**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

**5**

*Introductory Chapter: Interactions between Environmental Chemicals and KRAS Oncogene…*

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,

The major genetic pathways of colorectal cancers (CRCs) are usually divided

1. "The Chromosome Instability Pathway" representing the pathway of sporadic CRC through the KRAS, adenomatous polyposis coli (APC), and tumor sup-

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 [18–20]. 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

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

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 tumorassociated 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

*DOI: http://dx.doi.org/10.5772/intechopen.82459*

mutated K-Ras has an incidence of ∼50% [14].

pressor protein 53 (P53) mutations.

into two pathways [15, 16]:

and cetuximab [23, 24].

**3.2 Pancreatic cancer**

an incidence of ∼70–90% [14].

*Introductory Chapter: Interactions between Environmental Chemicals and KRAS Oncogene… DOI: http://dx.doi.org/10.5772/intechopen.82459*

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]:


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 [18–20]. 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**

*Oncogenes and Carcinogenesis*

**2. KRAS gene**

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 [1–3]. In the past 50 years, several oncogenes have been identified in different types of human cancers. There are many

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 [4–6]. 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 [7–9]. This chapter mainly focuses on CRCs, PC, and lung cancer and KRAS. Moreover, the interactions between KRAS mutations and environmental

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].

Colorectal cancers (adenomas or carcinomas) occur as a combination of unbal-

anced diet, environmental exposures, accumulation of genetic and epigenetic

**3. Cancers associated with KRAS**

**3.1 Colorectal cancers**

cancer drugs that target the proteins encoded by oncogenes [1–3].

factors in these particular cancers will also be mentioned.

**4**

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 tumorassociated 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 [27–29]. 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 wildtype and mutant groups [8].
