Did you know that…5-10% of all cancers are inherited? All you need to know about cancer inheritance.

In this new post we are going to address an issue suggested by several buddies, which passionate us and we consider of great relevance and interest. Let's talk about cancer inheritance and genetic changes that increase the likelihood to suffer it. Briefly, we are going to explain what cancer is, its prevalence and how certain genetic factors, mainly the presence of certain mutations or not, are very important in susceptibility to develop the disease. Among cancers with a hereditary component, we will focus on a particular type of colorectal cancer and breast cancer for being the most incidents and for causing high mortality and morbidity. Finally we are going to discuss a little what genetic tests are and how they can help us knowing our susceptibility to developing certain types of cancer. The amount of literature on cancer in general and about its particular inheritace is overwhelming. It has not been easy butchering the articles and books reviewed as well as to collect the key points with a coherence and consistency suitable for all kind of readers.

So, we hope you enjoy it and that you solve some questions.

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What is cancer, how and why it occurs?

Cancer is a major cause of morbidity and mortality worldwide. In 2012 8.2 million cancer-related deaths and 14 million new cases were recorded around the world. The incidence of new cases is expected to increase to 22 million over the next 20 years. The main types, ordered by mortality, are the following (2012 data):

1. Lung (1.59 million deaths).
2. Liver (0.75 million).
3. Gastric (0.72 million).
4. Colorectal (0.69 million).
5. Breast (0.5 million).
6. Esophagus (0.4 million).

There is much fear attached to the word cancer and no wonder seeing the numbers above. We all have a relative ora an acquaintance who has suffered or currently suffers this terrible disease, but few people really understand why or how it happens. Cancer starts with the transformation of a normal cell into a tumor cell, which begins to divide uncontrollably. Alterations leading to this process are the result of the interaction between genetic and external or environmental factors. The process of invasion of cancer cells to other organs or parts of the body is called metastasis and is the leading cause of cancer death.

There is an important inherited genetic factor that accompanies cancer. A common mistake is to think that cancer is hereditary. No, it is not. Which are hereditary are certain genetic mutations and polymorphisms that can make us more susceptible to develop it at some point in our lives. A mutation is a inherited or induced change in the sequence of a gene and whose effect may be harmless, harmful or beneficial. Furthermore, a polymorphism is a natural variation in the sequence of a gene within a population of individuals. In turn, these mutations may have high or low penetrance, defined as the percentage of individuals with a specific genotype that express the phenotype expected from this genotype. High penetrance mutations have a very strong effect and if they occur in a key susceptibility gene it may be sufficient to develop cancer at some point, but this is extremely rare. More common is the presence of polygenic mutations, that is, in several genes, which have low penetrance and independently have not much influence but whose overall effect is very important in susceptibility to developing the disease. These inherited mutations are called germline mutations. In this case, the mutation/s is/are in every cell of the body, including reproductive cells. That is why they are transmitted directly from parents. The cancer caused by these mutations are called hereditary and represents about 5-10% of all cancers.

Among external factors, also called carcinogens, we can find ionizing and ultraviolet (UV) radiation, tobacco smoke, alcohol or some infections caused by certain bacteria and viruses as hepatitis or papilloma, among others. Of these, tobacco is the most important risk factor, causing more than 20% of cancer deaths worldwide. These factors cause DNA damage in individual cells that may lead to mutations which are called acquired and are the most common cause leading to cancer. They are not transmitted from parents to children because they occur in isolated cells. Cancer developed due to these mutations is called sporadic and supposes approximately 90% of all occurring. Certain dietary and behavioral unhealthy habits also increase the likelihood of suffering. For instance, having a high body mass index, reduced fruit and vegetable intake or lacking of physical activity. Finally, aging is also a key factor in the onset of cancer due to the continuous accumulation of mutations, exposure to external factors and loss of efficiency in cell repair. That is why cancer is more prevalent in the elderly.

