BACKGROUND

Historically colorectal cancer (CRC) is diagnosed very often among men and women in the United States. Many studies have investigated the role of gene-diet interactions in the developing process of colorectal cancer (Kantor and Giovanucci, 2016).

It is necessary here to clarify exactly what is meant by saying the word diet. Diet is defined as the quantity of food consumed by a person. Dietary habits are the decision a person makes when chooses something to eat. Each individual may have specific food preferences according to personal tastes and local traditions. Personal dietary preferences may or may not play a crucial role in health and wellbeing (Theodoratou et all 2017).

From the other side Genes also need to be defined. Genes are responsible for protein formation, expression, and metabolic function. Natural genetic variations which occur in more than 1% of the general population are known as polymorphisms. Polymorphisms commonly involve variations at a single pair in a DNA sequence and are known as single nucleotide polymorphisms (SNPs). Genes can be switched on and switched off in response to metabolic signals that the nucleus receives from internal factors (hormones) or external factors (diet). Nutritional genomics is the science which studies the relationship between human genome nutrition and health (Theodoratou et all 2017).

A big number of dietary factors have been linked to colorectal cancer risk. Specifically, the consumption of folate, alcohol, vitamin D, calcium, fibers, fruit, vegetables, and red/processed meat have been associated with increased or decreased colorectal cancer risk. Clarifying the groups of the population for whom these dietary risk factors may affect more or less may help to develop intervention efforts. Additionally, the understanding of gene-diet interactions may lead us to understand the mechanisms by which dietary factors affect the risk of colorectal cancer, consequently improving our understanding of colorectal cancer etiology and supporting a causal role of diet in the development of colorectal cancer (Kantor and Giovanucci, 2016).

PATHOPHYSIOLOGY AND DIAGNOSIS OF COLORECTAL CANCER

Colorectal cancer is a deadly disease, which progresses gradually and it can be divided into five stages. Stage 0 can be described by a tumor at the region of the mucosa or inner lining of the colon. The second stage in colorectal cancer is when the cancer cells grow in the mucosa,  however, their invasive ability is restricted to the muscular region and it is not present in the neighboring tissues of the colon. Stage two can be categorized into 3 types based on invasive growth: the walls of the colon, the muscular layer of the abdomen lining, and nearby tissues. Stage 3 can be divided into 3 types depending on the growth of cancer. During this stage, cancer grows into the inner lining of the colonic muscular layer and forms lymph nodules in surrounding tissues. Based on the number of nodules formations, this stage can be named IIA, IIB, or IIC. The final stage is the worst one of the disease where cancer has been spread to distant parts of the body (Pandurangan et all 2018).

Pandurangan et all (2018). The different stages during the progression of colorectal carcinogenisis.

Tumor-suppressors are genes whose products control cell division and proliferation. They also participate in DNA repair mechanisms and other important processes such as apoptosis pathway. Loss of function of these genes may cause problems such as unregulated cell growth that can lead to malignancy.  APC mutation/ inactivation, K-ras activation, 18q loss, and P53 inactivation are included in the development of adenoma-carcinoma (Joyce and Kasi, 2018).

Margetis et all, (2017). The current model of colorectal cancer development: the adenoma-carcinoma sequence.

APC:






It is widely accepted that APC as a tumor-suppressor gene is mutated frequently in colorectal cancer. Mutation and inactivation of this specific gene is the initial point which is observed in colorectal tumourigenesis. Alterations in the APC gene is an early event for 85 % of sporadic (non inherited) colorectal cancers, apart from those that demonstrate a CpG island methylator phenotype (CIMP) or a hypermutable micro-satellite instability (MSI) phenotype because of mismatch repair (MMR) deficiency (Zhang and Shay, 2017).

K-ras:


K-rasis a proto-oncogene. Proto-oncogenes are normal genes that can become oncogenes after mutation. K-ras regulates cell movement and cell cycle, helps genes to be expressed, stop cell proliferation and increases survival and cell apoptosis. K-ras is extremely mutated in colorectal cancer and the most predominant oncogenic driver mutation in colorectal cancer. It is one of the initial processes although it is well known that it can occur at any stage (Margetis et all 2017).

