An overview

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Alison and Susan were referred to the familial cancer clinic by their GP ... Alison was very worried that she would be 'next' .... Easton D F, Steele L, Fields P, et al.


rm An overview

What are familial cancers? The answer to the question: 'What proportion of cancer is genetic?' is, strictly speaking, 100%. All cancers arise as a result of the accumulation of genetic mutations in several genes of a cell. In the great majority of cancers, however, these mutations are acquired rather than inherited, and occur only in cells of a specific tissue. Familial cancers result from a genetic mutation that is inherited from a parent, and is therefore present in all cells of the body from the time of conception. Individuals who carry a mutation in a familial cancer gene are at a substantially increased risk of developing particular types of cancer. Although individually rare, mutations in familial cancer genes are considered to account for 5-10% of all cancers (Table 7).1 Familial cancer syndromes A number of different familial cancer syndromes are now recognised (Table 2) and the genetic basis for many of these is understood. The genes that result in familial cancers fall predominantly into one of two categories. They are either: • genes that control the rate of cell division (tumour suppressor genes, or 'gatekeepers'), or • genes that are involved in the repair of damaged DMA ('caretakers'). Most are dominantly inherited, implying that if a parent carries a familial cancer mutation, each

child has a one in two chance of inheriting the faulty gene (and therefore the increased risk of cancer). For many of the familial cancer syndromes, penetrance is incomplete, and therefore some family members who carry a gene predisposing to cancer will never develop the disease. The three familial cancer syndromes of greatest clinical significance are: • hereditary breast-ovarian cancer syndrome (BRCA1 and BRCA2 genes), • hereditary nonpolyposis colorectal cancer (HNPCC) and • familial adenomatous polyposis (FAP). Hereditary breast-ovarian cancer syndrome Mutations in the genes BRCA1 and BRCA2 result in an increased risk for both breast and ovarian cancer. Mutations in these genes are dominantly inherited and about one person (female or male) in 500 in the general population is a 'carrier' of such a mutation.2 It is anticipated that other yet to be identified genes will also play a role in hereditary breast cancer. Features of hereditary breast-ovarian cancer syndrome include: • early age of onset of breast cancer • bilateral breast cancer • male breast cancer and • the coexistence of breast cancer and ovarian cancer in the same family. Reprinted from Australian Family Physician Vol 30, No 10, October 2001, pages 937-945 • 1

Familial cancers — an overview

What are the risks? For female carriers of mutations in BRCA1 or BRCA2, the risk of developing breast cancer before the age of 70 years is between 40-80%, while the risk of developing ovarian cancer is between 10-40%.3^ Breast cancer also occurs in about 6% of males with BRCA2 mutations.7 There is some evidence that carriers of BRCA1 and BRCA2 mutations may also be at increased risk of prostate cancer,68 pancreatic cancer9 and colorectal cancer.8

individuals and is characterised by autosomal dominant inheritance and early age of onset of colorectal carcinoma, more often occurring proximal to the splenic flexure. There is also an increased risk of extracolonic cancers, in particular cancer of the endometrium, which may actually be more common than colorectal cancer in females with HNPCC.10 Component tumours and approximate cancer risk to age 70 are included in Table 3.n

Hereditary nonpolyposis colorectal cancer (HIMPCC)

Also known as polyposis coli, FAP (which includes Gardner syndrome), is much less common than HNPCC, affecting about 1 in 10 000 individuals. Typically, there are 100s or even 1000s of adenomatous polyps throughout the colon and rectum. Familial adenomatous polyposis is caused by mutations in the APC gene, with about one-third of cases resulting as a fresh mutation in that individual (and thus having a negative family history). Without prophylactic colectomy, nearly 100% of individuals with classic FAP will eventually develop colon cancer,12 with a median age of diagnosis of 40 years. Polyps may also develop in the stomach (not premalignant) and duodenum (can be premalignant) and there is a modest increase in the risk of some other cancers including thyroid cancer and brain tumours. Familial adenomatous polyposis is a multisystem disease, and other signs (for the most part of trivial significance) include:

Also called Lynch syndrome, HNPCC results from a defect in one of the genes responsible for DNA mismatch repair (the major known ones being MLH1, MSH2 and MSH6). Hereditary nonpolyposis colorectal cancer affects about 1 in 1000 Table 1. Relative contributions to cancer Dietary Smoking Hereditary syndromes Occupational exposure Infectious agents Radiation, environmental pollution

