Open access

Introductory Chapter: Interactions between Environmental Chemicals and KRAS Oncogene in Different Cancers - Special Focus on Colorectal, Pancreatic, and Lung Cancers

Written By

Pinar Erkekoglu

Submitted: 05 October 2018 Published: 07 December 2018

DOI: 10.5772/intechopen.82459

From the Edited Volume

Oncogenes and Carcinogenesis

Edited by Pinar Erkekoglu

Chapter metrics overview

1,099 Chapter Downloads

View Full Metrics

1. Introduction

v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is an oncogene. The KRAS gene is located on the twelfth chromosome and belongs to the Ras family of oncogenes. These proteins play important roles in cell division, cell differentiation, and apoptotic cell death. Induction of KRAS with different environmental chemicals leads to high expression of K-Ras protein, which in turn causes high cellular proliferation. These cascade of events finally initiate certain types of cancers, particularly colorectal (CRC), pancreatic, and lung cancers. High calorie intake, diets rich in meat and fat, smoking, and alcohol consumption are the major risk factors of CRCs, and it was estimated that in CRC, mutated KRAS has an incidence of ∼50%. Exposure to certain environmental chemicals [organochlorine insecticides such as DDT and its metabolite dichlorodiphenyltrichloroethylene (DDE); herbicides such as EPTC and pendimethalin; N-nitrosamines; polychlorinated biphenyls (PCBs); benzene] and drugs (anti-diabetics drugs) can also contribute to the increased incidence of PC throughout the world. It was stated that in adenocarcinomas of the pancreas, mutated KRAS has an incidence of ∼70–90%. Lung cancer is the leading cause of deaths worldwide. KRAS gene mutations are much more common in long-term tobacco smokers with lung cancer when compared to nonsmokers. KRAS gene mutations are observed in 15–25% of all lung cancer cases, being more frequent in whites vs. Asian populations. Lung cancers with KRAS gene mutations typically indicate a poor prognosis and are associated with resistance to several cancer treatments. This chapter mainly focuses on KRAS, interactions between environmental chemicals, and KRAS oncogene in different cancers, particularly in colorectal, pancreatic, and lung cancers.

Most oncogenes are expressed as proto-oncogenes, involved in cell growth and proliferation or inhibition of apoptosis. If there are chemical, physical, or biological factors that cause mutations in such genes promoting cellular growth, these genes are mostly upregulated and cellular proliferation increases [1]. The cascade of events leading to proliferation usually predisposes the cell to cancer. In this case, they are termed as “oncogenes” [1, 2]. These genes are mutated and/or overexpressed at high levels in tumor cells. Normally, cells repair themselves or undergo apoptosis if there is an interruption on the cell cycle. However, the high expression of multiple oncogenes, along with mutated apoptotic and/or tumor suppressor genes and exposure to environmental chemicals that trigger such mutations can all act in concert and finally cause tumorigenesis [1, 2, 3]. In the past 50 years, several oncogenes have been identified in different types of human cancers. There are many cancer drugs that target the proteins encoded by oncogenes [1, 2, 3].

Genetic and environmental interactions usually determine the profiles of cancers. v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is a very important oncogene for the initiation of cancer [1]. It is usually found to be mutated in different types of cancer, particularly in colorectal cancers (CRCs), pancreatic cancer (PC), and lung cancer [4, 5, 6]. Concerning KRAS, different chemicals such as polychlorinated biphenyls (PCBs), certain antidiabetic drugs, and pesticides may be leading causes of KRAS mutations, and such mutations increase the expression of K-Ras protein in different tissues, leading to high cellular proliferation and finally carcinogenesis [7, 8, 9]. This chapter mainly focuses on CRCs, PC, and lung cancer and KRAS. Moreover, the interactions between KRAS mutations and environmental factors in these particular cancers will also be mentioned.


2. KRAS gene

The most important oncogene for several types of cancer is KRAS. Cytogenetic location of this gene is 12p12.1 [the short (p) arm of chromosome 12 at position 12.1] [10]. The KRAS gene belongs to the Ras family of oncogenes. RAS family oncogenes also include two other genes: H-RAS and N-RAS. These proteins play important roles in cell division, cell differentiation, and apoptotic cell death. KRAS causes the initiation of cancer through deregulation of the G1 cell cycle [10].

