The genetics of inherited cancers - Identification and management of known or suspected cancer predisposition gene mutation carriers
Cancer genetic counselling
This involves assessment of cancer risk, discussion of screening and management options, and the offer of genetic testing if appropriate.
This can be complex; it involves a risk estimate and this information has to be communicated to the patient in the manner most appropriate to the individual concerned so that they can understand and retain the information but are not made inappropriately anxious about their risks.
The first risk estimation is the chance that a familial cluster is due to genetic predisposition (the ‘prior probability’ of a genetic predisposition gene being present in a family). An extensive family history is important to determine this, often out to third-degree relatives. Confirmation of diagnoses is important for some sites (e.g. abdominal tumours) as these can be misreported in families in about 17% of cases. The risk estimation is based upon published data or clinical experiences when published data are lacking, which unfortunately is often the case with rare genetic conditions. There are also now computerized models for some common cancers which can aid prediction of the presence of a genetic mutation, such as the BOADICEA model for the chance of a BRCA1/2 mutation.
The second risk estimation is the chance that the individual has inherited a particular gene based upon their cancer status (affected or unaffected), their position in the family tree, and their age. This is termed the ‘posterior probability’.
The final calculation is the chance that cancer will develop, which is the posterior probability multiplied by the penetrance. The expression of this risk can be delivered in a number of formats: the optimal format is unknown. Currently, risk estimates tend to be given as a percentage risk or a ‘1 in X’ value and followed up with a written summary, incorporating this risk estimate, to the individual attending the genetics consultation. There are data which suggest that individuals prefer not to have, or do not remember, numerical information, but are able to report the qualitative category of their risk (low, medium, high) with reasonable accuracy.
Identification of an at-risk family
A family at genetic risk of cancer must first be identified. This is usually via the general practitioner (family doctor) or a hospital oncology clinic; it is now becoming more common for family history to be requested by cancer geneticists working as part of the multidisciplinary team coordinating the patient’s care. Because of the limited time available during most consultations, it is not appropriate to obtain a detailed family history from the patient. As a quick guideline, taking a history of all first-degree relatives only (parents, siblings, and children) and then asking if there are any other cancers in the family will detect 95% of familial syndromes. From this quick family history it should, however, be possible to make an assessment of whether the family history warrants further investigation.
Referral guidelines have been developed; for example in the United Kingdom, there are national guidelines for familial breast cancer. These guidelines aim to delineate the management and referral pathway according to the Kenilworth model whereby individuals whose risk does not exceed that of the general population are managed in the primary care setting, individuals at moderate risk are managed in secondary care, and individuals at high risk are managed in tertiary care in cancer genetics centres. In the cancer genetics clinic, after a full family history, initial clinical examination involves looking for any dysmorphic features and congenital anomalies. The skin should be carefully examined, as many cancer syndromes are associated with dermatological features, as noted above.
Throughout the consultation, it is important to be sensitive to any issues relating to bereavement due to the premature death of close relatives, particularly a parent or child. Unresolved bereavement may make it difficult for people to accept their own risks and make decisions about their own management. Some individuals are particularly worried when they are approaching the age at which their relatives were diagnosed. Others erroneously assume that they are more likely to have inherited the cancer predisposition gene because they resemble their affected relative, either physically or in temperament. Patients are sometimes unable to cope with their concerns, and referral for formal psychological counselling may be needed. Of particular concern are those individuals who have prophylactic surgery because of excess anxiety but who, while being temporarily relieved, could return at a later date with further cancer phobic symptoms. A psychological assessment and counselling should be part of the referral process before prophylactic mastectomy.
The subsequent management of an individual and their family will depend upon the final risk estimates regarding the inheritance of a cancer predisposition gene and the potential cancer risks. In general, management strategies fall into five categories, cancer screening, lifestyle changes, prevention strategies, cancer treatment considerations and genetic testing.
Not all of the screening schedules have been proven to reduce mortality from the relevant cancer, but these schedules represent a pragmatic approach to the management of individuals at increased risk. There is, however, some evidence that screening individuals with HNPCC by colonoscopy reduces mortality due to colorectal cancer, as any suspicious polyps observed on colonoscopy may be removed at an early stage. The guidelines promulgated by the United Kingdom National Institute for Health and Clinical Excellence (NICE) mentioned above have made recommendations for mammographic and MRI screening in certain groups at risk of familial breast cancer. Prostate and ovarian cancer screening are contentious and are currently subjects of research.
Lifestyle changes may involve avoidance of known cancer causing factors such as sunlight in Gorlin’s syndrome and X-ray exposure in the Li–Fraumeni syndrome. Other lifestyle changes are less well established in the prevention of cancer and are being assessed in trials.