35% 30% 5-10% 5% 5% 4%

Familial adenomatous polyposis

Table 2. Selected familial cancer syndromes Syndrome



Hereditary breast-ovarian cancer HNPCC Familial adenomatous polyposis Cowden syndrome Li-Fraumeni syndrome Familial melanoma Gorlin syndrome Von Hippel-Lindau syndrome

Breast, ovarian Colon, endometrial, other cancers Colon, duodenum Breast, thyroid Sarcoma, breast, brain, adrenocortical, other cancers Melanoma, pancreas Basal cell carcinomas Haemangioblastoma of retina and CNS, renal cell carcinoma, phaeochromocytoma Neurofibrosarcoma, phaeochromocytoma, optic glioma Pancreatic islet, pituitary adenoma Medullary thyroid carcinoma, phaeochromocytoma


Neurofibromatosis I Multiple endocrine neoplasia type 1 Multiple endocrine neoplasia type 2A and 2B Retinoblastoma

Retinoblastoma, osteosarcoma

2 • Reprinted from Australian Family Physician Vol. 30, No. 10, October 2001, pages 937-945




Familial cancers — an overview

Table 3. Cancer risk to age 70 in patients with HNPCC Colorectal cancer Endometrial cancer Stomach cancer Ovarian cancer Small bowel cancer Transitional cell cancer of ureter/renal pelvis Hepatobiliary tract cancer Pancreatic cancer

82% 60% 13% 12% 4%

• jaw cysts • sebaceous cysts, and • pigmented retinal lesions. Rare familial cancer syndromes As well as the foregoing 'big three', there are several rare syndromes of which there will only be a small number of families per state, or even in the whole country. It is beyond the scope of this article to review all of these, although some of the more important syndromes are listed in Table 2. Any family with a strong aggregation of cancers diagnosed at young ages, especially where these are of the same type, should be considered for the possibility of a syndrome diagnosis, although in some of these families no specific diagnosis is able to be made. How to identify families at risk of familial cancer Specific guidelines have been developed to help doctors recognise familial cancer syndromes. The following general features should raise suspicion: • early age of onset (less than 40-50 years) • multiple cancers in one individual • similar cancers in two or more family members on the same side of the family • different cancers fitting the spectrum of a known hereditary cancer syndrome, eg: - breast cancer and ovarian cancer (BRCA1/2) - bowel cancer and endometrial cancer (HNPCC) - breast cancer and thyroid cancer (Cowden syndrome)

Table 4. Preventive strategies in familial cancer • Patient awareness, eg. - early reporting of symptoms suggestive of cancer - breast self examination (hereditary breast cancer)

• Screening tests, eg. - colonoscopy (FAR and HNPCC) and duodenoscopy (FAP) - clinical breast examination and mammography (hereditary breast cancer) - transvaginal ultrasound (hereditary breast-ovarian cancer) - transvaginal ultrasound and endometrial sampling (HNPCC) • Prophylactic surgery, eg. - prophylactic colectomy (FAP, some cases of HHNPCC) - prophylactic mastectomy (hereditary breast cancer) - prophylactic oophorectomy (hereditary breast-ovarian cancer) • Medical management and chemoprophylaxis, eg. - oral contraceptive pill may reduce the risk of ovarian cancer in hereditary breast-ovarian cancer16 - tamoxifen may decrease the risk of breast cancer in women at high risk of breast cancer17 - nonsteroidal anti-inflammatory drugs, in particular COX-2 inhibitors, may have a role in preventing colorectal cancer18

• pathological features of a particular cancer which suggest that the cancer is part of a familial cancer syndrome (although most familial cancers cannot be distinguished from sporadic cancer on the basis of pathology alone). The role of the GP in familial cancer The general practitioner has an important role in identifying individuals and families potentially at risk of familial cancers, and in addressing the concerns of patients who think that there might be an hereditary predisposition to cancer in their family. This role comprises three main tasks: • taking a family history. A family history should include all first and second degree relatives and all individuals who have definitely or possibly been diagnosed with cancer, including the age of onset of cancer. Family histories should be updated regularly, since new information may alter a patient's risk. • assessment of risk. An assessment can be made on the basis of the family history as to whether the family fits into a high, low or intermediate risk group for cancer. Established

Familial cancers — an overview

Referral to familial cancer clinic STEP 1: Is familial cancer syndrome likely? Analysis of pedigree Verification of diagnosis Review of pathology

STEP 2: Is there a family member who has had cancer and is willing to have genetic testing to try to find the family specific mutation (mutation detection)?

Possible Increased risk of cancer. Advice about cancer prevention strategies.

