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Posts Tagged ‘carcinoma’


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

The metabolite pool of cells and tissues represents the end result of metabolism determined by genetic, environmental and nutritional factors. The metabolic profile of biological systems is closely related to the individual phenotype and reflects the biological endpoint of a multitude of pathways and their interaction with any confounding stimuli. Cancer cells exhibit activation of specific metabolic pathways to compensate for their extremely high energy demands. Indeed increased glucose uptake and lactate production and decreased respiration are key phenomena of tumour cell metabolism. In particular, the generation of an acidic microenvironment through increased lactate production, even under aerobic conditions, may confer extracellular matrix degeneration and exert toxic effects on surrounding cell populations, while being harmless for the cancer cell itself. Thus, the metabolic adaptations may indeed be critical for the development of accelerated proliferation and the invasive growth of tumour cell populations. The molecular mechanisms underlying the metabolic hallmarks of cancer are still poorly understood, although genetic, epigenetic and environmental factors driving cancer development and progression will interact to determine the metabolic phenotype of tumour cells. Recent studies suggest that metabolic changes play a pivotal role in the biology of renal cell carcinoma – a tumour entity that is largely resistant to conventional chemo- and radiotherapy. The metabolic profile of renal tumours may thus serve as a reliable biomarker of malignant transformation and biological behaviour.

Recent advances in metabolic profiling technologies by providing quantitative measures of metabolite profiles from gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) based technology present the opportunity to apply this technique in human specimens. Global metabolic profiling has emerged as a promising approach to characterize the metabolite pool within a cell, tissue or bodily fluid under certain conditions, such as health or disease status. Metabolic profiling is applied to monitor the health to disease continuum and has the potential of increasing our understanding of the mechanisms of disease. Thus the characterization of the metabolic features in tumours is expected to provide a better understanding of the mechanisms of malignant transformation and progression and may lead to the identification of metabolic biomarkers for cancer detection and prognostication. However, comparative profiling of low molecular weight compounds, such as sugars, lipids and amino acids, in cancer as compared to the corresponding normal tissue is a rather unexplored area. The objective of this study was to characterize the key metabolic features of renal cell carcinoma using GC-TOF-MS and mutual information as well as decision tree-based data analysis.

Hypoxia is key in tumour cell behaviour. Hypoxia, via hypoxia inducible factor, plays a key role in the metabolic changes in the kidney cancer cell and influences different pathways. Pathways that use tyrosine kinases and mammalian target of rapamycin are well studied. Hypoxia-related effects on vascular epithelial growth factors and angiogenesis will influence the metabolic status of the cell significantly. This is the basis of inhibitor-type drugs or antibody blocking agents and the effect on the clinical course of renal cell carcinoma patients. Detailed information about metabolic changes is crucial to understanding these mechanisms more clearly. Treating renal cell carcinoma patients is not like treating one disease. Renal cell carcinoma has different morphologic entities with distinct differences in cytogenetic background. These differences should be reflected in the different approaches of diagnostic and therapeutic strategies. This consideration will help to increase the efficacy of novel agents and decrease unnecessary side-effects. Metabolomics explains the importance of explaining genetic changes and the functional outcome of the tumour cells. In addition, epidemiologic differences in incidence and prevalence in different parts of the world may help provide insight into the etiology of kidney cancer. Factors that may influence renal cancer likelihood (eg, obesity, antihypertensive therapy) may have an explanation in metabolomics.

Source References:

http://www.europeanurology.com/article/S0302-2838(12)01352-8/fulltext

http://www.ncbi.nlm.nih.gov/pubmed/19845817

http://www.ncbi.nlm.nih.gov/pubmed/18072195

http://www.ncbi.nlm.nih.gov/pubmed/17123452

http://www.ncbi.nlm.nih.gov/pubmed/20464042

http://www.ncbi.nlm.nih.gov/pubmed/21930086

https://www.google.com.tw/url?sa=t&rct=j&q=&esrc=s&source=web&cd=8&cad=rja&ved=0CGwQFjAH&url=http%3A%2F%2Fjournals.sfu.ca%2Fcuaj%2Findex.php%2Fjournal%2Farticle%2Fdownload%2F665%2F466&ei=-ub8UbD0JcfolAXeyYGYBw&usg=AFQjCNFIzdti065pBEGKlEDkBDCPA4IwUw&sig2=scgq8qT9ffKa65MxAvpuNg&bvm=bv.50165853,d.dGI