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However, there are always exceptions: in one hand, an individual who is frequently exposed to carcinogens and whose lifestyle is sedentary and unhealthy is very likely to develop cancer during the course of his life, but it may not. On the other hand, a completely healthy individual with a healthy lifestyle and not usually exposed to harmful factors may fall victim to the whims of genetics inheriting certain mutations or polymorphisms that increase the susceptibility to suffer it. This post is going to focus on the latter case, on the inheritable genetic changes that increase our chances of becoming in a prey future of cancer.

On what genes these mutations occur?

Genes contain information that controls the functioning of cells encoding proteins that have specific functions. Therefore, each gene must have the correct instructions to make its protein and that it works properly.

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The presence of mutations in genes may cause alterations in the protein sequence with effects ranging from no effect at all to that protein synthesized being aberrant, nonfunctional, or directly non synthesized. According to the kind protein or proteins affected, this process can cause that cells multiply uncontrollably and become cancerous. There are several classes of genes whose mutation increases the risk of developing cancer. We will focus mainly on the tumor suppressor genes and genes encoding proteins involved in the control of DNA repair, cell cycle and death. Oncogenes, genes that can transform a healthy cell into a cancerous one, have also been included within these key genes but the truth is that inherited mutations in them are very rare, almost non-existent, so we shall not dwell on that.

Tumor suppressor genes:

They are "protectors" genes that encode proteins limiting cell growth by controlling how fast cells divide and when they die, as well as repairing DNA breakages. When a tumor suppressor gene is mutated its function may be compromised and can cause cells to grow without control, forming a tumor. BRCA1, BRCA2 p53 and APC are important examples of this kind of genes. In fact, the most commonly mutated gene in people with cancer is p53 (up to 50% of all cancers) but, however, most of its mutations are acquired and not transmitted through heredity. The inheritance of mutations that make these genes "defective" is related to an increased risk of developing cancer. For instance, high penetrance mutations in APC gene can lay the foundation for developing cancers such as familial adenomatous polyposis or FAP. Most inherited mutations in FAP are nonsense or frameshift changing, resulting in a truncated and nonfunctional protein. Given that APC gene is a tumor suppressor gene, a nonfunctional protein indicates itself what can happen. We are going to discuss about BRCA1 and BRCA2 in the context of breast and ovarian cancer in the next section, just because besides being tumor suppressor genes, they are involved in DNA repair.

Genes involved in DNA repair, cell cycle and death:

Mutations occur regularly and the human body has the ability to correct most of them. Proteins involved in DNA replication make mistakes when it is copied but they are corrected immediately by repair pathways proteins. Naturally, a failure in repairing DNA breaks increases the expression of p53, a tumor suppressor gene mentioned above and colloquially known as "guardian of the genome" encoding a transcription factor that modulates the expression of many other genes. If the damage is moderate, p53 slows the cell cycle so that the damage can be repaired and DNA replication can be done correctly. On the other hand, if the damage is severe p53 triggers the process of apoptosis or programmed cell death. There are individual differences in the ability of cells to repair DNA damage. Efficiency repair follows an inherited pattern and depends on the presence or absence of mutations in key genes involved that may cause encoding reduced efficiency proteins or even nonfunctional ones. If this occurs, the repair of these errors can be compromised, which is associated with a high risk of developing cancer by accumulation of mutations. Berwick and Vineis summarized 64 different studies that investigated and quantified DNA repair processes. In these studies, decreased repair capacity was associated with 2-10 fold increased risk of developing cancer (Berwick et al. 2000). In the following scheme the signaling pathways involved in repairing breaks in DNA are shown (click to enlarge).

Frank et al. 2004

The inheritance of defects in DNA repair processes is quite common because they are robust molecular mechanisms that facilitate the accumulation of mutations. With robust mechanisms or signaling pathways we mean evolutionarily highly conserved molecular pathways for its importance to the cell survival. Natural selection can not eliminate mutations in these pathways because of its importance, so they accumulate increasing the risk of developing cancer in the long term. This often occurs during the natural aging process.

