Unstable genome: a friend and a foe of cancer

As multicellular organisms, we grow because our cells are dividing to produce more and more cells. Hundreds of billions of cells in the human body are dividing at any given moment. This process must be tightly regulated because, during cell division, our hereditary information in chromosomes is also divided among the two resulting daughter cells. But, why is that so important?

Throughout several posts in this blog, we have already learned about the concept of DNA as being the blueprint of life. That it contains all the genetic information necessary to instruct our cells to build proteins, the building block of life. It’s like having sheet music to guide musicians to perform an intricate musical piece or a recipe book to prepare complicated dishes. With such a vital role, you can imagine that we must keep our DNA intact. Otherwise, failures in safeguarding the DNA can have dangerous, even lethal, effects on our cells.

To get you more into the topic, let’s talk about some examples of these genome maintenance failures and how they can turn growing, dividing cells into deadly invaders, namely cancer cells, which can cause cancer.

Caretaking the genome

Every day, our DNA is constantly prone to damage, either internally (naturally occurring inside our body, e.g., from metabolic or hydrolytic processes) or externally (environmental factors, e.g., UV light, ionizing radiation, genotoxic chemicals). Most such DNA lesions are temporary because they are immediately corrected by a set of processes called DNA repair, which is part of the genome caretaking mechanism. In fact, out of the tens of thousands of random lesions created every day in our DNA, only less than 0.02% accumulate as permanent mutations in the DNA sequence. The rest are fixed quite efficiently by our DNA repair proteins.

On the other hand, if left unrepaired, certain DNA lesions can cause errors when chromosomes are divided during cell division (i.e., chromosome missegregation) resulting in parts of the chromosome getting broken/rearranged. In case you missed it, Siobhan previously explained how we humans have our DNA packaged into a set of 46 chromosomes (44 from somatic/body cells and two from germ/sex cells). While this is true in normal/healthy conditions, in some inherited defects and certain types of cancers associated with breakage/loss/rearrangement/gain of chromosomes, abnormal chromosomal numbers may arise. In the laboratory, we can actually “paint” each human chromosome a different color to allow for its identification using a technique called karyotyping. This way, cell geneticists can detect the occurrence of chromosomal abnormalities.

When DNA maintenance processes fail, permanent changes in the DNA can occur. Such a change is called a mutation and can be harmful when it occurs in an important position in the DNA sequence. But rest assured, our DNA maintenance processes only rarely make such mistakes, so your genome is in good hands.

Genomic instability as a friend: cancers develop through accumulated mutations

Now that you know how essential your genome guardians are, can you imagine what happens if they are not working?

Several studies have linked many human diseases as consequences of having defective DNA repair, including inherited predisposition to cancers. People with the disease xeroderma pigmentosum, for example, have defects in the processes that repair DNA damage induced by UV light, and they have a higher chance of getting skin cancers.

For a long time, it has been established that cancer is fundamentally a genetic disease: it arises from harmful changes (mutations) in the DNA. Most human cancer cells accumulate genetic changes at an unusually high rate and therefore are termed genetically unstable. However, the degree of this instability differs from cancer to cancer and from patient to patient.

Fortunately for us, a single mutation is not enough to transform a normal cell into a cancer cell; otherwise, we would not be viable organisms since spontaneous mutations do occur every now and then. On the contrary, cancer formation typically requires a significant number of rare (epi)genetic changes to accumulate in a single cell’s descendants (if you’re wondering what the heck epigenetics is, go see Tiago‘s post!). To put it more easily, the incidence of cancer rises steeply with age (in most types of cancer). This is why maybe you have heard about cancer being a disease of old age — because it takes a long time for an individual clone of cells to accumulate a large number of mutations.

Interestingly, the mutations that encourage cancer formation do not weaken mutant cells. Instead, they give these cells a competitive advantage over their neighbors. Normally, our cells deploy a cellular suicide program called apoptosis to eliminate these ‘bad’ mutant cells, so accumulated mutations do not always mean cancer. However, in carcinogenesis (the initiation of cancer formation), as an initial population of mutant cells grows, it slowly evolves: new mutations, which will benefit cell proliferation and survival, occur. This process continues as they gain more properties to avoid cell death, displace their normal neighbors, and attract blood supplies to nourish their growth; classical features of cancer. Ultimately, in metastasis (dangerous spreading of cancer from its original site to a new one), the tumor cells need to become even more invasive — they must be able to escape their home tissue and survive and grow in new sites.

Genomic instability as a foe: developing cancer treatments exploiting specific mutations

In developing anti-cancer therapies, researchers exploit some molecular properties unique to cancer cells to distinguish them from normal cells, so that they can specifically target cancer while sparing the normal cells. One such feature is genomic instability. Yes, the very thing that initiates cancer formation can also be its demise. Genomic instability makes cancer cells both dangerous and vulnerable—dangerous because of the improvement in their ability to evolve and grow, and vulnerable because the treatment that causes even more extreme genetic disruption can eventually kill them.

Some tumors are not very good at repairing damaged DNA due to, for instance, having faulty DNA repair proteins. A well-known example of important DNA repair proteins is BRCA (BReast CAncer gene). In normal conditions, BRCA proteins help the cells to repair damaged DNA properly. When it is mutated, damaged DNA will accumulate over time resulting in alterations in the genome. If further mutations happen to important genes such as the above-mentioned oncogenes or tumor suppressor genes, cell growth will become uncontrollable and ultimately lead to cancer formation. Indeed, people who have BRCA mutations have a high chance of developing ovarian or breast cancers.

Exploiting this vulnerability, scientists have discovered a strategy to attack these particular cancer cells. In the clinic, several breast or ovarian cancer patients with mutations in their BRCA genes are treated with drugs that target other DNA repair proteins. This way, as more unrepaired DNA damage accumulates, cancer cells (which have defective BRCA proteins) will not keep up with the high level of damage, which can lead to toxic gene loss and genome damage. Such a concept of combining treatment with specific defects present only in cancer cells (and not normal cells) to induce cell death is called synthetic lethality and is a promising personalized cancer therapy widely studied in the field.

Studies on genomic instability have allowed us to understand how cancers form; how a tiny, harmless cell can develop into deadly invaders that rage out of control. They have also led us to create new ways to diagnose and treat the disease. Unfortunately, in real-life situations, these concepts do not always work as effectively as we expect. We have seen that genomic instability can provide a unique feature that cancer therapies can exploit. Still, at the same time, it can trigger genome chaos which increases the chance of cancer cells to evolve resistance to therapeutic drugs. In this case, therapy regimens where a cocktail of several different anti-cancer agents are used could be the way to go. Discovering the correct combination could be a long, difficult journey. But now, as we advance our tools for identifying specific genetic changes that cancer cells have, the prospects are promising.

Featured image source: Janssen et al., Science 333, 1895-8 (2011)

Check out our previous posts related to this topic:

• Minh‘s story on how immune cells are also frenemies of cancer cells
• My post on how the environment surrounding cancer cells can help them to flourish and even spread