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Molecular biomarkers could detect biochemical changes associated with disease processes. The key metabolites have become an important part for improving the diagnosis, prognosis, and therapy of diseases. Because of the chemical diversity and dynamic concentration range, the analysis of metabolites remains a challenge. Assessment of fluctuations on the levels of endogenous metabolites by advanced NMR spectroscopy technique combined with multivariate statistics, the so-called metabolomics approach, has proved to be exquisitely valuable in human disease diagnosis. Because of its ability to detect a large number of metabolites in intact biological samples with isotope labeling of metabolites using nuclei such as H, C, N, and P, NMR has emerged as one of the most powerful analytical techniques in metabolomics and has dramatically improved the ability to identify low concentration metabolites and trace important metabolic pathways. Multivariate statistical methods or pattern recognition programs have been developed to handle the acquired data and to search for the discriminating features from biosample sets. Furthermore, the combination of NMR with pattern recognition methods has proven highly effective at identifying unknown metabolites that correlate with changes in genotype or phenotype. The research and clinical results achieved through NMR investigations during the first 13 years of the 21st century illustrate areas where this technology can be best translated into clinical practice.

In the last decade, proteomics and metabolomics have contributed substantially to our understanding of cardiovascular diseases. The unbiased assessment of pathophysiological processes without a priori assumptions complements other molecular biology techniques that are currently used in a reductionist approach. A discrete biological function is very rarely attributed to a single molecule; more often it is the combined input of many proteins. In contrast to the reductionist approach, in which molecules are studied individually, “omics” platforms allow the study of more complex interactions in biological systems. Combining proteomics and metabolomics to quantify changes in metabolites and their corresponding enzymes will advance our understanding of pathophysiological mechanisms and aid the identification of novel biomarkers for cardiovascular disease.

Marginal deficiency of vitamin B-6 is common among segments of the population worldwide. Because pyridoxal 5′-phosphate serves as a coenzyme in the metabolism of amino acids, carbohydrates, organic acids, and neurotransmitters, as well as in aspects of one-carbon metabolism, vitamin B-6 deficiency could have many effects. NMR spectral features of selected metabolites indicated that vitamin B-6 restriction significantly increased the ratios of glutamine/glutamate and 2-oxoglutarate/glutamate and tended to increase concentrations of acetate, pyruvate, and trimethylamine-N-oxide. Tandem MS showed significantly greater plasma proline after vitamin B-6 restriction, but there were no effects on the profile of 14 other amino acids and 45 acylcarnitines. These findings demonstrate that marginal vitamin B-6 deficiency has widespread metabolic perturbations and illustrate the utility of metabolomics in evaluating complex effects of altered vitamin B-6 intake.

Hepatocellular carcinoma is one of the most common malignancies worldwide, and it has a poor prognosis due to its rapid development and early metastasis. An understanding of tumor metabolism would be helpful for the clinical diagnosis and therapy of hepatocellular carcinoma. To investigate the metabolic features of hepatocellular carcinoma, a non-targeted metabolic profiling strategy based on liquid chromatography-mass spectrometry was performed. The results revealed multiple metabolic changes in the tumor, and the principal changes included elevated glycolysis, inhibition of the tricarboxylic acid cycle, accelerated gluconeogenesis and β-oxidation for energy supply and down-regulated Δ-12 desaturase. Furthermore, increased levels of anti-oxidative molecules, such as glutathione, and decreased levels of inflammatory-related polyunsaturated fatty acids and the phospholipase A2 enzyme were also observed. The differential metabolites found in the tissue were tested in serum samples from the chronic hepatitis, cirrhosis and hepatocellular carcinoma patients. The combination of betaine and propionylcarnitine was confirmed to have a good diagnostic potential to distinguish hepatocellular carcinoma from chronic hepatitis and cirrhosis. External validation of cirrhosis and hepatocellular carcinoma serum samples further shows the combination biomarker is useful for hepatocellular carcinoma diagnosis.