18q:


LOH (loss of heterozygosity), affecting 18q increased from zero in normal tissue to 13% in small adenomas, 47% in larger ones and 73% in carcinomas. Many studies have been carried out to define the potential prognostic effect of LOH 18q in CRC. LOH in 18q has been inversely linked to MSI. There are many tumor-suppressor genes in 18q, e.g. Deleted in Colorectal Carcinoma (DCC), Mothers Against Decapen-taplegic Homolog 4 (SMAD4), SMAD2, and CDK5 And ABL1 Enzyme Substrate (CABLES1) (15) which might interfere with and subsequently explain the prognostic value of LOH 18q (Sideris and Papagrigoriadis 2014).

P53:


The p53 tumor-suppressor gene exhibits molecular abnormalities noticed in several human cancers and it is linked to the transition from adenoma to carcinomain colorectal cancer. Activation of p53 DNA damage stress response includes DNA repair and regulates the cell cycle to prevent oncogenic mutations. Alteration of p53 in CRC results in the loss of apoptosis and finally leads to malignancy (Pandurangan et all 2018).

From the other side, the scientists in order to detect the carcinoma often use fecal occult blood testing (FOBT), flexible sigmoidoscopy and colonoscopy while CT colonography is a more recent addition to the CRC screening modalities. The most common technique used is colonoscopy which illustrates the crypt in real time and helps to clarify whether a polyp exists or not (Nikolouzakis et all 2018).

NUTRITION ASSOCIATION WITH GENETIC ASPECTS IN COLORECTAL CANCER

It is widely accepted that gene variants are associated with different responses to nutrients and this variation can be linked to different cancer risks. Identifying gene-diet interactions may be vital in the understanding and prevention of cancer. In this review, despite a large number of studies, only a limited number of observations were classified as convincing. In this review ( Theodoratou et all 2017) only alcohol and whole grain intake are classified as convincing(class I).

Alcohol may cause alterations at tumor initiation, promotion, progression, and conversion. Specifically, ethanol and the most toxic acetaldehyde binds to DNA and causes DNA damage. At the initiation point, ethanol may activate pro-carcinogens which are present in a food by induction of cytochome P450 2E1. Moreover, at the cancer promotion stage, the expression of oncogenes and tumor-suppressors can be changed due to DNA methylation which is caused by alcohol consumption. Finally at the progression stage alcohol may cause immune suppression resulting in a tumor cell spread. ( Theodoratou et all 2017)

From the other side in this review (Theodoratou et all 2017) the consumption of whole grains was found to reduce the risk of developing colorectal cancer. Dietary fibers, resistant starch, and oligosaccharides are included in the protective mechanism of whole grains. Additionally, whole grains contain antioxidants, phytate, phyto-oestrogenes, vitamins, and minerals which could prevent DNA from oxidative damage and cancer in general. However, there is an inconsistency with this argument. The protective effects of whole grains could not be explained properly because the evidence was classified as suggestive.

In contrast from all gene-diet interactions only the interaction between 10p14 locus and processed meat which is referred to colorectal cancer was classified as a moderate (grade BBB). The mechanism between the rs4143094 variant in 10p14/GATA3 and consumption of red meat is not clear. GATA binding protein 3 has been linked to T cell development and Th2 cell differentiation. It is considered that red processed meat causes an inflammatory response that requires GATA to be functional and the lack of that leads to malignancy ( Theodoratou et all 2017). The key problem with this explanation is that the biological mechanism for this interaction combined with the weak score leads to the need for further research.

CONCLUSIONS

The overall evidence to date illustrates that nutrient-gene impacts on cancer are not as impressive as expected to be and really difficult to be decrypted. Studies which investigate single diet-gene interactions may provide statistically significant results but most of them are inconsistent when are compared with large-scale systematic evidence. It is suggested that large- scale trials with clinical outcomes should be performed and focus on complex diets and not only in one specific nutrient. These kinds of studies are more preferable rather than observational nutrition analyses because they offer more consistent results. Unfortunately today these kind of studies are difficult to be carried out due to lack of knowledge of the genetic architecture of many biomarkers that are affected by nutrients ( Theodoratou et all 2017).

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