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Cancers are a feature of the evolution of ataxia telangiectasia. This chapter outlines the mechanisms and the main types of cancers found in the disease.

Cancer is undoubtedly one of the greatest risks in the Ataxia Telangiectasia, in fact, second to lung infections.

About ¼ of people with AT develop cancer, the risk increasing with age.

The incidence of cancer is also higher in families of patients with AT.

 

Cancer

"Cancer" includes a large number of diseases that are sometimes expressed in a visible way: skin, growing tumors ..., but not always: cancer affecting blood cells by the bone marrow in an organ (lung, bone) before symptoms appear. But they all have some common points:

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The video above shows the formation of a cancerous tumor that can not grow beyond a certain size (1mm) without recruiting its own network of blood vessels to provide nutrients to cancer cells for their development: this is angiogenesis. It shows also how the metastases are spread in the body by the bloodstream.
  • Everyone is not equal in front of cancer: development of cancer depends on the genetic material of each individual. This explains the hereditary factor and the presence in families of a single type of cancer.
  • Environment and exposure to risk factors are also highly contributory factors (cigarettes, pollutants, radiation ...).
  • On a "healthy" subject, the development of cancer can take decades. The progressive weakening of the body's defenses can explain it.
  • All cancers are degeneration of cells that are not recognized as such by the immune system and thus can proliferate, increasingly altering the functioning of the body.


Process in AT

In the chapter "The ATM gene", it has been described the process which, during the cell cycle, allows in the body of patients with AT the multiplication of abnormal cells after double-strand breaks in DNA.

This corresponds perfectly to the definition of a cancer and explains the cancer cases observed among them: stomach, brain, ovaries, skin, liver, larynx, lung and parotid gland (the largest of the salivary glands).

In the vast majority of cases, cancers in patients with AT are leukemia ou des lymphoma, cancers of the immune system.

 

Cancers in families of children with AT

A heterozygote is a healthy carrier of a defective allele (an individual has two alleles, ie two copies of each gene). We, parents of children with ataxia telangiectasia, are heterozygous for a mutation in the ATM gene.

By the late 80s, researchers note that heterozygotes for mutations in ATM (parents, aunts and uncles, grandfathers, grandmothers, cousins, etc ...) have abnormally high cancer rates, breast cancer being the highest. But every study on the subject has its share of inaccuracies and their results do not get to a clear idea.

For this reason, in June 2003, a team of INSERM led by Prof. Dominique Stoppa-Lyonnet launches a study in France, as part of a large-scale international study on breast cancer and over a significant period of several years. This study is called CoF-AT

 

Outlook

In summary, it is clear that one of the major and logical consequences of the lack of ATM protein is a very strong predisposition (X 1000) of AT children with cancer and especially those of the immune system.

We parents can do something for once just by preserving factors known to promote these conditions.

Of course, the sensitivity of people with AT to commonly used techniques in the fight against cancer, chemotherapy and radiotherapy, limits potential treatments. But it does not mean that treating cancer is impossible, far from that.

In reality, these treatments do not satisfy the researchers because they are not specific enough and cause damage to healthy parts of the body which is already weakened by the cancer itself, even if it is less and less true with new treatments. It's almost as if to catch a criminal for sure, the police fired into the crowd.

Many other more accurate ways are being considered (see Research), such as with stem cells, genetically modified viruses, nanoparticles ...


And since our children are hypersensitive to cancer, since the ATM gene is central to certain cancer process, then it is interesting for the research against cancer and by extension, against Ataxia Telangiectasia.

Lymphomas are among the most common cancers in people with Ataxia Telangiectasia.

The important role of the ATM gene in the normal process of DNA repair in cells is the explanation.

Treatments exist and can give good results.

 

  • A abnormality (or several) in the multiplication of lymphocytes (white blood cells already specialized)
  • Their proliferation in organs of the lymphoid tissue (especially in the lymph glands)
  • The potential harm of all organs.