Current diagnostic techniques have increased the detection of prostate cancer; however, these tools inadequately stratify patients to minimize mortality. Recent studies have identified a biochemical signature of prostate cancer metastasis, including increased sarcosine abundance. Prostate tumors had significantly altered metabolite profiles compared to cancer-free prostate tissues, including biochemicals associated with cell growth, energetics, stress, and loss of prostate-specific biochemistry. Many metabolites were further associated with clinical findings of aggressive disease. Aggressiveness-associated metabolites stratified prostate tumor tissues with high abundances of compounds associated with normal prostate function (e.g., citrate and polyamines) from more clinically advanced prostate tumors. These aggressive prostate tumors were further subdivided by abundance profiles of metabolites including NAD+ and kynurenine. When added to multiparametric nomograms, metabolites improved prediction of organ confinement and 5-year recurrence. These findings support and extend earlier metabolomic studies in prostate cancer and studies where metabolic enzymes have been associated with carcinogenesis and/or outcome. Furthermore, it suggests that panels of analytes may be valuable to translate metabolomic findings to clinically useful diagnostic tests.

Source References:

http://www.ncbi.nlm.nih.gov/pubmed/23828598

http://www.ncbi.nlm.nih.gov/pubmed/23827455

http://www.ncbi.nlm.nih.gov/pubmed/23776431

http://www.ncbi.nlm.nih.gov/pubmed/23824744

http://www.ncbi.nlm.nih.gov/pubmed/23824564

Published related articles on this open access online scientific journal:

 

World of Metabolites: Lawrence Berkeley National Laboratory developed Imaging Technique for their Capturing

 

Aviva Lev-Ari, PhD, RN 06/13/2013

 

https://pharmaceuticalintelligence.com/2013/06/13/world-of-metabolites-lawrence-berkeley-national-laboratory-developed-imaging-technique-for-their-capturing/

 

Metabolite Identification Combining Genetic and Metabolic Information: Genetic association links unknown metabolites to functionally related genes

 

Aviva Lev-Ari, PhD, RN 10/22/2012

 

https://pharmaceuticalintelligence.com/2012/10/22/metabolite-identification-combining-genetic-and-metabolic-information-genetic-association-links-unknown-metabolites-to-functionally-related-genes/

 

Metabolomics: its applications in food and nutrition research

 

Dr. Sudipta Saha, Ph.D., RN 05/12/2013

 

https://pharmaceuticalintelligence.com/2013/05/12/metabolomics-its-applications-in-food-and-nutrition-research/

 

Increased Cardiovascular Risk: Intestinal Microbial Metabolism

 

Aviva Lev-Ari, PhD, RN 05/07/2013

 

https://pharmaceuticalintelligence.com/2013/05/07/increased-cardiovascular-risk-intestinal-microbial-metabolism/

 

Late Onset of Alzheimer’s Disease and One-carbon Metabolism

 

Dr. Sudipta Saha, Ph.D., RN 05/06/2013

 

https://pharmaceuticalintelligence.com/2013/05/06/alzheimers-disease-and-one-carbon-metabolism/

 

Importance of Omega-3 Fatty Acids in Reducing Cardiovascular Disease

 

Dr. Sudipta Saha, Ph.D., RN 04/29/2013

 

https://pharmaceuticalintelligence.com/2013/04/29/importance-of-omega-3-fatty-acids-in-reducing-cardiovascular-disease/

 

Mitochondrial Metabolism and Cardiac Function

 

Larry H Bernstein, MD, FACP, RN 04/14/2013

 

https://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/

 

How Methionine Imbalance with Sulfur-Insufficiency Leads to Hyperhomocysteinemia

 

Larry H Bernstein, MD, FACP, RN 04/04/2013

 

https://pharmaceuticalintelligence.com/2013/04/04/sulfur-deficiency-and-hyperhomocusteinemia/

 

Ca2+ Signaling: Transcriptional Control

 

Larry H Bernstein, MD, FACP, RN 03/06/2013

 

https://pharmaceuticalintelligence.com/2013/03/06/ca2-signaling-transcriptional-control/

 

Calcium (Ca) supplementation (>1400 mg/day): Higher Death Rates from all Causes and Cardiovascular Disease in Women