The KRAS gene expresses a protein called “K-Ras,” which is part of a signaling pathway known as “the RAS/microtubule-associated protein (MAP) kinase signaling (MAPK) pathway.” The protein carries the mitogenic signals from the “epidermal growth factor receptor (EGFR)” on the cell surface to the cell nucleus. These signals provide instructions for growth, proliferation, maturation, or differentiation to the cell. The K-Ras protein converts a molecule called guanosine-5′-triphosphate (GTP) into another molecule called guanosine-5′-diphosphate (GDP), and therefore, it is a “GTPase.” By such conversion, K-Ras protein almost acts like a “switch,” which is turned on and off by the GTP and GDP molecules. In order to transmit signals, K-Ras must bind to GTP, and this turns on the protein [10]. However, K-Ras protein is inactivated when it converts the GTP to GDP. This means that when this particular protein is bound to GDP, it does not send signals to the nucleus. In several pathological conditions [cardiofaciocutaneous syndrome, Noonan syndrome, Costello syndrome, autoimmune lymphoproliferative syndrome (ALPS), and epidermal nevus] and different cancers [colorectal (CRC), pancreatic (PC), and lung cancer; cholangiocarcinoma; and core binding factor acute myeloid leukemia (CBF-AML)], KRAS mutations are observed in patients [10].


3. Cancers associated with KRAS

3.1 Colorectal cancers

Colorectal cancers (adenomas or carcinomas) occur as a combination of unbalanced diet, environmental exposures, accumulation of genetic and epigenetic instability, and oncogenic gene activations [11, 12]. It is certainly clear that unbalanced diet is a major risk factor for the development of CRCs. A constant, high, or prolonged exposure of colon to carcinogens is the primary cause for malignant transformation of colonocytes [11, 12]. If hereditary disposition (in terms of mutations in key genes controlling cell cycle and replication) is already present, genome instability will accelerate tumorigenesis process [13]. It was estimated that in CRC, mutated K-Ras has an incidence of ∼50% [14].

The major genetic pathways of colorectal cancers (CRCs) are usually divided into two pathways [15, 16]:

  1. “The Chromosome Instability Pathway” representing the pathway of sporadic CRC through the KRAS, adenomatous polyposis coli (APC), and tumor suppressor protein 53 (P53) mutations.

  2. The “Microsatellite Instability Pathway” representing the pathway of hereditary non-2 primary KRAS mutation generally leads to a self-limiting hyperplastic or borderline lesion and may be implicated in the serrated pathway through which serrated adenomas and carcinomas may also develop.

The KRAS mutation alone is not sufficient or necessary to drive the malignant transformation. Therefore, additional “drivers” should be present in the development of CRC. These additional factors include but are not limited to high calorie intake, diets rich in meat and fat, smoking, and alcohol consumption [17]. KRAS mutations are frequently found in <95% of early dysplasia, including aberrant crypt foci (ACF), and also in hyperplastic polyps [18, 19, 20]. The sequence in which the KRAS mutation occurs in relation to the APC mutation is important. The dysplastic lesion often progresses to carcinogenesis if a mutation in KRAS gene occurs right after an APC mutation [21, 22]. Because of the key role in EGFR signaling, the presence of a KRAS mutation predicts a very poor response to specific antibody (monoclonal antibodies) treatment with EGFR inhibitors such as panitumumab and cetuximab [23, 24].

3.2 Pancreatic cancer

Pancreatic cancer is a multifactorial and extremely aggressive type of cancer. Pancreatic tumors are usually highly chemoresistant, and many types of PC have very bad prognoses. Little information regarding the possible association of different risk factors with the known genetic alterations (such as activation of KRAS oncogene and inactivation of the p53 gene) is present in the literature [8, 25]. However, it was stated that in adenocarcinomas of the pancreas, mutated KRAS has an incidence of ∼70–90% [14].