It can develop from one of the two main families of lymphocytes: B lymphocytes or T lymphocytes

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Subtitles:
"Lymphoma is a type of cancer that begins in the white blood cells called lymphocytes. Lymphocytes are the main components of our immune system. They circulate in the blood vessels but also in their own network of blood vessels and lymph nodes. Hence, they can integrate the blood or tissues to respond to the intrusion of bacteria or viruses. lymphomas develop when cells multiply and grow uncontrollably to form tumors and overwhelm the organs and tissues. "




Process in AT

In the article "Immunity and AT", it is explained how double-strand breaks occur normally in large numbers in the process of acquired immunity in specific T cells and B cells which produce antibodies .

As people with AT can not manage these breaks and allow the multiplication of imperfect cells, it does not seem abnormal to find a high percentage of lymphomas in cancers that arise.

Nevertheless, the mechanism of lymphoma is not clear yet: the real difficulty comes from the number of abnormalities that may lead to lymphoma, making it equally difficult to classify them. There are however, two main types of cancers of the lymphatic system: Hodgkin lymphoma (Hodgkin's disease) and non-Hodgkin's lymphoma (NHL).



Hodgkin lymphoma (Hodgkin's disease)

{flv width="350" height="262"}Lymphomedehodgkin{/flv}</div> <div style="font-size: 1em; font-family: arial,helvetica,sans-serif; text-align: justify;">It is characterized by abnormal cell proliferation in one or more lymph nodes and the presence of special transformed cells called Sternberg cells.<br /> The disease may spread and affect other organs or bone marrow. It is suspected some viruses, like Epstein-Barr virus (a herpes virus that infects asymptomatically 95% of the world population and is responsible for infectious mononucleosis), play a role in the disease development.</div> <p><br /><br /></p> <h4 style="clear: both;">Non-Hodgkin's lymphoma (NHL)
{flv width="350" height="262"}Lymphomenonhodgkinien{/flv}</div> <div style="font-size: 1em; font-family: arial,helvetica,sans-serif; text-align: justify;">All other cancers of the lymphatic system are classified as "non-Hodgkin lymphoma" and include a wide variety of cell degeneration.



Diagnosis

The diagnosis of lymphoma is obviously easier when nodes are palpable and the physician may thus request additional tests, and for sure more difficult when the glands are deeper. Symptoms such as:
  • Fever
  • Night sweats
  • Increasing the size of the spleen
  • Effects on viscera
  • etc...
may help guide research.

The speed of diagnosis is not necessarily a determining factor, some lymphomas regressing even spontaneously. But the likelihood of recurrence is high.



Treatments

Research on lymphoma has made huge progress and treatments are now available with good chances of success (a majority of cases leading to complete cure). Although one of the main manifestations of lymphoma is increasing the size of lymph nodes, surgery does not treat the condition, which relies on chemotherapy with sometimes radiotherapy. Because of the risks of these treatments for patients with AT, they must be fit, but good results can be obtained.

With lymphoma, leukemia accounts for 50% of cancers observed in ataxia telangiectasia.

Once again, the central role of the ATM gene in the cell cycle is the most likely explanation (see The ATM gene").

Treatment of leukemia are constantly improving, for our young patients as well.


Leukemias are cancers characterized by abnormalities of white blood cell precursors in the bone marrow, with or without the presence in blood of abnormal cells.



Process in AT

The bone marrow is the site of production of all blood cells from stem cells:

  • Red cells
  • Platelets
  • Precursors of white blood cells (different types of "babies" white blood cells that take their final function elsewhere).

Thumbnail image

It is an uncontrollable increase in the reproduction of these "babies" white blood cells in the bone marrow that creates leukemia. Therefore, they empeach the production of other vital cells (such as red cells or platelets) and flood the body of immature white blood cells, thus ineffective, which may also block some vital organs.

