Frequently Asked Questions - Familial/Inherited breast cancer

1. What are familial, hereditary and sporadic breast cancer?
2. What exactly is a genetic mutation and how could it lead to the occurrence of breast cancer?
3. Are there a lot of genes the pathogenic mutations of which may cause breast cancer?
4. Will all women with a pathogenic genetic mutation present with breast cancer?
5. How high is the risk of developing breast cancer? Might one develop other forms of cancer as well? Are men also at risk from these mutations?
6. Are mutations always passed on to the next generation?
7. Can the pathogenic mutation skip a generation?
8. What are the indications for testing in women?
9. Is a genetic test actually beneficial? Or is it just a cause for additional stress and anxiety?
10. What are the options if a pathogenic mutation is detected?
 
1. What are familial, hereditary and sporadic breast cancer?

Familial breast cancer is the cancer presenting itself very frequently in the members of a family (first and second relatives) without any genetic mutation being detected which could be blamed for it.  Hereditary is the breast cancer that is due to the existence of a genetic mutation that can be passed on from the parent (father or mother) to the child (son or daughter). Sporadic is the breast cancer which presents itself without any genetic mutation and does not affect many members of the same family.


The most common type of breast cancer is the sporadic one (85-90%). It is possible that many cases of familial cancer are basically connected to hereditary cancer, the genetic mutation responsible for which has not been yet identified. Hereditary breast cancer is estimated at about 5-10% of all breast cancer cases.

 
2. What exactly is a genetic mutation and how could it lead to the occurrence of breast cancer?

Genes are the pieces of the genetic code, the DNA, of all living organisms, which determine all of their features. Mutation is a change in some gene that causes a change in one or more features of the organism. Mutations often result in the evolution and adjustment of species and in biodiversity (no person is identical to another except monozygotic twins); in these cases they are considered beneficial mutations. However, sometimes they lead to pathological or deadly conditions and are considered pathogenic mutations. Most of the times they have neither unfavorable nor favorable consequences and they are considered neutral.

Genes such as BRCA1 and BRCA2 play a protective role. They produce a protein that repairs damages in the DNA of the cells or destroys them when the damages are beyond repair.  They are also part of the mechanism that detects pathogenic cancer cells in the body and makes sure they are destroyed. A mutation in these genes may cause them to malfunction, leading to the unhindered creation and development of malignant tumors, mainly in the breasts and ovaries and less often in other organs.

 
3. Are there a lot of genes the pathogenic mutations of which may cause breast cancer?

Since discovery of the first gene the mutations of which are associated with increased risk of breast cancer in 1994, a total of 18 genes have been discovered. These genes are divided into high-penetrance genes (i.e. high risk for occurrence of cancer), moderate-penetrance genes (moderate risk) and low-penetrance genes (low risk). The genes most frequently associated with breast cancer are BRCA1 and BRCA2, which fall under the category of high-penetrance genes. Genes which are also associated with breast cancer but the pathogenic mutations of which are rarer are the following:

·         High-penetrance (CDH1, NBS1, NF1, PTEN, TP53,STK11)

·         Moderate-penetrance (ATM, BRIP1, CHEK2, PALB2, RAD50)

·         Low-penetrance (FGFR2, LSP1, MAP3K1, TGFB1, TOX3)

 
4. Will all women with a pathogenic genetic mutation present with breast cancer?

No. The presence of a pathogenic mutation increases the risk of breast cancer occurrence greatly; however, not all women with mutation present with the disease. If there is BRCA1 or a BRCA2 mutation, the risk of breast cancer occurrence during the lifetime is 56-84% and 60-80% respectively. In cases of low-penetrance genes, the risk is lower.


It has not become completely understood yet why some people with a pathogenic mutation ultimately do not present with the disease.

 
5. How high is the risk of developing breast cancer? Might one develop other forms of cancer as well? Are men also at risk from these mutations?

In case of a BRCA1 mutation the risk of developing breast cancer is 56-84% and in case of a BRCA2 mutation 60-80%; the risk of developing breast cancer in Li - Fraumeni syndrome (due to a TP53 or CHEK2 mutation) is 49% and in Cowden syndrome (PTEN mutation) 25-50%. The most common mutations are detected in the BRCA genes. On the other hand, the Li - Fraumeni and Cowden syndromes as well as other genetic syndromes are extremely rare.

Apart from breast cancer, BRCA mutations also create high risk for developing ovarian cancer (36-63% for BRCA1 mutations and 10-27% for BRCA2 mutations). Some other forms of cancer also occur more frequently in people with BRCA mutations (both men and women) than in the general population, but nevertheless in low rates (colon cancer, pancreatic cancer, melanoma). Men with BRCA1 mutation also face 1-5% chances of developing breast cancer and men with BRCA2 mutation 25-30% chances of developing prostate cancer and 5-10% chances of developing breast cancer.

In cases of Li - Fraumeni syndrome, malignancy might occur in almost any part of the body (sarcomas, leukemia, brain tumors, melanomas, kidney tumors, stomach cancer, pancreatic cancer, colon cancer etc.). People with this syndrome have 50% chances of developing cancer until the age of 40 and 90% until the age of 60!

In cases of Cowden syndrome there is a high possibility of developing thyroid cancer, endometrial cancer, renal cancer etc.). A lot of benign tumors are also developed in people with this syndrome.

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6. Are mutations always passed on to the next generation?

No. When a parent (father or mother) carries a pathogenic mutation, each child has 50% chances of inheriting it. This is because each child inherits half of the father's genetic material (genes) and half of the mother's. So, each child has 50% chances of inheriting the healthy half and 50% chances of inheriting the pathogenic half from the parent with the mutation.

 
7. Can the pathogenic mutation skip a generation?

The pathogenic mutation as a piece of genetic information is transferred from parent (father or mother) to the child (son or daughter). This means that it cannot be present in one generation, absent in the next one and present again in the one after it. The result of the mutation (the development of cancer) may be present in one generation, skip the next and reappear in the one after it. This can happen for several reasons such as:

Example 1: A young woman presents with breast cancer; her parents are healthy and her family history only includes ovarian cancer from her father's mother (her grandmother). A BRCA1 mutation is detected. It seems to have skipped a generation but in fact the father, who inherited the mutation from his mother, simply did not develop any malignancy because chances were low (since he was a man). However, he passed the mutation on to his daughter, who due to her gender had very high chances of developing a malignancy in the breast or the ovaries.


Example 2: A young woman presents with breast cancer; her parents are healthy and her family history only includes breast cancer from her mother's mother (her grandmother). A BRCA2 mutation is detected. It seems to have skipped a generation but in fact mother, who inherited the mutation from her mother, simply did not develop any malignancy because she died from another cause at a relatively young age.

 
8. What are the indications for testing in women?

Indications for testing are previous disease plus positive family history, disease at an early age, and heavy family history. 

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9. Is a genetic test actually beneficial? Or is it just a cause for additional stress and anxiety?

The detection of the pathogenic genetic mutation is a valuable piece of information. The woman can manage the information in one of the available ways in order to drastically reduce the risk to her life. If she has not given birth, she may plan to have child-birth at an early age and not pass the mutation on to her descendants by means of the ovules selection technique. If she has already given birth, she makes sure that the descendants are informed -at the proper age- of their chances to carry the mutation and get tested themselves.

 
10. What are the options if a pathogenic mutation is detected?

If a pathogenic mutation is detected, the woman may choose between strategies to reduce the risk of developing cancer (prophylactic surgical procedures) and intensive screening programs. Both options have pros and cons. The final decision is made by the woman herself and is a result of consideration of many factors.


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