Increasing data on the molecular pathogenesis of PC have shown that genetic alterations, such as mutations of KRAS and particularly epigenetic dysregulation (DNA methylation, histone acetylation, or microRNA expressions) of tumor-associated genes [i.e., silencing of the tumor suppressor p16 (ink4a)], are suggested to be hallmarks of PC. Serine/threonine-protein kinase (Raf), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), and Ral guanine nucleotide dissociation stimulator (RaLGDS) are the major effectors of KRAS in adenomas of pancreas [26, 27].

Repeated acute pancreatic injury and inflammation are important contributing factors in the development of PC. Alcohol consumption, cigarette smoking, diet (high coffee consumption), environmental chemicals [organochlorine insecticides such as DDT and its metabolite dichlorodiphenyltrichloroethylene (DDE); herbicides such as s-ethyl dipropylthiocarbamate (EPTC) and pendimethalin; N-nitrosamines; polychlorinated biphenyls (PCBs); benzene], and drugs [diabetes drugs like glucagon-like peptide-1 (GLP-1) agonists, such as exenatide; dipeptidylpeptidase-4 inhibitors (DPP-4), such as sitagliptin; calcium channel blockers such as nifedipine, nicardipine, and diltiazem] can also contribute to the highly increasing incidence of PC throughout the world. On the other hand, gall stones, diabetes, and obesity are the major pathological factors associated with PC [27, 28, 29]. In a study by Slebos et al., mutations in KRAS codon 12 were found in 75% of the PC patients. However, there were no differences in blood PCB levels between the KRAS wild-type and mutant groups [8].

3.3 Lung cancer

Lung cancer is the primary cause of cancer-related deaths worldwide. Active and passive smoking are the two of primary causes of lung cancer. Lung cancers are classified as small cell (non-epithelial) or non-small cell carcinomas (epithelial-derived). Small cell carcinomas are highly malignant; has the ability to metastasize easily and chemotherapy is the choice of treatment. However, treatment of non-small cell cancer primarily involves surgical excision, supplemented by radiation or chemotherapy. Although this treatment method may provide partial or full recovery, it also increases the risk for concurrent diseases. Using anti-cancer drugs with “high efficacy and low-toxicity” is the priority goal in this field [30, 31].

KRAS gene mutations are observed in 15–25% of all lung cancer cases. These mutations are more frequent in white populations than in Asian populations. About 25–50% of whites with lung cancer have KRAS gene mutations, whereas 5–15% of Asians with lung cancer have KRAS gene mutations [14].

In lung adenocarcinomas, both KRAS-activating mutations and in and EGFR mutations can be observed. KRAS appear to be mutually exclusive. Three different mutations in the KRAS gene have been associated with lung cancer [32]. Nearly all of the KRAS gene mutations associated with lung cancer change the amino acid glycine at position 12 or 13 (Gly12 or Gly13) or change the amino acid glutamine at position 61 (Gln61) in the K-Ras protein. These mutations cause a constantly activated KRAS, which directs the cells to proliferate in an uncontrolled way, and the high cellular proliferation leads to tumor formation [33].

Even though KRAS mutations were identified in non-small cell lung tumors more than 20 years ago, the clinical value of determining KRAS tumor status is recently gaining importance. Recent studies indicate that patients with mutant KRAS tumors fail to benefit from adjuvant chemotherapy and do not respond to EGFR inhibitors. There is a clear need for therapies specifically developed for patients with KRAS-mutant non-small cell lung cancers [34, 35]. KRAS gene mutations are much more common in long-term tobacco smokers with lung cancer when compared to nonsmokers. Lung cancers with KRAS gene mutations typically indicate a poor prognosis and are associated with resistance to several cancer treatments [33, 34, 35].


4. Conclusion

KRAS is a very important oncogene. K-Ras protein is upregulated in different cancers and can cause bad prognosis of the disease. However, KRAS mutations are not sometimes enough to initiate cancer. Therefore, along with KRAS mutations, several environmental chemicals and drugs may contribute to the cascade of events leading to cancer.

