Mechanisms
Colorectal Cancer (CRC) occurrence is connected to environmental factors, hereditary factors, and individual ones. CRC has a genetic heterogeneity that makes it a challenge to understand individual cell mutations and their clinical implications (Thanikachalam & Khan, 2018). The current essay explores and critically analyses the manifestations of genetic mechanisms and clinical implications of inter-tumor and intra-tumor heterogeneity to demonstrate the complexity of factors contributing to the illness.
Chromosomal Instability or APC pathway
The occurrence of CRC follows a series of mutations in adenomatous polyposis coli (APC) that happen early during polyp development. The adenomatous polyps are the precursors of colorectal cancer, the growth of which is regulated by a single gene (Thanikachalam & Khan, 2018). The APC tumor suppressor also plays a critical role in random colon cancer, and it is mutated in about 70% of colorectal cancers (Thanikachalam & Khan, 2018). Colorectal cancer possesses a uniquely high mutation rate despite the evenness in distributing a mutation inactivator germline on the gene’s surface. This is caused by somatic mutations that are crowded at the 5 inches section of exon 15 between amino acid residues 1280–1500. Knudsen proposed that a single APC mutation pairs with the deletion of chromosomes of the wild alleles (Thanikachalam & Khan, 2018). However, deletion of the wild alleles is not witnessed in the tumors of familial adenomatous polyposis (FAP) in patients with germline APC transformation, although they result in prematurely halt codon, hence a shortened gene.
APC generation is stopped by obtaining DNA from blood leucocytes and magnifying the pieces of APC using a chain reaction with the following translation into vitro. After that, the vitro is translated into proteins that are truncated (Ashworth & Lord, 2018). The alteration is expected in the benign APC polyps, and the chances of expression remain unchanged. Therefore, mutations lead to the loss of alleles that suppress malignant phenotype development. Chromosomal instability causes molecular events that initiate and promote tumors. This process is linked to hereditary and environmental factors, as well as gained somatic mutations in the colorectal epithelium.
There exists a correlation between genotype and phenotype in families that exhibit APC mutation. There is an increased risk of tumor development among relatives with germline mutations within codons 1445-1578 (Siegel et al., 2020). People with the I1307K polymorphism have two times increased risk of CRC than the general population. When new wild inactivating APC arises from the same allele containing the polymorphism 11307K, a tumor potentially develops due to phosphorylation reduction of β-catenin via the proteasomes pathway (Siegel et al., 2020). The β-catenin is responsible for regulating TCF-responsive genes that are necessary for the proliferation and alteration of colonic epithelial cells. The APC acts to inhibit the proliferation of colonic epithelium cells. Furthermore, localization at the ends of microtubules indicates an important function in regulating cellular migration and cytoskeleton (Gomez et al., 2016). In colonic epithelial cells, they interact with hDLG using its COOH terminus.
Microsatellite Instability
Microsatellite instability, or DNA Mismatch Repair Pathway, is an alteration in the numbers of mono, bi-, tri-, and tetraploid nucleotide, which repeats in the microsatellites. These changes are considered to be responsible for hereditary non-polyposis cancer (HNPC-syndrome), which occurs due to the mutation in genes such as hMSH6, hMSH2, hMLH1, hPMS2, and hPMS1. The genes convert protein necessary to repair a mismatch in the DNA. The uncorrected error in DNA replication leads to a defect in which many genes experience mutations (Thanikachalam & Khan, 2018). The tumor growth results from uncontrolled modifications with a short sequence; such tumors are called Lynch syndrome. This syndrome increases colon cancer susceptibility in the proximal colon and is mostly associated with women and the aged population.
CpG Island Methylator Phenotype (CIMP)
The promoters of the methylation pyrimidine ring, mostly the MGMT and MLH1, characterize the CIMP mechanism. This methylation reduces with age and also during carcinogenesis, resulting in the hypermethylation of the cytosine and colon cancer. It is characterized by TGFβRII mutations, which render epithelium cells aberrant to the impacts of TGF-β (Benjamin et al., 2018). Such a process underscores the significance of the TGF-β mechanism in colorectal tumorigenesis. The tumor phenotype is progressively transformed and promoted by mutation through growth, invasive of new cancerous cells. However, there are tumor suppressors that code protein molecules capable of maintaining normal cell operations.
Clinical Implications of Inter-tumor and Intra-tumor Heterogeneity
Heterogeneity of cancer describes the variation in the expression of its profiles. It is related to the availability of genetically distinct clones that result from epigenetic changes and evolutionary changes. Colorectal cancer treatment is complicated and depends on the stage and location of the growth, and it mostly involves the use of surgery, chemotherapy and radiation with a variety of responses to these treatments (Siegel et al., 2017). However, high inter-tumor and intra-tumor variation make it difficult to eradicate the growths.
The inter-tumor heterogeneity describes the divergence between synchronous primary developments of a similar type increasing in a patient or between initial growth and its similar metastases. Similarly, intra-tumor divergence is the disparity in the growth of the identical neoplasm. The difference in the tumor of the same neoplasm results from high genomic instability; hence, treatment practices require much precision (Srivas et al., 2016). Besides, non-genetic factors such as lifestyle, environment, nutrition, and diet influence the non-neoplastic cells responsible for immunity. Surgical interventions are effective if the metastases are wholly removed. When surgery has successfully removed cancerous cells, chemotherapy treatments are encouraged to kill the remaining malignant cells (Ashworth & Lord, 2018). The combination of heterogeneity-informed treatment strategies will ensure positive patient outcomes.
Conclusion
Therefore, as the case of CRC demonstrates, the intersection of genetics and external factors significantly impact the likelihood of CRC occurrence and the necessity of incorporating the heterogeneity of clinical implications for successful treatment. It is necessary to understand the stage of the growth and its location to decide on the most appropriate therapy option. The patient’s lifestyle also impacts their responses to treatment, making it necessary for a changed lifestyle that boosts the immune system. Environmental factors such as exposure to mutagenic substances also increase the susceptibility to tumor growth. Thus, understanding the heterogeneity of CRC is vital for adequate treatment.
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