For many years now it has been recognised that certain cancers run in families – breast cancer and colorectal cancer spring to mind. But what about the other types?
Anyone who has read articles in the popular media will have seen the genes BRCA1 and BRCA2 mentioned in connection with breast cancer.
What are these genes and who do they affect? Up to 10% of breast cancers are thought to arise from an inherited predisposition to the disease. Mutations in two genes, BRCA1 and BRCA2, account for most of these cases, although there are other genes associated with hereditary breast cancer.
A simple blood test can now be used to detect mutations in these genes. How is it that these mutations increase susceptibility to cancer?
BRCA1 has been localised to chromosome 17q and BRCA2 to chromosome 13q. Both genes apparently function as tumour suppressor genes. So individuals who inherit a mutated (changed) copy of these genes which no longer have these tumour suppressing properties, do not have the physiological ability to prevent the uncontrolled growth of cancer.
The exact mechanism of action of these two genes, and exactly how mutated copies lead to breast and ovarian cancer, is not clear. BRCA1 apparently suppresses the growth of ovarian and breast cancer lines, and BRCA1 and BRCA2 seem to take part in the mechanism of DNA production and repair.
How is your risk of breast cancer increased by carrying one of these gene mutations?
We know that most hereditary breast cancers are associated with mutations to BRCA1 and BRCA2. The information on the risks of cancer associated with carrying these genes has been derived from studies of families in which many female members have developed breast and ovarian cancers at an early age.
Women inheriting a BRCA1 mutation have a 55 to 85% risk of developing breast cancer, compared with a 12.5% risk in the general population. They also seem to develop the cancer at an earlier age. More than 50% of carriers are diagnosed before the age of 50. They also have a much greater chance of developing cancer in the other breast later in life. Early studies suggest that breast-conserving surgery may not be a good option for these women since there seems to be a higher risk of developing cancer in the remaining part of the breast.
Women with BRCA1 mutations also have an increased risk of developing ovarian cancer; 15 to 60% by the age of 70, against one to two percent generally. BRCA1 mutation carriers who have developed breast cancer have a 44% chance of ovarian cancer by the age of 70.
The risk is only three percent in those women who have sporadic, non-inherited, breast cancer.
There may be other cancers associated with BRCA1 mutations. It seems that men carrying these mutations have an increased risk of prostate cancer, although there are as yet no figures on the increased risk in comparison with the general population. There may be an association with colorectal cancer, but this is still being studied.
BRCA2 mutations are associated with an increased risk of breast cancer in men as well as women. The risk in women carrying mutations is between 55 and 85%, while that in men rises to about six percent. Breast cancer in men is very rare, with only 1600 cases diagnosed every year in America.
There is not as strong an association between ovarian cancer and BRCA2 mutations as there is between this cancer and BRCA1 mutations.
However, the risk is still slightly higher than that in the general population at 15 to 27%. Prostate cancer also appears to be associated with BRCA2 mutations, and some studies have suggested a link with pancreatic cancer.
As many as 25% of people with colorectal cancer may have a family history of the disease which suggests that there is a hereditary component.
These hereditary large bowel cancers can be divided into two main groups:
Polyposis coli, also called familial popyposis of the colon, is a rare condition. Those affected have literally thousands of polyps – little knobs of tissue which stick out of the bowel wall – in their large bowels. These polyps are of a particular cell type called adenomatous.
The condition is transmitted through families as a dominant gene, although there are rare sporadic cases which have arisen as a result of a mutated (changed) gene.
It is thought that polyposis coli is associated with a loss of genetic material from one chromosome. The lost genetic material may have contained tumour suppressor genes which would normally have prevented the growth of cancers.
The polyps are rarely present before puberty but are generally detectable by the age of 25. If left untreated, colorectal cancer will have appeared in almost all patients by the age of 40.
There are families with a hereditary predisposition to colorectal cancer who have no evidence of polyps in the large bowel. There are several groups of people who have a risk as high as 50% for the development of colorectal cancer.
Their cancers arise in a particular part of the large bowel, higher up than normal, in an unusually high frequency. These same families often include patients who have multiple primary cancers. There is a particular associated between colorectal cancer and cancer of the womb (endometrial cancer) in women for example.
Again the trait is transmitted as a dominant gene and the average age for the appearance of the cancer is under the age of 50, a good 10 to 15 years earlier than for the general population.
Screening, genetics and cancer
People who have a family history of either polyposis or non-polyposis colorectal cancer should have regular and intensive screening, certainly from their early 20s.
This screening should include direct visualisation of the bowel through an endoscope since simply looking for blood in the stool is not adequate.
Fairly simple for colorectal cancer. Those with a family history of breast or ovarian cancer do not have such a simple decision, since both who to screen and what to do with the results are not simple questions.
Who should be tested?
Most cases of breast cancer are sporadic, that is, not inherited. So how do you know if you should think about testing?
In order to determine whether you should be tested your specialist will take an extensive family history, looking for the following features:
Early onset of breast or ovarian cancer, which is a common feature of hereditary cancers. Early is considered younger than 40 to 45 in breast cancer and younger than 50 in ovarian cancer.
