more than one million individuals develop colorectal cancer ( crc ) each year worldwide , and the disease - specific mortality rate is nearly 33% in the developed countries . crc can be separated into two sites : colon cancer ( 72% ) , and rectum cancer ( 28% ) , although incidence of crc is generally reported together . classification of crc is referred to their pathological stage , which can be observed after surgery . because the clinical and pathological stages may be different , imaging tests of the observed stage about 95% of crcs are sporadic ( with no background of a family history of the disease ) ; in such cases , mutated genes occur by chance . familiar crcs are less common ( about 5% ) and occur when gene mutations are passed within a family from one generation to the next . in these cases , mutated genes ( germline mutation ) are inherited . inherited crcs include : hereditary nonpolyposis colorectal cancer ( hnpcc ) or lynch syndromes i and ii , familiar adenomatous polyposis ( fap ) , myh associated polyposis ( map ) , peutz - jeghers syndrome ( pjs ) , and juvenile polyposis syndrome ( jps ) [ 1 , 2 ] . factors that regulate and control cell growth are key points to the development of the cancer . proteins in insulin pathway play a significant role in the initiation of cell growth and proliferation of colorectal cancers . diet , lifestyle , physical activity , body size , and sex steroids , and genetic factors affect the regulation of insulin . inflammation , hormones and energy - related factors are critical elements associated with colon cancer . snp related functional proteomics involve the identification of functional snps that modify structure and function of protein active sites . developing a source of the modifications generated by functional ( coding ) snps in disease related proteins will direct the mutations in the population for proper treatment . polymorphisms in genes which are involved in insulin pathway cause hyperinsulinemia ; insulin resistance and hyperinsulinemia are prevalent in obese patients . hyperinsulinemia has been hypothesized to play a role in the obesity - colorectal cancer relationship .epidemiological studies have demonstrated that interactions between genetic and environmental factors may play important roles in the pathogenesis of cancer . individual genetic susceptibility   suggests that genetic background is one of the critical crc risk factors [ 9 , 10 ] . in this review , we integrate and assess studies from the literature relating to polymorphisms of insulin pathway protein genes in the context of colorectal carcinoma . insulin , insulin - like growth factors , insulin - like growth factor receptors ( igf r of type 1 and type 2 ) and insulin - like growth factor binding proteins ( igf - bp 1 - 6 ) , play an important role in the normal control of growth related processes . also , they can act in endocrine ( like a hormone ) , and in an autocrine / paracrine manner . indeed , tumor cells could induce their own proliferation by the synthesis of endogenous igf molecules . this process of autocrine stimulation causes faster tumor growth .hormone induction and polymorphism in igfs gene influence the expression level of igfs . some studies have demonstrated a relationship between higher igf1 levels , lower igfbp3 levels , and an increased risk of colorectal cancer [ 14 - 16 ] . in addition to serum igf and igfbp levels , it is important to understand the frequency of a genetic polymorphism in a given population to assess its role in potential risk of a disorder . data suggests high heterogeneous relationship between colorectal cancer and insulin like growth factor polymorphisms [ 17 - 20].in 2013 , a meta - analysis suggested that igfbp3 a-202c and gly32ala polymorphisms may not be associated with colorectal cancer development . igf family is involved in the regulation of somatic growth , cell proliferation , transformation , and apoptosis . igf - i , by binding to the igf - i receptor , stimulates growth and metabolism and activates a protein tyrosine phosphorylation signal transduction cascade that is similar to the one involved in insulin action . growth hormone ( gh ) binds to gh receptor ( gh - r ) which leads to igf-1 production . igf-1 binds to igf - r1 , and causes enhanced growth cell proliferation , and also anti - apoptotic effects . interactions of igf - bps with igf-1 reduce the affinity of igf-1 for igf - r1 . connection of igf - bps with ecm decreases the affinity of igfbps for igfs , and therefore increases the level of free igfs . igfbps control the level of igf and its function which lead to change in igf signaling . igfbps by binding to igf - i , generally inhibit its action and thereby reduce its bioavailability [ 27 , 28 ] . in rats , insulin enhances the growth of aberrant crypt foci , crc precursor lesions , and increases the number and size of the tumors . some studies have confirmed that insulin increases the neoplastic proliferation of cell lines and that the insulin receptor is commonly expressed in human neoplasms . several common genetic variants within the insulin signaling pathway that are associated with hyperinsulinemia and insulin resistance have been identified . the relation between genetic variants that cause insulin resistance and colorectal cancer can predispose insulin resistance and also increase susceptibility to colorectal neoplasia [ 32 , 33 ] . population based studies have provided evidences that polymorphic variation of relevant genes can cause colorectal cancer risk by changing the circulating level of insulin and insulin like growth factors . observations are consistent with vivo