While actress Angelina Jolie has spoken publicly of her double mastectomy so that women who are unaware that they are living under the shadow of cancer can be tested, Prof. Christian Scerri says it is important to understand why testing for the breast cancer-related gene might be useful for some but not for others.
[attach id=263099 size="medium"]The appearance of cancer requires the derangement of more than one cancer-related gene.[/attach]
The news that Hollywood actress Angelina Jolie’s preventive mastectomy following the discovery that she had tested positive for a faulty BRCA1 gene went viral within a few minutes after it was made public.
While Jolie stated she chose not to keep her story private “because there are many women who do not know they might be living under the shadow of cancer” and that it was her hope they will be able to be tested, it is important to understand why testing for the gene might be useful for some but not for others.
How do cells control their internal functions?
Seen under a microscope, cells (apart from red blood cells) contain a nucleus that is the central repository of the information that directs the cell internal physiological processes.
Each human cell contains around 30,000 discrete genes capable of producing around 100,000 different proteins
This information is stored in genes, which can be considered discrete pieces of information that can be deciphered or translated into proteins. To do this, the protein translating mechanism needs to know where the gene starts and ends, as well as various other controlling regions.
On comparing the gene and the DNA molecules that compose it to chapters within books and the letters in the alphabet, the DNA “words” are composed of three “letters”, each corresponding to a specific amino acid that make up the protein. These “DNA chapters” are found within specific “books”, called chromosomes.
The human cell has 22 identical pairs of chromosomes, numbered one to 22 and either two X chromosomes (in the female) or an X and a Y chromosome in the male.
Each parent passes one of each pair of chromosomes, with the father passing either an X or a Y (this occurs randomly). Each human cell contains around 30,000 discrete genes capable of producing around 100,000 different proteins.
What causes cancer?
Cells can turn on or off genes, depending on their needs of the moment. The ability of cells to do this is the way they specialise and they transform from stem cells to specific cells. DNA mutations can result in either a lack or a decrease in production of specific proteins or else the production of abnormal proteins.
In both cases, this can result in disrupting intracellular biochemical pathways. All cancer is the result of multiple gene mutations. Similar to written instructions explaining how to use an appliance or a new car, the DNA code might have errors that could either result in minor, non-consequential mistakes, or be highly disruptive, resulting in a complete loss of the required instructions.
Most of the gene mutations that are a cause of cancer fall within two types of controlling genes: one type is called oncogenes that are derived from normal genes called proto-oncogenes, which limit cell divisions to the required quantities.
Once mutated, proto-oncogenes become oncogenes and lose their controlling ability, causing cells to continue dividing indefinitely.
A useful analogy is that of comparing a cell to a car. A car needs to have some type of speed control to keep it safe.
Proto-oncogenes can be considered to be the working accelerator pedal, while oncogenes can be considered an accelerator pedal that is stuck down.
The second group are called tumour suppressor genes. As the name implies, these genes suppress tumours through either the correction of errors in the DNA that can occur during cell division or else by instructing the cells to die (apoptosis or programmed cell death) when the DNA damage cannot be repaired.
Mutations in this group of genes, cause loss of function and thus errors in DNA copying can go unchecked, again causing cellular dysfunction and uncontrolled cellular divisions.
Inherited vs acquired mutations
Mutations within cancer genes can either be inherited through one of the parents or else acquired through the interactions of genes and the environment.
Most cancers are due to acquired mutations and these are not transmitted to children.
The appearance of cancer requires the derangement of more than one cancer-related gene.
Acquiring mutations in a number of genes usually requires long-term exposure to the environmental cause and rarely to exposure to high levels of particular environmental risk (e.g. radiation). Thus, sporadic cancer would usually appear at a late stage in life.
In contrast, persons that have inherited one mutated cancer gene would usually require only one acquired mutation in the other normal gene for cancer to appear.
Thus, in inherited cancer, numerous cases of similar or related cancer would usually appear within a family and the age of appearance would be younger than for acquired cancer.
Hereditary breast cancer
To date, there are around 33 breast cancer related genes that are thought to be responsible for around eight to 10 per cent of all breast cancers.
