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Cancer: clearing the air
Early detection of cancer can help assess whether other members
in the person's family are at risk. A guide.
What is hereditary cancer?
It refers to the occurrence of cancers in a family due to the passing of abnormal genes from one generation to the other.
When can one suspect that cancer is likely to be hereditary?
- Cancer in two or more close relatives.
- Earlier age of onset than usual.
- Involvement of both sites in paired organs.
- Cancers occurring in the context of specific features of a known syndrome (individual or family with features of birth defects).
- An individual with multiple cancers.
Which are the cancers in this category?
- A partial list will include
- Breast and ovarian cancers
- Large bowel and rectal cancers (colon and rectum)
- Multiple Endocrine Neoplasia 2 (MEN 2) (cancer involving several endocrine organs)
- Hereditary Retinoblastoma (an eye cancer in children)
- Hereditary Wilm's tumour (kidney cancer in children)
- Hereditary Melanoma (a form of skin cancer).
- Li Fraumeni syndrome
- Neurofibromatosis 1 and 2
- von Hippel-Lindau syndrome
Why detect hereditary cancers?
Detection can help assess whether other members in the family are at risk. This would allow early detection of cancer or can facilitate preventive measures.
How can we detect these cancers?
A questionnaire is sent to elicit information about instances of cancer in the family. The family member with cancer (proband or index patient) will be first studied for abnormalities in known genes, using molecular techniques.
What is predictive testing?
It refers to the identification of the abnormal gene in apparently normal relatives of a cancer patient, who is known to harbour the abnormal gene.
Who should be offered predictive testing?
It can be offered to first or second degree relatives of a cancer patient, who has a known gene abnormality, provided the cancer that is predisposed by the abnormality is amenable to intervention (prevention or early detection).
What are the limitations of predictive testing?
If the cancer patient in a family does not have a detectable abnormality in a known gene, then screening other members would be difficult. A positive test is more informative than a negative test, as the latter may be due to limitations of the testing procedure.
What measures are there for prevention of cancer in individuals at risk?
The options available depend on the type and site of cancer. They can vary from a more aggressive screening programme for early detection of the abnormality to removal of the organ at risk (like removal of the large bowel or both breasts).
I resemble my relative who has cancer. Am I at increased risk for cancer?
The genes involved in hereditary cancer are not related to the genes associated with an individual's appearance. Hence, appearance and cancer do not go together. It is essential to test for the genes known to be involved in hereditary cancer to assess the risk.
How much data do we have in the Indian context on hereditary cancers?
We have very little information at present. Hence, the risks and incidence which are likely to be quoted are often derived from Western data, which is not always comparable. This is why we need to have our own data for better models.
Hereditary breast and ovarian cancers
What is the incidence of hereditary breast and ovarian cancer?
Ten to 15 per cent of breast cancers are likely to be associated with hereditary factors. In ovarian cancers this is likely to be less than 10 per cent.
What do we know about the genes involved in breast and ovarian cancers?
They are: BRCA1, BRCA2, ATM, p53. In ovarian cancers, BRCA1, and, to a lesser extent BRCA2 are involved. These genes are involved in repair of the DNA in a cell.
When can one suspect that breast cancer is hereditary?
The involvement of more than one blood relatives either in the maternal or paternal side.
Early onset of breast cancer (at or less than 35 years of age).
Two cases of breast cancer diagnosed under the age of 50 years.
Three cases of breast cancer diagnosed under 60 years of age.
Four or more cases of breast cancer diagnosed at any age.
Presence of breast and ovarian cancer in the family or in the same individual.
Male breast cancer with a relative (of either sex) with breast cancer.
When can one suspect that ovarian cancer is hereditary?
Ovarian cancer in two or more members of the family occurring at any age.
Ovarian cancer in women under 45 years of age.
How can we detect these cancers?
First a questionnaire is sent to elicit information about instances of cancer in the family.
Second, informed consent will be taken from the patient with cancer (proband or index case) in the family for permission to do genetic analysis. After this, genetic analysis for abnormalities in known genes will be done.
When will predictive testing be done?
Predictive testing can be done to identify family members at risk for breast or ovarian cancer, if a family member has cancer with a known abnormality of the genes predisposing to hereditary cancer. However, before this is done, genetic and psychological counselling for members of the family who are apparently normal will be done. Testing can be done only after written informed consent is given by individual members.
What samples will be needed for the study?
In most instances a blood sample will suffice.
What is the risk of developing cancer if a family member is found to carry the abnormal BRCA1 or BRCA2 genes?
The risk of developing breast cancer would be 85 per cent by the age of 70 years (i.e., if 100 women are found to have an abnormal gene, 85 of them would develop cancer by the time they reach 70 years. Conversely, 15 of the 100 women, may not develop breast cancer, by 70 years of age).
The risk of developing ovarian cancer has been found to vary from around 30 per cent to 85 per cent by 70 years of age.
Does the abnormality in BRCA1 or BRCA2 predispose to other cancers?
BRCA1: There is a slightly increased risk (three fold higher) for the development of prostate cancer in men who carry the abnormality. In addition, the risk for colon cancer is also increased (four fold higher)
BRCA2: An increased risk for prostate and pancreatic cancer may also be seen. Other cancers which have been reported include those from the alimentary tract.
What measures are available for the prevention of cancer in individuals at risk?