experimental studies [ 29 , 34 ] that demonstrate growth - promoting effects of exogenous insulin , and dietary - induced hyperinsulinemia ; they have shown that insulin increases the growth of colon epithelial and carcinoma cells in vitro . it has been suggested that insulin may promote colorectal carcinogenesis directly by activating its own receptor , the receptors for igf - i , or hybrid insulin / igf - i receptors . the role of insulin in colorectal carcinogenesis is supported by recent experimental and observational studies [ 15 , 38 ] . elevated circulating levels of insulin may lead to changes in igfbp concentrations through increasing igf - i bioavailability ; and this insulin mediation , via inducing pathophysiologic changes in concentrations of circulating igf - i and igfbps , promotes colorectal carcinogenesis . when insulin binds to its receptor , pi3k pathways can be activated and cause cell proliferation and survival . polymorphism of insulin gene and its association with colorectal cancer were demonstrated by some studies . overexpression of the insulin receptor ( ir ) can induce cell transformation in vitro and human colorectal adenocarcinomas . studies show a relationship between adiponectin [ adipoq ] and its receptors [ adipors ] with obesity and insulin resistance . the association of adipoq and its receptor genes in the development of obesity and insulin resistance confirms the role of adipoq and its receptor genes in colorectal carcinogenesis [ 43 , 44 ] . several studies have demonstrated the inverse association between serum adipoq and colorectal cancer risk [ 45 - 47 ] . it was demonstrated that in vitro , adipoq presented growth inhibition and apoptosis induction in colorectal cancer cell lines . in vivo , mice with lack of adipoq in serum showed more intestinal tumors . circulating adipoq level showed a significant negative association with metabolic syndrome traits , whereas adipors level had a positive association with metabolic syndrome traits . adiponectin can suppress the cell proliferation of colon cancer via adipor- and -r2-mediated ampk activation . adipoq has the anticancer role through connection to its receptors , which have been demonstrated to repress colon cancer cell lines . adipoq plays a suppressing role by activating peroxisome proliferator - activated receptor - a ( ppar - a ) which causes inhibition of fas activity [ 52 , 53 ] . some studies have demonstrated the elevated expression of adipors in colorectal carcinomas than in normal gastrointestinal tissue . it was shown that the inverse relation of adiponectin with risk of endometrial cancer is not always depend on igf - i , igf - ii , igfbp-3 , leptin , bmi , but the combination of high bmi and low adiponectin levels lead to a more than six - fold excess risk of endometrial cancer .in obesity , reduced adiponectin levels lead to the development of insulin resistance and compensatory and chronic hyperinsulinemia [ 57 , 58 ] . adiponectin has a proapoptotic activity because of inhibition of tnf - a production and angiogenesis . therefore , altered effects of tnf - a on tumor cell due to low adiponectin levels can potentially lead to carcinogenesis through proliferation . the association between genes of the adiponectin pathway and risk of colorectal cancer has been reported in case - control studies [ 56 , 60 ] . lep and lep receptor : leptin is a 16 kda glycolprotein product of the leptin gene ( lep ) , which is expressed almost exclusively ( > 95% ) by adipocytes . plasma leptin levels are elevated in obesity and are raised with an increase of fat mass . leptin exerts its physiological action through the leptin receptor , which is expressed in colon cancer cell lines , human normal colonic , and adenomatous polyps [ 63 , 64 ] . it is evident that leptin physiological properties are associated with energy homeostasis function and obesity . in addition , leptin is associated with inflammatory response , insulin signaling , bone remodeling and neuroendocrine function . leptin can act as a mitogen , transforming or migration factor for many different cell types [ 66 , 67 ] . some studies have shown an association between high leptin levels with increased crc risk [ 68 , 69 ] . leptin and its receptor are associated with energy balance , adiposity , insulin , inflammation and vitamin d ; and these mentioned factors are associated with colon cancer [ 70 - 72 ] . colon cancer is the third most common cancer in men and the second in women worldwide . therefore , understanding the role of genetic alteration in colorectal neoplasia will provide improved interventions for this malignancy . polymorphisms in insulin [ igfs , igfbps , ins , and insr ] and obesity [ adipo , adipor , lep , lepr ] genes promote cancer development and progression at various stages of the carcinogenic process . since genetic mutations are involved in the initiation and progression of colorectal cancer , information on these changes may provide a clue for better diagnostic , prognostic , and appropriate treatment .
colon cancer is the cancer of the large intestine ( colon ) , which is located in the lower part of digestive system . 
 colon cancer is the third most common cancer in men and the second in women worldwide.genetic background is thought to play a role in modulating individual risks of this cancer.many studies support an association between insulin pathway gene polymorphisms and regulation of tumor cell biology in colorectal cancer . 
 this review examines the role of polymorphisms of insulin and obesity pathway genes ( igfs , ins , insr , adipoq , adipoqr , lep and lepr ) in development of colorectal cancer .