It can be stated that in CRCs, PC, and lung cancer, KRAS mutations should be evaluated in clinics. On the other hand, the exposures of different environmental chemicals and drugs (pesticides, PCBs, tobacco smoke, alcohol, N-nitrosamines, benzene, antidiabetics, calcium channel blockers, etc.) should be evaluated along with KRAS mutations, and the patients with preneoplastic lesions should be warned about such exposures. As KRAS gene mutations generally indicate a poor prognosis and are associated with resistance to several cancer treatments, new drugs targeting different molecules in KRAS triggering pathways should be developed in order to overcome this resistance, particularly in CRCs, PC, and lung cancer.


  1. 1. Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators in human disease. Cell. 2017;170(1):17-33
  2. 2. Denis JA, Lacorte JM. Detection of RAS mutations in circulating tumor cells: Applications in colorectal cancer and prospects. Annales de Biologie Clinique. 2017;75(6):607-618
  3. 3. Ryan MB, Corcoran RB. Therapeutic strategies to target RAS-mutant cancers. Nature Reviews. Clinical Oncology. 2018;15(11):709-720
  4. 4. Ciliberto D, Staropoli N, Caglioti F, Chiellino S, Ierardi A, Ingargiola R, et al. The best strategy for RAS wild-type metastatic colorectal cancer patients in first-line treatment: A classic and Bayesian meta-analysis. Critical Reviews in Oncology/Hematology. 2018;125:69-77
  5. 5. Li D, Jiao L. Molecular epidemiology of pancreatic cancer. International Journal of Gastrointestinal Cancer. 2003;33(1):3-14
  6. 6. Zhang J, Park D, Shin DM, Deng X. Targeting KRAS-mutant non-small cell lung cancer: Challenges and opportunities. Acta Biochimica et Biophysica Sinica Shanghai. 2016;48(1):11-16
  7. 7. Nakanishi Y, Bai F, Inoue K, Takayama K, Pei XH, Harada T, et al. Polychlorinated biphenyls promote 1-nitropyrene-induced lung tumorigenesis without the induction of K-ras gene mutation in a/J mice. Teratogenesis, Carcinogenesis, and Mutagenesis. 2001;21(6):395-403
  8. 8. Slebos RJ, Hoppin JA, Tolbert PE, Holly EA, Brock JW, Zhang RH, et al. K-ras and p53 in pancreatic cancer: Association with medical history, histopathology, and environmental exposures in a population-based study. Cancer Epidemiology, Biomarkers & Prevention. 2000;9(11):1223-1232
  9. 9. Szablewski L. Diabetes mellitus: Influences on cancer risk. Diabetes/Metabolism Research and Reviews. 2014;30(7):543-553
  10. 10. Genetics Home Reference. US National Library of Medicine. KRAS gene KRAS proto-oncogene. GTPase. Available from:
  11. 11. World Cancer Research Fund, American Institute for Cancer Research. Continous Update Project Report. Food, Nutrition, Physical Activity, and the Prevention of Colorectal Cancer. 2011. Available from:
  12. 12. Lynch HT, de la Chapelle A. Hereditary colorectal cancer. The New England Journal of Medicine. 2003;348:919-932
  13. 13. Weitz J, Koch M, Debus J, Höhler T, Galle PR, Büchler MW. Colorectal cancer. Lancet. 2005;365:153-165
  14. 14. Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature. 2001;410(6832):1111-1116
  15. 15. Kukor Z, Mayerle J, Krüger B, Tóth M, Steed PM, Halangk W, et al. Presence of cathepsin B in the human pancreatic secretory pathway and its role in trypsinogen activation during hereditary pancreatitis. The Journal of Biological Chemistry. 2002;277(24):21389-21396
  16. 16. Lee H, Herrmann A, Deng JH, Kujawski M, Niu G, Li Z, et al. Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer Cell. 2009;15(4):283-293