Out of these 33, the BRCA1 and BRCA2 are thought to be responsible for around 80 per cent of the families with hereditary breast cancer. Thus, though not 100 per cent sufficient to diagnose all cases, currently only BRCA1 and BRCA2 testing is available in most genetic clinics, including Malta.
These two genes are situated in two different chromosomes, 17 and 13 respectively. Though not related, both are tumour suppressor genes and, therefore, a mutation in one predisposes to possible breast and related cancer.
Children of individuals who carry a mutation in one of these genes have a 50 per cent chance of inheriting the mutation, which increases the lifetime risk of breast cancer.
However, the actual risk is modified by a number of lifestyle and biological factors, such as early menarche (age of first period), late menopause, age at first pregnancy (over 30 years increases slightly the risk), obesity especially after menopause, hormone therapy, alcohol and lately heavy smoking.
Apart from breast cancer, carriers of BRCA1 and BRCA2 mutations are also at risk of ovarian cancer in females as well as breast and early prostate cancer in males (though the risk in males is mostly associated with BRCA2 mutations).
To date, there are around 33 breast cancer-related genes that are thought to be responsible for around eight to 10 per cent of all breast cancers
How to identify candidates for genetic testing
In addition to the breast cancer cases that show a clear pattern of inheritance, another 25 per cent have some family history.
Though proper genetic assessment and counseling should be only offered by medical genetic specialists, initial risk assessment could be done by medical doctors or specialist nurses.
The instances when hereditary breast cancer is highly suspected:
• present in more than two generations
• early age of onset (<40 years)
• present in a male relative or if a male relative has early onset prostatic carcinoma
• associated with other types of cancer, congenital malformations or genetic syndromes
Individuals that fit these criteria should seek specialist advice from a medical genetics specialist.
Is there a need for predictive genetic testing in hereditary breast cancer cases?
Predictive genetic testing for hereditary breast cancer has a number of positive effects that include:
• clarification of the actual risk evaluation;
• targeting individualised prevention efforts towards the identified carriers (intensified screening procedures, early screening through the use of MRI, prophylactic mastectomy with reconstruction and lifestyle changes, among others);
• excluding the non-carriers and thus reduce the psychological stress.
Though the advances in molecular biology techniques have increased the ability to identify mutations within specific genes and thus individuals at risk, the results obtained can sometimes be ambiguous.
This may happen under two conditions: the first is when no cancer survivors are available for testing, meaning the presence or absence of particular mutations within the genes cannot be ascertained and negative results (no mutations identified in possible carriers) cannot be an assurance that no mutations actually exist.
The second case is even more complicated as during any genetic analysis, gene changes that are not clearly pathogenic can be identified, and, therefore, they cannot be assumed to be responsible for the seemingly hereditary cases within particular families. Another possibility is the presence of one of the rarer genes.
Future work
The human genome project and massive sequencing has opened the door to the possible concurrent testing of a large number of genes.
At present, the University of Malta in conjunction with the Breast Screening Unit of the Health Ministry, Malta Council for Science and Technology and three Italian institutions (University of Palermo, Azienda Ospedaliera Universitaria di Palermo Paolo Giaccone and Azienda Sanitaria di Siracusa) have initiated a 24-month project, partly financed through the Cross Border Cooperation Programme Italy-Malta 2007-2013, that is targetting breast cancer.
This project aims at establishing common databases and risk evaluation tools between the centres, identifying natural and man-made risks for breast cancer, as well as the predominant genes and mutations in the two regions, possible biomarkers that can be used for the diagnosis, prognosis and treatment of breast cancer and finally to continue in the elucidation of internal cellular pathways that could be used as therapeutic targets for future treatment protocols.
One of the deliverables of this project shall be the formulation of a region specific, gene array testing platform that could cheaply and quickly identify not only BRCA1 and BRCA2 gene mutations, but also mutations within a number of other breast cancer related genes.
Prof. Scerri is consultant, Molecular and Clinical Genetics, at Mater Dei Hospital, and heads the Department of Physiology and Biochemistry at the University of Malta.