Primary prevention strategies include prophylactic surgery and chemoprevention. The evidence in support of the efficacy of these measures is variable, mainly due to the rarity of the genetic mutations making clinical trials difficult to perform. Established measures include total colectomy in the familial adenomatous polyposis syndrome, total thyroidectomy in the MEN2 syndrome, and bilateral salpingo-oophorectomy in women with BRCA1/2 mutations. Limited retrospective data suggest that the risk of breast cancer is reduced by 90% following prophylactic mastectomy although there is still a small residual risk (about 1.5%) due to the inability to remove all breast epithelial tissues at mastectomy.
The role of chemoprevention is much less certain. In meta-analyses tamoxifen reduces breast cancer risk by at least 33%, but it should be noted that the type of tumour prevented is hormone receptor-positive, and this has a better prognosis. The oral contraceptive pill reduces ovarian cancer risk by about one-third in those on the pill for 2 years. Recent data report a reduction in colon cancer risk in HNPCC families in individuals who have taken aspirin after 5 years.
Data are emerging which report a difference in prognosis when certain genetic changes are present in the germ line; e.g. ovarian cancer due to mutations in BRCA1/2 has a better prognosis and a higher response to platinum-based chemotherapeutic agents. Certain syndromes are associated with altered response to treatment, e.g. colonic tumours which have microsatellite instability are less responsive to 5-fluorouracil. Agents are now being developed which specifically target tumours with certain genetic defects, e.g. the PARP inhibitors, which enforce the cancer cell to use the homologous recombinant DNA repair pathway which is deficient in BRCA1/2-null cells, have resulted in promising early response rates in tumours in patients with germ-line BRCA1/2 mutations.
Genetic testing is possible for most cancer predisposition genes and is performed on DNA from venous blood after genetic counselling. Genetic testing may either be diagnostic (the detection of a mutation in an individual affected by cancer) or predictive (the detection of a mutation in a clinically unaffected individual). Mutations in cancer predisposition genes often occur throughout the gene and the vast majority of mutations so far have only been observed in limited numbers of families, except in specific ethnic groups with known founder mutations such as the Icelandic and Ashkenazi populations with BRCA1/2 mutations. Hence, unless an individual is a member of such a group, the specific mutation for that family must first be identified. An affected family member is tested first because they are the family member most likely to have the cancer-predisposing mutation. Once a mutation is identified, it is important to check that the ‘mutation’ is likely to be cancer causing and not a normal variant of the gene (polymorphism). When a pathogenic mutation is identified, predictive testing may be offered to unaffected family members for the identified mutation.
Misleading results may occur if an unaffected individual has a genetic test in order to identify a mutation without first identifying it in an affected relative. A negative result (i.e. no mutation is identified in the cancer predisposition gene tested) may not be a true negative for several reasons:
- The family history is caused by a gene other than the one being tested or may not be genetic at all.
- The alteration may be regulatory which means that it controls how the gene is expressed but the gene itself (and therefore the test which looks at the gene code) is normal.
- The genetic test sensitivity is not 100% for the genetic coding mutations and may therefore have missed mutations.
When the specific mutation has been identified in an affected individual, if it is not found in an unaffected relative, this is then a truly negative result. The personal and wider social implications of positive and negative results are issues discussed during genetic counselling sessions. A positive result could have psychological implications as well as widespread repercussions involving the rest of the family. A negative test result may have psychological consequences due to the recognized ‘survivor guilt syndrome’, which has been documented in the setting of Huntington’s disease.
There is a moratorium on the use of some genetic information in the United Kingdom, as detailed on the Association of British Insurers’ website http://www.abi.org.uk.
For genes predisposing to adult-onset cancers, testing of young children is not advised as the age of cancer onset permits the individual to make their own decision to have genetic testing once they have reached adulthood, following full genetic counselling. Children are offered genetic testing when it may alter management, for example, in the MEN2A syndrome when thyroidectomy is offered before age 5, in retinoblastoma to avoid unnecessary eye examinations, or in FAP where regular colonoscopies or colectomy may be avoided.
Recently genetic testing has been licensed for preimplantation genetic diagnosis for certain cases of hereditary cancer.
Cancer is a common disease and only a proportion of cases will be due to the inheritance of mutations in specific genes that predispose to cancer. However, because cancer occurs with high frequency in the population, this represents a large number of individuals. The developments of more rapid genome sequencing will enable cancer genetics to become part of cancer care as more targeted treatments are developed for such individuals and targeted screening is undertaken in their relatives.