  17. 17. Lee MS, Gu D, Feng L, Curriden S, Arnush M, Krahl T, et al. Accumulation of extracellular matrix and developmental dysregulation in the pancreas by transgenic production of transforming growth factor-beta 1. The American Journal of Pathology. 1995;147(1):42-52
  18. 18. Alrawi SJ, Schiff M, Carroll RE, Dayton M, Gibbs JF, Kulavlat M, et al. Aberrant crypt foci. Anticancer Research. 2006;26(1A):107-119
  19. 19. Feng Y, Bommer GT, Zhao J, Green M, Sands E, Zhai Y, et al. Mutant KRAS promotes hyperplasia and alters differentiation in the colon epithelium but does not expand the presumptive stem cell pool. Gastroenterology. 2011;141:1003-1013. e1-10
  20. 20. Otori K, Oda Y, Sugiyama K, Hasebe T, Mukai K, Fujii T, et al. High frequency of K-ras mutations in human colorectal hyperplastic polyps. Gut. 1997;40:660-663
  21. 21. Grady WM, Carethers JM. Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology. 2008;135:1079-1099
  22. 22. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nature Medicine. 2004;10:789-799
  23. 23. Markman B, Javier Ramos F, Capdevila J, Tabernero J. EGFR and KRAS in colorectal cancer. Advances in Clinical Chemistry. 2010;51:71-119
  24. 24. Kolodecik T, Shugrue C, Ashat M, Thrower EC. Risk factors for pancreatic cancer: Underlying mechanisms and potential targets. Frontiers in Physiology. 2014;4:415
  25. 25. Nussinov R, Tsai CJ, Muratcioglu S, Jang H, Gursoy A, Keskin O. Principles of K-Ras effector organization and the role of oncogenic K-Ras in cancer initiation through G1 cell cycle deregulation. Expert Review of Proteomics. 2015;12(6):669-682
  26. 26. Neureiter D, Jäger T, Ocker M, Kiesslich T. Epigenetics and pancreatic cancer: Pathophysiology and novel treatment aspects. World Journal of Gastroenterology. 2014;20(24):7830-7848
  27. 27. Edderkaoui M, Eibl G. Risk factors for pancreatic cancer: Underlying mechanisms and potential targets. Frontiers in Physiology. 2014;5:490
  28. 28. Andreotti G, Freeman LE, Hou L, Coble J, Rusiecki J, Hoppin JA, et al. Agricultural pesticide use and pancreatic cancer risk in the agricultural health study cohort. International Journal of Cancer. 2009;124(10):2495-2500
  29. 29. Fritschi L, Benke G, Risch HA, Schulte A, Webb PM, Whiteman DC, et al. Occupational exposure to N-nitrosamines and pesticides and risk of pancreatic cancer. Occupational and Environmental Medicine. 2015;72(9):678-683
  30. 30. Kutkowska J, Porębska I, Rapak A. Non-small cell lung cancer—Mutations, targeted and combination therapy. Postepy Higieny i Medycyny Doświadczalnej (Online). May 17 2017;71(0):431-445
  31. 31. Lin PY, Chang YJ, Chen YC, Lin CH, Erkekoglu P, Chao MW, et al. Anti-cancer effects of 3,5-dimethylaminophenol in A549 lung cancer cells. PLoS One. 2018;13(10):e0205249
  32. 32. Karachaliou N, Mayo C, Costa C, Magrí I, Gimenez-Capitan A, Molina-Vila MA, et al. KRAS mutations in lung cancer. Clinical Lung Cancer. 2013;14(3):205-214
  33. 33. Prior IA, Lewis PD, Mattos C. A comprehensive survey of Ras mutations in cancer. Cancer Research. 2012;72(10):2457-2467
  34. 34. Chapman AM, Sun KY, Ruestow P, Cowan DM, Madl AK. Lung cancer mutation profile of EGFR, ALK, and KRAS: Meta-analysis and comparison of never and ever smokers. Lung Cancer. 2016;102:122-134
  35. 35. Subramanian J, Govindan R. Molecular profile of lung cancer in never smokers. EJC Supplements. 2013;11(2):248-253

Written By

Pinar Erkekoglu

Submitted: 05 October 2018 Published: 07 December 2018