 

Aviva Lev-Ari, PhD, RN 02/19/2013

 

https://pharmaceuticalintelligence.com/2013/02/19/calcium-ca-supplementation-1400-mgday-higher-death-rates-from-all-causes-and-cardiovascular-disease-in-women/

 

A Second Look at the Transthyretin Nutrition Inflammatory Conundrum

 

Larry H Bernstein, MD, FACP, RN 12/03/2013

 

https://pharmaceuticalintelligence.com/2012/12/03/a-second-look-at-the-transthyretin-nutrition-inflammatory-conundrum/

 

Pancreatic Cell News: Beta cell dysfunction attributed to saturated non-esterified fatty acid palmitate

 

Aviva Lev-Ari, PhD, RN 11/27/2012

 

https://pharmaceuticalintelligence.com/2012/11/27/pancreatic-cell-news-beta-cell-dysfunction-attributed-to-saturated-non-esterified-fatty-acid-palmitate/

 

Metabolic drivers in aggressive brain tumors

 

Prabodh Kandala, PhD, RN 11/11/2012

 

https://pharmaceuticalintelligence.com/2012/11/11/metabolic-drivers-in-aggressive-brain-tumors/

 

Advances in Separations Technology for the “OMICs” and Clarification of Therapeutic Targets

 

Larry H Bernstein, MD, FACP, RN 10/22/2012

 

https://pharmaceuticalintelligence.com/2012/10/22/advances-in-separations-technology-for-the-omics-and-clarification-of-therapeutic-targets/

 

Expanding the Genetic Alphabet and Linking the Genome to the Metabolome

 

Larry H Bernstein, MD, FACP, RN 09/24/2012

 

https://pharmaceuticalintelligence.com/2012/09/24/expanding-the-genetic-alphabet-and-linking-the-genome-to-the-metabolome/

 

Risks of Hypoglycemia in Diabetics with CKD

 

Larry H Bernstein, MD, FACP, RN 08/01/2012

 

https://pharmaceuticalintelligence.com/2012/08/01/risks-of-hypoglycemia-in-diabetics-with-ckd/

 

Nitric Oxide in bone metabolism

 

Aviral Vatsa, PhD, MBBS, RN 07/16/2012

 

https://pharmaceuticalintelligence.com/2012/07/16/nitric-oxide-in-bone-metabolism/

 

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Abbreviations:

 

Kinase inhibitors (KIs)

Adenosine triphosphate (ATP)

Mitogen-activated protein kinases (MAPK)

Tyrosine kinase (TK)

Papillary thyroid carcinomas (PTC)

Radioiodine (RAI)

Medullary thyroid carcinoma (MTC)

Mammalian target of rapamycin (mTOR)

Neuroendocrine tumors (NETs)

Adrenocortical carcinoma (ACC)