Some external factors are recognized as potential causes of development of leukemia. Among the main, we find:
  • Radiation (X-rays, radioactivity ...)
  • Chemicals (pesticides, fertilizers, benzene ...)
  • Some medical treatments like chemotherapy and radiotherapy for an earlier and cancer.

But even if they do not constitutent the majority of cases of leukemia, we know that these factors generate DNA breaks in cells and in people with AT and the absence of ATM protein allows these abnormal cells to reproduce. This transformation mechanism is certainly highly contributory to the fact that these patients are prone to leukemia.

Diagnosis

Symptoms are:
  • Low platelets: bleeding
  • Decrease of red blood cells: anemia, paleness, palpitations
  • Decrease of white blood cells with an immediate impact on the immune system: repeated serious infections
  • Fever, headache, and sometimes paralysis

We are talking about:

  • Lymphocytic leukemia when the babies white cells involved were designed to give lymphocytes(B and T cells, see Immune system")
  • Myeloid leukemia for the other cell lines
  • Acute leukemia if the abnormality involves immature white blood cell precursors. In this case, the proliferation of cells is very rapid, leading rapidly to the onset of clinical signs of the disease
  • Chronic leukemia if the abnormality does not affect the differentiation of precursors that can still differentiate into mature cells but whose function is abnormal. Typically, the symptoms may be delayed and evolution may be more indolent in the beginning.



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The cause of the occurrence of leukemia is still the same: a abnormal quantitative production of immature white blood cells, but the reasons are different. This movie deals with chronic myeloid leukemia caused by a translocation between chromosomes 9 and 22. The final part, which talks about treatment options, forgets to include a new molecule with spectacular results in this type of leukemia: Gleevec (also known as Sprycel or Tasigna)



Leukemia or lymphoma?

It may be noticed finally that the boundary between lymphoma and leukemia is not always very marked: in some non-Hodgkin's lymphoma, cells may be present in blood and certain aggressive lymphomas (lymphoblastic or Burkitt's lymphoma) may present an affected bone marrow and treated on a common treatment program to lymphomas and leukemias. Conversely, chronic lymphocytic leukemia are sometimes classified as lymphoma ... not easy to sort things out.

The mechanisms of malignant transformation are very similar and the main difference may be summarized as follows:

  • acute leukemia (lymphoblastic): abnormality leading to blockage of maturation and abnormal accumulation by overgrowth of lymphocytes precursors that invade the bone marrow, hindering its functioning(reduction of other normal blood cells, red cells, unaffected white cells and platelets ) and sometimes also present in the circulating blood.
  • chronic lymphocytic leukemia and non-Hodgkin lymphoma: abnormality leading to the accumulation of abnormal lymphocytes (usually B) but without abnormal differentiation. In chronic lymphocytic leukemia, accumulation occurs primarily in bone marrow and lymph nodes and abnormal lymphocytes are present in excess in the circulating blood. The normal bone marrow functioning is obstructed very late in the evolution that is generally very slow (lazy). In non-Hodgkin lymphoma accumulation is mainly in the lymph (and sometimes other organs) and more rarely in the bone marrow (and in this case abnormal cells can also be observed in blood but as a rule generally in small amounts).



Treatments

Children with AT are predisposed to acute lymphoblastic leukemia and chromosomal abnormalities on chromosome 14 are frequently observed (see Laboratory and Immunity and AT). The treatment of acute leukemia will be to destroy the degenerated cells by chemotherapy fairly strong. But this does not happen without collateral damage and the need to replenish a capital of healthy cells in the bone marrow may pass through a bone marrow transplant.
Generally speaking, treatments have results that are improving and can treat between 70 and 80% of patients. The problem in AT being the patient's hypersensitivity to chemotherapy, it is necessary to adapt the treatments, but conclusive results can be obtained. Non-Hodgkin lymphoma and Hodgkin's disease can be also treated with diverse but usually lighter chemotherapy often possible in day hospital. Sometimes, radiotherapy (radiation) is associated.

