Chromosomal Instability and Colorectal Cancer

Colorectal cancer is one of the most common types of cancer worldwide, and in the United States, it is estimated to reach over 150,000 new cases (for both colon and rectal cancer) and 53,000 deaths in 2024. The development of colorectal cancer is a complex process involving several genetic and environmental factors. One of the key genetic factors associated with the formation of colorectal cancer is chromosomal instability (CIN).

But, before we dive into what CIN is, it helps to first understand how chromosomes behave at status quo.

Chromosomes are structures made of DNA that are found in the nucleus of every cell. Normally, cellular genetic material exists in cells as chromatin, which consists of DNA wound around histones to form nucleosomes. When a cell is getting ready to divide, the chromatin becomes condensed into chromosomes.

A normal human cell typically contains 46 chromosomes, which can be organized into 23 pairs. Every pair of chromosomes contains one chromosome of paternal and maternal origin. We refer to these somatic cells as diploid cells. The 23 chromosome pairs can be further classified as sex chromosomes and autosomes.

Sex chromosomes are the chromosomes involved with determining the sex of the individual. Those who have two X chromosomes are assigned the female sex, while those who have the X and Y chromosomes are male. Autosomes, on the other hand, simply refer to the other chromosomes that are not sex chromosomes. There are 22 pairs of such chromosomes, each of them assigned a number based on their relative size.

When somatic cells undergo mitosis and divide, the 46 chromosomes are first duplicated to ensure that the new cells both contain a full copy of cellular DNA. As the cell divides, the chromosomes are pulled towards opposite ends of the dividing cell until the nuclear membrane reforms.

However, it is possible for the mitotic process to go wrong, and can result in the newly divided cells containing a wrong number of chromosomes. This condition of abnormal chromosome numbers can be referred to as aneuploidy.

Chromosomal instability, therefore, is the “persistently high rate of loss and gain of whole chromosomes”, and is a commonly observed condition in solid tumors.

CIN can arise due to defects in genes involved in the cell cycle checkpoint pathway, DNA repair and chromosome segregation. These genes play a critical role in ensuring the proper distribution of chromosomes during cell division. Mutations in these genes can disrupt this process, leading to the accumulation of chromosomal abnormalities in daughter cells.

Cancerous growth is often characterized by the loss of function in tumor suppressor genes, or by the activation and overexpression of oncogenes. Chromosomal abnormalities can lead to these tumorigenic genetic alterations. This can happen when CIN results in the loss of heterozygosity (LOH), or the loss of one copy of a gene. LOH can lead to inactivation of tumor suppressor genes such as p53 and result in uncontrolled cell growth and division.

The inactivation of p53 can in turn exacerbate and increase the rate of CIN.

The p53 gene encodes the tumor suppressor protein p53, and plays important roles in cell cycle checkpoints and apoptosis. One study investigating the loss of p53 and genetic instability found that chromosome loss and duplication was more likely to occur in p53-deficient mice compared to wild-type mice.

CIN is a common feature of colorectal cancer, with up to 85% of colorectal cancers exhibiting some form of chromosomal abnormalities. The degree of CIN varies between tumors, with some tumors exhibiting a high degree of chromosomal abnormalities and others exhibiting a lower degree of chromosomal abnormalities.

CIN can also contribute to the heterogeneity of colorectal cancer, which refers to the presence of different subpopulations of cells within a tumor. Heterogeneity can make tumors more resistant to treatment and increase the likelihood of recurrence.

Several studies have suggested that CIN is associated with a poor prognosis in colorectal cancer. For example, a study published in the journal Nature Genetics found that colorectal cancers with a high degree of CIN had a worse prognosis than colorectal cancers with a low degree of CIN. The study conducted on mice predisposed to intestinal cancer showed that moderate levels of CIN promoted formation of adenomas in the entire intestinal tract, while high levels of CIN resulted in adenoma burden concentrated in the distal colon.

The link between CIN and colorectal cancer (and cancers in general) means there is potential for CIN to be an important biomarker. While some studies are examining if loss of heterozygosity can be used as a novel biomarker and target for anticancer drugs, others are investigating if the expression level of genes involved in chromosome segregation can be used as predictive biomarkers to inform cancer therapies.

Having additional and more diverse drug targets and biomarkers can help further the development of effective cancer treatments, and improve the outlook for patients who previously lack treatment options.