that strongly correlates with overall survival.

Colorectal cancer cells are capable of producing hematopoietic growth factors HGFs. Hematopoietic growth factors are involved in the regulation of growth and spread of cancer. HGFs regulate the proliferation of hematopoietic progenitor cells and can also affect the proliferation of nonhematopoietic cells Figure 2. Cell surface receptors for HGF have been detected in colon cancer cell lines and the stimulation of tumor cells proliferations occurs via these receptors.

Several studies have shown that HGFs can also stimulate the proliferation of nonhematopoietic cells and the effect of these cytokines is not limited to bone marrow cells. Receptors of HGFs have been detected in colorectal cancer cell lines and stimulation of CSFs receptors induced the proliferation of tumor cells. HGFs may also induce normal cells, such as tumor-associated macrophages TAM and endothelial cells, to produce additional cytokines that support the malignant process.

Several cell lines of a malignant tumor have been demonstrated to secrete large amounts of CSFs. Mroczko et al found that blood concentration of M-CSF and granulocyte-colony stimulating factor G-CSF were significantly higher in colorectal cancer patients in comparison to controls.

In addition, it was found that M-CSF serum levels were higher in patients with lymph node or distant metastases. Newly conducted research by Jelski et al on the use of enzymes as markers for colorectal cancer, including alcohol dehydrogenase ADH , cathepsin D and lysosomal exoglycosidases reported that the activity of alcohol dehydrogenase is significantly higher in cancerous cells than that in healthy tissue and the activity of aldehyde dehydrogenase ALDH is not different between healthy and cancer tissues.

This would suggest that cancer cells have a greater capability for ethanol oxidation and considerably less ability to remove acetaldehyde than healthy tissues. Acetaldehyde concentration may increase in cancer tissue and intensify the carcinogenesis.

Moreover, the same studies showed that only the activity of ADH I the most important colon isoenzymes of alcohol dehydrogenase is markedly higher in colorectal cancer than in healthy colon cells. The increase of total activity of alcohol dehydrogenase was positively correlated with isoenzyme class I of ADH, so the cause of the increase of serum total alcohol dehydrogenase in the course of colorectal cancer is an elevation of class I ADH isoenzymes.

These results suggest a potential role for ADH especially ADH I as markers for colorectal cancer, but further investigation and confirmation through a prospective study is necessary. Development of colorectal cancer and its metastases can be supported by exoglycosidases released by macrophages. Their activity is also high in other cancers, such as thyroid, renal, pancreatic, ovarian, as well as such diseases as idiopathic arthritis hypertension, glomerulonephritis or following liver transplantation.

Ornithine decarboxylase ODC activity is higher in colorectal cancer and increases gradually from normal, through adenomatous, to cancerous. In the case of cancer including colorectal cancer , death is rarely caused by the primary tumor itself but is due to determination, ie the distant metastases, that may develop years after the primary tumor resection.

Circulating tumor cells CTC have been reported in patients with metastatic CRC as an independent predictor of overall and progression-free survival.

There are at least three advantages to CTCs. The first is the monitoring of the treatment efficacy of CRC patients. The second is the molecular characterization of captured CTCs for targeted treatment, and the third is the cultivation of captured CTCs for drug sensitivity testing.

All of these approaches allow researchers to recognize and respond to changes of the phenotype of cancer cells during disease progression and introduce personalized medicine into clinical practice. Despite promising results, decisions regarding disease stage and adjuvant treatment still do not include CTC results. This is largely due to the lack of standardized and automated CTC detection systems, such as CellSearch, which currently holds a dominant position in the field of CTC detection devices.

Cytokeratin 20 CK20 is a well-established marker for colon epithelium. Welinder et al suggest that CK20 is a biomarker for CTCs in patients with metastatic colorectal cancer.

Prognostic and predictive factors in pancreatic cancer

Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. A Corrigendum to this article was published on 01 March With the exception of KRAS mutations and their association with clinical resistance to epidermal growth factor receptor EGFR -specific antibody therapy, there is no compelling evidence that these markers have a role in clinical decision making. Chromosomal instability is associated with a worse prognosis, and microsatellite instability with a better prognosis.


Genetic prognostic and predictive markers in colorectal cancer. Nat Rev Cancer. Jul;9(7) doi: /.