Radiation are among the causes that create DNA double-strand breaks in the nucleus of cells.

If these damaged cells multiply, cancer can develop. In reality, everything depends on the dose and repair capacity of the individual who receives it.

As people with ataxia telangiectasia can not repair these DNA breaks (see ATM: DNA controller), , this makes them extremely sensitive to radiation.

As for tobacco, pollution or other known carcinogens, special precautions can be taken to minimize the "radiation" risk.



Mode of action

Thumbnail imageContrary to common belief, radiation is not only acting instantly by disintegration of the body it is going through, but mainly cause a destructive chemical reaction. This involves four steps:
  1. Immediate physical phase: the energy of radiation causes the agitation of atoms and removes from them few electrons, forming ions.
  2. Chemical phase: it may last a few seconds. Previously formed ions interact mainly with water, producing free radicals, especially oxidizing agents. These free radicals will then attack the cellular macromolecules, particularly DNA.
  3. Biochemical phase: this is the phase where the repair mechanisms of the cell are switched on. One of these operates ATM, the protein encoded by the gene deficient in ataxia telangiectasia.
  4. A phase named "biological": it concerns all the consequences of the actual conduct of the previous phase. These consequences are extremely varied and not all known. Different stages of cell reproduction can be blocked, the cells may die or reproduce with abnormalities and create cancers. The same dose of radiation can have very different biological consequences.

 

Radiation in our environment

We are literally overwhelmed by all kinds of radiation:

  • {youtubejw}5Fj2LgCosu8{/youtubejw}
    Natural radiation: natural radioactivity of the earth, visible light, infrared, cosmic rays at high altitude, ultraviolet whose dangers are now well known.
  • {dmotion}xbi9uc{/dmotion}
    Radiation from our modern environment: power lines, screens, computer networks (WLAN, Bluetooth), mobile phone network whose operators studies say they are harmless unlike independent studies (try to put your head in a microwave oven or face a radar that operate both substantially the same frequency as your mobile: after a while you'll get a little hot head) ...
  • Medical devices radiation : X-rays and gamma used for diagnosis (radios and scanners) or for radiotherapy beams. As for the sun, the potential damage depends on the type, intensity and duration of exposure to radiation.

 

Radiation and medical machinery

Medical examinations using radiation are:

Thumbnail imageX-radiography ::
Although in recent years, the radiation doses used are less strong, "radio" is still a radiating mean of investigation. Unfortunately, in case of a trauma, radiography is often the most available and fastest way to make a diagnosis ... waiting for the system EOS.


Thumbnail imageScanners (CT scan):
They also use X-rays, but at higher doses and can see more details of more body parts. But their limited number, the difficulty to implement them and the cost of each examination limits its use.


Thumbnail imageScintigraphies:
They are also irradiating examinations as a radioactive liquid is injected to patients (gamma radiation). They allow to visualize the movement of fluids and to detect abnormal network as a blocked artery, the irrigation system of a cancer cluster ... (see Radiation and ionization")


Radiothérapy: Thumbnail image
Like chemotherapy, radiotherapy is intended to cause self-destruction (apoptosis - see cell cycle in The ATM gene") of cancer cells by breaking DNA molecules of these cells with high radiation (the chemotherapies are doing the same but by chemically interfering with DNA). They can be administered from outside the body by bombarding the affected area, or inside by placing a radioactive source closer to the tumor.

Problem: in one as in the other case and regarding the current state of the care centers equipment, nearby healthy cells are also affected. The normal healing of surrounding tissue can recover from these injuries, while cancer cells are unable to recover. That explains the differential effect of cancer treatment between healthy and diseased tissues and ultimately their usefulness in the treatment of these diseases.
However, in inducing DNA breaks, chemotherapy as radiation are mutagenic, that is to say they can induce long-term occurrence of mutations in DNA, some of which may accumulate and lead to the development of secondary cancers.