Aggressive screening for early detection (breast self-examination starting in early adulthood; six monthly clinical breast examination starting from 25 years of age; annual ultrasound/mammography (if necessary) from 25-40 years).
Prophylactic surgery (removal of both breasts (mastectomy) and both ovaries (oophorectomy). However, they do not completely remove the risk.
Chemoprevention (Tamoxifen, a drug used in the treatment of breast cancer has been shown to be beneficial in a group of women at risk. Since it has a few major side effects, newer drugs are being evaluated).
Ovarian cancer:
Although screening procedures using blood tests or ultrasound can be done they are not very reliable.
Prophylactic surgery (removal of ovaries removes the risk for ovarian cancer. However, there is still a chance that cancer can arise from the lining of the abdominal cavity).
Colon (large bowel) cancer:
Through there is a slightly increased risk, cancer in the large bowel does not appear to occur at an early age. Hence the general screening programme can be followed (yearly stool examination for traces of blood beginning from 50 years of age; An examination of the large bowel using flexible endoscope (colonoscopy) beginning from 50 years of age), one every five years.
Prostate cancer
In men with an abnormality of BRCA1 and BRCA2, there is a slightly increased risk for prostate cancer. Prostate cancer screening can be done (digital rectal examination and PSA (blood test) should be done annually from the age of 50 years).
What if my test result is reported negative even though my relative with cancer has an abnormality in the known gene?
If the member who is apparently normal has tested negative, then their risk for developing cancer will be equivalent to that of those in the general population. They can then follow the standard guidelines for screening.
Hereditary colo-rectal (large bowel) cancer
What is the incidence of hereditary large bowel cancer?
Large bowel (colo-rectal) cancers have a hereditary basis in six per cent of cases.
What are the types of hereditary large bowel cancer?
There are two types of hereditary colo-rectal cancers — Familial Adenomatous Polyposis (FAP) and Hereditary Non-Polyposis Colo-rectal cancer (HNPCC).
In FAP, multiple polyps (adenomas, which to start with are benign) occur throughout the large bowel, virtually carpeting the mucosal surface. Malignancy arises in some of these polyps usually by 20-40 years of age. The gene involved is Adenomatous Polyposis coli (APC) gene.
In HNPCC, multiple polyps are not seen. The defect appears to lie in the DNA mismatch repair genes, five of which have been identified so far as being involved in HNPCC. These genes are MSH2, MLH1, PMS1, PMS2 and MSH6. Of these, MSH2 and MLH1 are the most important.
What are the other cancers seen in hereditary colo-rectal cancer?
In FAP, there is a slightly increased risk of cancer also occurring in the stomach, the first part of the small bowel, the mouth of the pancreas, the thyroid and the brain. In children, the liver can also be affected.
In HNPCC, either it is large bowel specific (Lynch I) or may be associated with increased risk for cancer in the uterus, ovary, other regions of the gastrointestinal tract, renal pelvis and urinary bladder (Lynch II).
When do we suspect that large bowel cancer has a hereditary basis?
Families with three or more cases of the following:
Large bowel cancer and either
Uterine cancer or ovarian cancer or other gastrointestinal cancers (stomach, liver, small bowel) or kidney or bladder tumours.
Families with cases of large bowel cancer or uterine cancer diagnosed before 45 years of age.
Individuals with adenomas diagnosed before 40 years of age.
Do all patients with a known gene abnormality develop hereditary large bowel cancer (in other words, what is the penetrance of the gene)?
The risk of developing large bowel cancer if one of the HNPCC genes is abnormal is around 80 per cent by 70 years of age. In other words, if there are 100 subjects with one of the HNPCC gene abnormality, 80 of them will develop cancer by the time they reach 70 years of age; 20 of the 100 may not develop cancer. HNPCC gene mutation carriers have a 30-40 per cent risk for the development of uterine cancer by 70 years of age. In the case of ovaries the risk is 10 per cent.
In FAP, the penetrance is 100 per cent (that is all patients with the APC gene abnormality develop large bowel cancer by 40-45 years of age).
What measures are available for prevention of cancer in individuals at risk?
For asymptomatic carriers of the abnormal gene, options available include:
HNPCC: Examination of the large bowel upto its junction with the small bowel using flexible endoscope every one or three years starting from 20 - 25 years of age.
FAP: Examination of the distal region of the large bowel using flexible sigmoidoscopy starting from the age of 10-12 years and repeated once every one or two years. At times, examination of the entire large bowel using colonoscopy, may be necessary.
Annual screening for uterine cancer using endometrial aspirate or specialised ultrasound examination beginning at 25 years of age. Annual urinalysis beginning at 25 years of age; Annual skin surveillance examination.
In FAP, annual thyroid examination will be needed.
In children at risk for FAP, abdominal examination and a blood test may be needed every six months, to detect a liver tumour, until they reach six years of age.
Prophylactic surgery
In FAP: Prophylactic removal of the entire large bowel once polyps are seen in the large bowel during the surveillance examinations.
In HNPCC: In a mutation carrier, if adenomas are detected, surgical removal of the large bowel can be considered as an option. Once cancers are detected during surveillance, removal of the major portion of the large bowel can be done.
Once a woman completes her family, prophylactic removal of the uterus and both ovaries can be considered (prophylactic hysterectomy and prophylactic bilateral oophorectomy).
DR. T. RAJKUMAR
The writer is scientific director and Professor and Head, Department of Molecular Oncology, Cancer Institute (WIA), Chennai.
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