Kinase inhibitors (KIs) are a group of small organic molecules that interfere with the interaction between the kinase domain and adenosine triphosphate (ATP) or other mechanisms such as allosteric inhibitors, thereby inhibiting phosphorylation of the kinase and activation of downstream signaling pathways. The majority of KIs available in clinical practice are non-selective, being active against several molecular targets. They exhibit anticancer activity by targeting molecules that activate signalling pathways which promote cellular survival, proliferation and growth. Besides, KIs act as anti-angiogenic agents by halting the activation of specific receptors of angiogenic factors, thus inhibiting intracellular pathways that stimulate angiogenesis. In the last 15 years, several KIs have been developed and introduced into anticancer clinical trials. Aggressive forms of endocrine cancer are not uniformly responsive to cytotoxic chemotherapies while radiotherapy has mainly a palliative role. To date, therapeutic approach of endocrine tumors which persist after surgery and are not responsive to cytotoxic chemotherapies is challenging. Treatment with KIs is gaining a growing role in this clinical context. The present review focuses state-of-theart role of KIs for the treatment of advanced endocrine neoplasms. The protein kinases transfer the g-phosphate of ATP to the hydroxyl group of a serine, threonine or tyrosine residue on a target protein. Phosphorylation results in a number of diverse conformational and/or functional modifications in different proteins, thus initiating a downstream cascade of reactions. Thereby, the protein kinases act as effectors of intracellular cascades, such as the mitogen-activated protein kinases (MAPK) and the PI3K/Akt pathways, which regulate crucial cellular processes including proliferation, differentiation and survival. Abnormal activation of these pathways is strikingly involved in the process of human oncogenesis. Moreover, activity of angiogenic factors with a demonstrated role in survival and spread of cancer cells are mediated by receptors with tyrosine kinase (TK) function. To date, treatment with KIs is considered the most promising frontier in the field of oncology, especially in cases where the role of a particular protein kinase has a direct causal relevance to cancer through its inappropriate activation. Activating mutations of protein kinases genes have been associated with several types of endocrine cancer. About 70% of papillary thyroid carcinomas (PTC), the most common type (80-85%) of thyroid cancer, arise as a result of single activating somatic mutations of protein kinases genes. These involve single point mutations of BRAF and RAS and rearrangements of RET named RET/ PTC oncogenes. Furthermore, BRAF mutations are associated with radioiodine (RAI) unresponsiveness and increased rates of disease recurrence and mortality. The prominent role of the protein kinase RET in the pathogenesis of medullary thyroid carcinoma (MTC) has been widely demonstrated. RET proto-oncogene encodes a cell membrane TK receptor which regulates activation of the MAPK and PI3K/Akt pathways. Germline RET point mutations are responsible of hereditary forms of MTC, while approximately 50% of sporadic MTCs harbor activating RET mutations. Furthermore, there is a clear correlation between genotype and tumor behavior. A recent study performed by Moura et al. demonstrated that the majority of sporadic RET-negative MTC harbor mutations of HRAS, thus confirming that abnormal activation of the MAPK and PI3K/Akt pathways is a crucial step for MTC tumorigenesis. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays an important role in cellular growth and homeostasis. mTOR is activated by both phosphorylation through PI3K/Akt pathway and autophosphorylation at specific serine residues. As hyperactivation of the mTOR pathway has been detected in many human cancers, mTOR has become one of the most promising targets in anticancer therapy. Recent studies found that mTOR pathway is involved in the pathogenesis of neuroendocrine tumors (NETs) and adrenocortical carcinoma (ACC), thus stimulating trials with selective mTOR inhibitors for the treatment of these endocrine cancers.

Several retrospective and Phase II studies have been published about efficacy and safety of KIs in endocrine cancer but only few randomized Phase III clinical trials have been completed. To date, the largest experience has been gained in the treatment of advanced forms of MTC and NETs. Vandetanib and cabozantinib have been recently approved by the FDA for the treatment of advanced, progressive MTC. Given the toxicity related to the long-term administration, some authors suggest a selective use of these compounds in MTC patients having a wide disease burden and/or a strong progression of disease. Nevertheless, MTC usually exhibits an indolent behavior with just a slow progression of disease even in metastatic patients. Therefore, further studies are needed to identify therapeutic approaches which could improve the risk/benefit ratio in this kind of patients. Treatment with the mTOR inhibitor everolimus, alone or in combination with somatostatin analogs, should be considered in this field. In 2011, sunitinib and everolimus have been definitively approved for the treatment of advanced pancreatic NET. Given the slowly progressing nature of NET, even in advanced cases, patients are likely to be treated with these agents for many months and possibly years. Therefore, issues of long-term safety and compliance will require special attention in the future. Unfortunately, lack of available comparative studies between these targeted therapies makes it difficult to suggest the optimal sequence of treatments. Currently, treatment with TKIs represents the only feasible approach in patients with advanced RAI-refractory DTC. Nevertheless, none of these agents has been approved yet. Two randomized Phase III clinical trials evaluating activity of sorafenib and lenvatinib have recently completed patient accrual, but results are not available yet. Use of KIs has shown promising but still anecdotal results in the treatment of other types of endocrine cancers such as ATC, PGL/PCC and ACC and Phase II/III trials are needed to assess feasibility and activity of KIs in these fields. Finally, a better understanding of the molecular pathogenesis of other endocrine malignancies such as aggressive pituitary tumors and parathyroid carcinoma would be crucial for providing the rationale to the use of KIs.