Patients suffering from AT, due to the genetic defect that leads to defective function of the ATM protein, increase the toxicity of anticancer treatment on these two aspects. Normal and immediate damage on healthy cells affected by chemotherapy or radiotherapy "heal" slower and less well as they would in the absence of ATM default. This has the effect of an acute toxicity (normal and transient decrease of white blood cells and platelets after these treatments may be more marked and more prolonged, leading to a higher risk of infection and bleeding ).

In addition, ATM also playing a role in DNA repair by preventing the accumulation of mutations, the patients with AT exposed to chemotherapy or radiotherapy will have a greater risk of mutations associated with these treatments. The risk of developing secondary cancers is higher.

Despite all the advances that promise that these techniques will still be used for a long time (see Radiation and ionization"), awareness of the potential harmful effects of radiation led to development of exams not irradiating or so little that the amount of radiation used is negligible. They are:



{youtubejw width="200" height="150"}rcRm1MrFE8Q{/youtubejw}</div> <div style="text-align: justify;"><span style="text-decoration: underline;"><strong>MRI (magnetic resonance imaging)</strong><br />MRI appears to be the least invasive examination and is not radiating. It merely "observe" the reaction of hydrogen atoms in strong magnetic excitation to determine the nature and shape of the tissue. It can also measure brain activity and is very effective to make a precise diagnosis of the soft tissues of the body. However, the results are much worse on the skeleton.


Thumbnail imageEOS
EOS is a radiography system developed from the work of French Nobel laureate in physics Georges Charpak. It uses X-radiation at very low level to reconstruct the 3D skeleton. (See Radiation and ionization")



 

{youtubejw width="200" height="150"}7-xB_42-0A8{/youtubejw}</div> <p><span style="clear: both; text-decoration: underline;">

 

Protecting children with AT

Children with ataxia telangiectasia are very vulnerable to radiation as they are unable to properly perform the process of cellular repair. It is therefore essential to protect them wherever possible. Here are some suggestions, not exhaustive:

Radiation from our modern environment :
:
It is difficult to get an accurate picture of the actual harmfulness of certain devices, but nothing prevents us from taking a few precautions, especially for mobile phones: choosing a phone meeting the emission standards, use a wired headset, not keep the phone to close to the body, carry it in a heavy bag ...

Solar Radiation
Observe the widely distributed instructions today:

  • Limitation and choice of hours of exposure. Application of maximum index protective cream renewed regularly
  • Beach "anti-uv" clothes are on sale in sports shops, but in addition to previous precautions
  • Pay attention to the phenomenon of reverberation on the sea or the mountains. Small clouds are transparent to UV.

Medical field
The general philosophy is to minimize the examinations using radiation, except of course in an emergency. The precautions are:

  • Notify the physician of the sensitivity of patients with AT: he will then decide, depending on the severity of the condition, whether to use a radiographic examination or not. Indeed, if the equipment level of developed countries is easily using medical imaging for confirmations or ambiguity resolutions, medical diagnosis can often arise from clinical observation alone. Again, this does not concern emergency medicine.
  • The modern medical imaging devices require lower and lower radiation levels. Restrictions on their use, if they are true, are of less concern. Nevertheless, all health care centers are not equipped with the latest technical advances in this field: the more a device is old, the higher the level of radiation that is issued is likely to be high. If so and there is no emergency, postpone the examination.
  • When applied to treat a tumor, radiation therapy has made ??such progress in the precision of his administration that it might soon be considered calmly. Meanwhile, the circumstances will decide. (See Radiation and ionization)


As a conclusion, whenever a patient with ataxia telangiectasia shows a problem requiring a medical examination, it is essential to ask the question: What is the medical examination that will provide the best ratio: quality of diagnosis/ quantity of radiation. It might be interesting that each child examinations and radiation doses received were indicated on their health records.

However, the continuing progress of medical imaging suggest that less severe doses of radiation will be used in future for medical diagnostics.

In general, the precautions are simple, you just have to think about implementing them.

L' AT, c'est quoi?

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