Improving diagnosis, prognosis and prediction by using biomarkers in CRC patients (Review)

Despite many studies of the likely survival outcome of individual patients with colorectal cancer, our knowledge of this subject remains poor. Until recently, we had virtually no understanding of individual responses to therapy, but the discovery of the KRAS mutation as a marker of probable failure of epidermal growth factor receptor EGFR -targeted therapy is a first step in the tailoring of treatment to the individual. With the application of molecular analyses, as well as the ability to perform high-throughput screens, there has been an explosive increase in the number of markers thought to be associated with prognosis and treatment outcome in this disease.

Prognostic and Predictive Biomarkers: Tools in Personalized Oncology

Colorectal cancer is one of the most common cancers in the world, and it is one of the leading causes of cancer-related death. Despite recent progress in the development of screening programs and in the management of patients with colorectal cancer, there are still many gaps to fill, ranging from the prevention and early diagnosis to the determination of prognosis factors and treatment of metastatic disease, to establish a personalized approach. The genetic profile approach has been increasingly used in the decision-making process, especially in the choice of targeted therapies and in the prediction of drug response, but there are still few validated biomarkers of colorectal cancer for clinical practice. The discovery of non-invasive, sensitive, and specific biomarkers is an urgent need, and translational proteomics play a key role in this process, as they enable better comprehension of colorectal carcinogenesis, identification of potential markers, and subsequent validation. This review provides an overview of recent advances in the search for colorectal cancer biomarkers through proteomics studies according to biomarker function and clinical application. Colorectal cancer CRC is the third most commonly diagnosed cancer among adults and is the third leading cause of cancer-related death in the United States 1.

Oncology indispensably leads us to personalized medicine, which allows an individual approach to be taken with each patient. Personalized oncology is based on pharmacogenomics and the effect of genetic differences in individuals germline and somatic on the way cancer patients respond to chemotherapeutics. Biomarkers detected using molecular biology tools allow the molecular characterization of cancer signatures and provide information relevant for personalized treatment. Biomarkers can be divided into two main subgroups: prognostic and predictive. The aim of the application of prognostic biomarkers, which provide information on the overall cancer outcome in patients, is to facilitate cancer diagnosis, usually with no need for putting invasive methods into use. Predictive biomarkers help to optimize therapy decisions, as they provide information on the likelihood of response to a given chemotherapeutic. Among the prognostic factors that identify patients with different outcome risks e.

Pansini 5, Naples, Italy. Colorectal cancer CRC is one of the most spread neoplasia types all around the world, especially in western areas. It evolves from precancerous lesions and adenomatous polyps, through successive genetic and epigenetic mutations. Numerous risk factors intervene in its development and they are either environmental or genetic. Aim of the Review. Alongside common screening techniques, such as fecal screening tests, endoscopic evaluation, and CT-colonography, we have identified the most important and useful biomarkers and we have analyzed their role in the diagnosis, prevention, and prognosis of CRC. Biomarkers can become an important tool in the diagnostic and therapeutic process for CRC.


Regulation of TS expression was determined to be critical for the efficacy of fluoropyrimidines, therefore identifying genetic alterations that regulate TS gene.


Current Tissue Molecular Markers in Colorectal Cancer: A Literature Review

Cancer Immunotherapy and Identification of Prognostic and Predictive Biomarkers

This is an open access article distributed under the terms of Creative Commons Attribution License. Colorectal cancer CRC is ranked as one of the most common types of cancer. In fact, according to data from the USA, for the male population it is ranked third of the most diagnosed, after lung and prostate cancer, and for the female population, it is ranked second, following breast cancer 1. Moreover, it is considered as one of the leading causes of cancer-related death worldwide 2 , 3 In the USA alone, CRC is responsible for the second greatest number of cancer-related deaths. As a matter of fact, the American Cancer Society estimated that for alone, the number of first diagnosed CRC cases and that of deaths due to CRC was as high as , and about 50,, respectively 4. It is clear that CRC is a rather heterogeneous disease by means of its various clinical manifestations, biological behavior and in-tumor variety of mutations 5 , 6 making it a true challenge, not only to detect in an early stage, but also to treat or even manage in the long term. Such genes may be tumor suppressor genes, oncogenes, mismatch repair genes and cell cycle regulating genes in colon mucosal cells 7.

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PDF | Despite many studies of the likely survival outcome of individual patients with colorectal cancer, our knowledge of this subject remains.

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