Source References:

http://www.ncbi.nlm.nih.gov/pubmed/23675883

http://www.ncbi.nlm.nih.gov/pubmed/23450053

http://www.ncbi.nlm.nih.gov/pubmed/17993229

http://www.ncbi.nlm.nih.gov/pubmed/17253488

http://www.ncbi.nlm.nih.gov/pubmed/20605972

http://www.ncbi.nlm.nih.gov/pubmed/10387987

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Curator: Venkat Karra, Ph.D.

Cancer is a broad group of various diseases involving unregulated cell growth. It is medically known as a malignant neoplasm. In cancer, cells divide and grow uncontrollably and invade nearby parts of the body. The cancer may also spread to more distant parts of the body through the lymphatic system or bloodstream, it is called metastasis. However, not all tumors are cancerous. Some tumors do not grow uncontrollably, do not invade neighboring tissues, and do not spread throughout the body which are called Benign tumors.

There are more than 100 types of Cancers. Follow the link to know more:

http://www.cancer.gov/cancertopics/types/alphalist

Classification of Cancers:

There are five broad groups that are used to classify cancer.

  1. Carcinomas: These are characterized by cells that cover internal and external parts of the body such as lung, breast, and colon cancer.
  2. Sarcomas:These are characterized by cells that are located in bone, cartilage, fat, connective tissue, muscle, and other supportive tissues.
  3. Lymphomas:These are cancers that begin in the lymph nodes and immune system tissues.
  4. Leukemias:These are cancers that begin in the bone marrow and often accumulate in the bloodstream.
  5. Adenomas:These are cancers that arise in the thyroid, the pituitary gland, the adrenal gland, and other glandular tissues.

Causes

  • Hereditary (about 5-10%)
  • Environmental (90-95% of cases) factors e.g.,
  • Tobacco (25-30%) – about 70% of the lung cancers are due to tobacco habit
  • Infections (15-20%)
  • Radiation (both ionizing and non-ionizing, up to 10%)
  • Obesity (30-35%) and
  • Pollutants,Sedentary life, poor diet etc. are likely to cause cancer.

These can directly damage genes or combine with existing genetic faults within cells to cause the disease.

Detection

Presence of certain signs and symptoms, screening tests including medical imaging etc. can be used.

Diagnosis

Cancer can be diagnosed by microscopic examination of a tissue sample called biopsy.

Visit Link for details: http://cancer.stanford.edu/information/cancerDiagnosis/

Treatment

Cancer is usually treated with chemotherapy, radiation therapy and surgery.

Survival

Survival depends greatly by the type and location of the cancer and the extent of disease at the start of treatment. The risk of developing cancer generally increases with age.

Young People with Cancer, visit the following link for details:

http://www.cancer.gov/cancertopics/coping/youngpeople/page6

For Types of Childhood Cancer, visit the following link:

http://www.cancer.gov/cancertopics/coping/youngpeople/page13

For common medical procedures, visit the following link:
http://www.cancer.gov/cancertopics/coping/youngpeople/page6

Signs and Symptoms

Initially there will be no signs and symptoms but only appearing as the mass that continues to grow or ulcerates. The findings that result depends on the type and location of the cancer. For example,

Mass effects from Lung Cancer – can cause blockage of the bronchus resulting in cough (coughing up blood if there is ulceration) or pneumonia.

Oesophageal Cancer – can cause narrowing of the esophagus making it difficult or painful to swallow.

Colorectal Cancer – may lead to changes in bowel habits and bleeding leading to anemia.

General symptoms may include:

  • Unintentional weight loss,
  • Fever,
  • Being excessively tired,
  • Changes to the skin,
  • Hodgkin disease,
  • Leukemias, and
  • Persistent fever due to Cancers of the liver or kidney.

Symptoms of metastasis include:

  • Enlarged lynph nodes which can be felt or sometimes seen under the skin and are typically hard),
  • Enlarged liver or spleen which can be felt in the abdomen,
  • Pain or fracture of affected bones, and
  • Neurological symptoms.

It is nearly impossible to prove what caused a cancer in any individual, because most cancers have multiple possible causes. For example, lung cancer could be due to tobacco habbit or could be a result of air pollution or radiation.

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