Anyone with multiple primary cancers and associated cancers should be considered. The occurrence of breast and ovarian cancer in the same person is strongly indicative of an inherited cancer. If family members have ovarian, pancreatic, colorectal, prostate cancer, or breast cancer in both breasts then there is more likely to be a mutation of BRCA1 or 2 present.
Breast and/or ovarian cancer in two or more first-degree relatives or in at least two generations, suggests hereditary cancer.
Affected daughters of male relatives should also be considered, since men have the same chance as women of passing the gene on to their children, even though they have a lower risk of cancer themselves.
An autosomal dominant pattern of inheritance. This means that on taking the family history it becomes apparent that the mutation is passed down through men and women, each having a 50% chance of passing the mutation to his or her children. Cancers can skip generations because 15 to 45% of female carriers never develop cancer, and male carriers have a low risk of cancer. However, these people can still pass the mutations on to their children.
People of Ashkenazi Jewish origin, that is from Central or Eastern Europe, have an increased frequency of mutations of BRCA1 and BRCA2. These mutations have also been found in Jewish families without a strong family history of cancer.
What do the test results mean?
Before testing, all patients must insist on full counselling by an experienced genetic counsellor.
There is more than one possible outcome to testing, including an "inconclusive" outcome. What are these?
A known mutation is identified - a "true positive" result. In this case testing has shown a mutation clearly associated with an increased risk of breast or ovarian cancer shown by family history.
No carrier state found - a "true negative" result. In this case no mutation is found. This is only a true negative if it is found, for example, in a healthy woman whose aunts have tested positive, but who has no history of cancer on her mother's side of the family. Despite the fact that her aunts have tested positive, she obviously has not inherited the mutation from her father, and there is no indication that it is present in her mother's family.
An inconclusive result may occur in particular situations. If a negative test results from only partial testing, then the mutation may be present on the untested portion of the BRCA1/2 gene. Even in complete testing, the mutation could be present in a different part of the gene, or in another gene which predisposes to hereditary breast cancer. There are also situations in which a BRCA1 or BRCA2 mutation is found, but the clinical significance of the mutation is not known. All genes can undergo benign changes, called polymorphisms. But in the case of the unknown mutation, it could also be deleterious. At present we are not able to distinguish between the two.
With a combination of a strong family history and a true positive result, the rest of the family, including more distant relatives such as aunts and cousins, will be offered testing. It is important that each subsequent family member offered testing is fully counselled by an experienced genetic counsellor.
What do we do with the results?
In all medical situations investigations should only ever be carried out if they are going to make a difference to managing the patient. At present we are in the situation where we are able to test for these mutations which we know confer an increased risk of certain cancers, but we cannot yet offer a definitive management program having found them.
However, "yet" is the operative word, and there is plenty of research being carried out on screening and prevention which should mean that we will be able to offer management alternatives to women with these mutations very soon.
At the moment there are certain general measures which should make a difference to outcome in women who are found to have mutations of BRCA1 and BRCA2.
Obviously, any woman with these mutations will increase her surveillance for breast cancer with regular breast self-examination and mammograms.
Some women may consider removal of both breast and ovaries to decrease the risk of cancer, although it is important to recognise that even this does not decrease the risk of cancer to zero.
Although the current evidence is not conclusive, it would seem that tamoxifen and raloxifene may protect against breast cancer in women without the BRCA1/2 mutations. Studies are currently being carried out to determine whether this effect is seen in women carrying the mutations.
The effects of long-term use of the oral contraceptive pill in women carrying the BRCA1/2 mutations is not clear. In healthy women long-term use of the oral contraceptive pill is associated with a decreased risk of ovarian cancer, and overall, does not increase the risk of breast cancer.
However, a study of Ashkenazi Jewish women suggests that women carrying BRCA1/2 mutations may have an increased risk of breast cancer associated with long-term use of the pill. But, the sample size of this study was small and more work needs to be done before making conclusive statements.
There is little or no information on the risks of hormone replacement therapy (HRT) in women with these mutations. Since women carrying BRCA1/2 mutations may consider having their ovaries removed at an early age to prevent them from developing ovarian cancer, this is a pertinent problem.
In the general population there may be some evidence of a slightly increased risk of breast cancer with HRT use. However, some people believe that HRT can be used in BRCA1/2 carriers who have had prophylactic mastectomy and oophorectomy (removal of the ovaries). Larger studies are currently underway to determine whether risks for breast and ovarian cancer in BRCA1/2 carriers are affected by using HRT.
The other major problem with testing comes when the insurance companies start thinking about using it to determine risks in those buying life-insurance.
In any application for life-insurance a family history of cancer would become apparent, since the state of health and cause of death of siblings and parents is required. Should insurance companies then be able to insist on testing for these mutations, as they now do for HIV in South Africa?
Up to 45% of female carriers never develop cancer. Should they be penalised for carrying a mutated gene which may have no effect on their longevity? Only 10% of breast and ovarian cancer is hereditary anyway, so would insuring these people really make a lot of difference to the financial burden carried by the insurers?
With the increasing number of genetic tests available these are questions which are being asked by consumers and the insurance industry alike. At present we have no answers, but it is up to consumers to keep a close watch on what is happening in the industry to prevent the potential for unfair practice.
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