Within cancers triggered by inherited mutations in genes pathways of DNA repair, cell cycle and death, let's talk briefly about human nonpolyposis colorectal cancer or HNPCC and more in detail on breast cancer. Both are the hereditary cancers with most incidence and mortality. In fact, if we remember the mortality ranking posted above breast and colorectal cancer are among the deadliest (0.69 and 0.5 million deaths in 2012, respectively).

Human nonpolyposis colorectal cancer (HNPCC) and breast cancer.

HNPCC, also known as Lynch syndrome, is one of the most common forms of inherited predisposition to colorectal cancer, causing 2-7% of diagnosed colorectal cancers. It arises from germline mutations in MLH1 (50% cases) and MSH2 (40% cases) genes which are involved in the repair of DNA damage, specifically in the mismatch repair. All people affected have a 80% chance of developing colorectal cancer. In addition, these individuals have a very large risk of malignant tumors in other locations. For example, women with HNPCC have a 50-60% chance of suffer endometrial cancer, but also it has been reported cases of stomach, small bowel, ovary, pancreas or brain cancer, among others.

On the other hand, women with germline mutations in BRCA1 or BRCA2 genes have a high risk of developing breast and ovarian cancer. In a population study in 2003 (Antoniou et al. 2003) a meta-analysis of 500 families with identified mutations in these genes showed that the risk of breast or ovarian cancer at age 70 in BRCA1 mutations carriers is 65% and 39%, respectively. For BRCA2 risk was 45% and 11%, respectively. Focusing on breast cancer, the cumulative risk of developing it increases with age in both healthy and people with a genetic predisposition, which also occurs in most cancers. However, the risk of suffering is much higher in the carriers of mutations in BRCA1 and BRCA2, and the increase of risk with age is much more pronounced, as shown in the graph of risk of carriers vs noncarriers obtained from a study with 5318 Ashkenazi jews (Struewing JP et al. 1997). This article, though somewhat old, laid the basis for many other population studies and subsequent discoveries about breast cancer.

Struewing JP et al. 1997

As happened with HNPCC, carriers of mutations in these genes have also a increased risk of other malignant disorders. If the presence of mutations with high penetrance in such genes has been diagnosed, prophylactic mastectomy can be a convenient option. It is an invasive technique but decreases the risk of breast cancer in carriers about 89.5-100%. As known example, Angelina Jolie underwent preventively to this operation in both breasts in 2013.

What can we do to know if we have any of these mutations?

A genetic test consists in analyzing the DNA of an individual looking for mutations in key genes to make a diagnosis or to know if there is some predisposition to a certain disease. High penetrance mutations are easy to detect and most loci (locations on a chromosome) associated with a high risk of cancer have already been identified. However, the identification of common mutations with low penetrance is more difficult and complex, and requires more time and effort. These tests can help us to:

• Estimate the risk of developing some type of cancer in our lifetime.
• Know if we can transmit mutations that increase the risk of cancer to our offspring.
• In the presence of mutations, to help us to rethink our lifestyle, trying to reduce the risk of developing the disease and performing periodic screenings.

There is no test that can tell us certainty if we will develop cancer, but they give us an estimate of the risk of developing it taking into account all risk factors. It is advisable to do genetic susceptibility tests if there is family history of cancer or if you have developed some type of cancer at an early age. It is very important the early genetic counseling and regular medical screenings.

Finally, here you can watch a very illustrative video from Jewels Genetics Known explaining step by step what hereditary cancer is, using BRCA1 and BRCA2 genes as an example of key susceptibility genes in developing cancer.

This concludes our post of cancer inheritance. We hope to have dispelled doubts or to have oriented you in the pathogenesis of such a complex disease. From individual mutations with high penetrance to polygenic mutations with low penetrance, genetic influences our susceptibility to develop cancer. Hereditary cancer, as we have seen, represents only 5-10% of the total, but it still means thousands and thousands of deaths annually. It is essential to try to keep a healthy lifestyle, including proper nutrition and regular exercise.

For any questions or comments do not hesitate to contact us. Thank you.

REFERENCES

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