STEP 3: Genetic testing - mutation detection. Is a mutation detected in a familial cancer syndrome gene?

STEP 4: Genetic testing — predictive testing. Offered with appropriate counselling to other family members who have not themselves had cancer. Does a tested family member prove to have the mutation?

guidelines are available for the assessment of family history of bowel cancer 13 and breast-ovarian cancer,14 and documents summarising these are readily available through the Anti Cancer Councils in each state. • management. All patients at potentially high risk of cancer based on family history should be referred to a familial cancer clinic. It may also be appropriate to refer some patients at moderate risk to these services. Preventative strategies for high risk patients should be arranged in conjunction with the familial cancer clinic (Table 4). Low risk patients can be reassured that their family history does not place them at high risk of developing cancer, and recommendations for this group should focus on primary prevention (eg. dietary advice), early detection of symptoms, and screening according to guidelines for the general population. The role of the familial cancer clinics

Negative predictive test: individual not at increased risk of developing cancer. Close surveillance no longer necessary.

POSITIVE PREDICTIVE TEST: individual at definite increased risk of cancer. Advice about cancer prevention strategies, screening recommendations and possibly prophylactic surgery.

Figure 1. Management of referrals to familial cancer clinics.

4 • Reprinted from Australian Family Physician Vol. 30, No. 10, October 2001, pages 937-945

Table 5 provides a list of familial cancer clinics in Australia. Familial cancer clinics provide: • risk assessment • genetic testing • counselling and • surveillance advice to families where there may be an inherited component to cancer.15 The management of patients referred to a familial cancer clinic is outlined in Figure 1 and management examples are described in Cases 1 and 2. The goal of the familial cancer clinic is to reduce the morbidity and mortality from cancer among high risk patients. The process begins with the identification of such patients on the basis of their family history, and involves the systematic recording of the family pedigree. Emphasis is on cancer type and age of onset, and confirmation of diagnosis is sought whenever possible from death certificates, medical histories or pathology reports. Central to this process is the ability of the familial cancer clinic staff to interpret the pedigree, to make a diagnosis of a familial cancer syndrome should it be present, and then to recommend appropriate strategies for cancer screening, early detection and prevention in those at high genetic risk. Ideally a presump-

Familial cancers — an overview

live diagnosis of a familial cancer syndrome is to be confirmed with genetic testing in an affected family member. Genetic testing and familial cancer Genetic testing for HNPCQ FAP and hereditary breast-ovarian cancer is available through most familial cancer clinics. Testing for other familial cancer genes is also available in some centres, predominantly on a research basis. Genetic testing for familial cancer genes falls into two main categories: mutation detection and predictive testing. Mutation detection

consuming and costly, and is therefore currently limited to individuals from high risk families who have themselves been affected by cancer. Pre- and post-test counselling is mandatory in all cases of testing for familial cancer genes. In many high risk families no cancer causing mutation is found. By no means does this necessarily imply that no mutation is present in the family, because current methods will not detect all mutations in all familial cancer genes. High risk families where no mutation is detected must therefore still be treated as being potentially at increased risk of cancer. •^ Predictive testing

Mutation detection describes the initial screening The second phase of genetic testing is predictive of one or more genes looking for the family spe- testing. Predictive testing involves testing for the cific mutation. Mutational analysis is both time presence of a family-specific mutation in a family Table 5. List of familial cancer clinics in Australia


Canberra Genetic Counselling Clinic Canberra Hospital Woden Valley ACT 2606 Tel: 02 6244 4042 New South Wales Prince of Wales Hospital Hereditary Cancer Clinic High Street

Randwick NSW 2031 Tel: 02 9382 2577

Sydney Children's Hospital Department of Medical Genetics High Street Randwick NSW 2031 Tel: 02 9382 1718 or 02 9382 1704 Royal Prince Alfred Hospital Department of Molecular and Clinical Genetics Camperdown NSW 2032 Tel: 02 9515 5300 St George Hospital Clinical Genetic Counselling Service Kogarah NSW Tel: 02 9350 2315 Familial Cancer Service, Westmead Department of Medicine, Westmead Hospital Westmead NSW 2145 Tel: 02 9845 5079 Breast Centre Strathfield Private Hospital 3 Everton Road, Strathfield NSW 2135 Tel: 02 9744 3319

Concord Family Cancer Clinic MODU, Admin 3 Concord Repatriation General Hospital

NSW 2139

Tel: 02 9736 6262 Department of Clinical Genetics Liverpool Health Service PO Box 103 Liverpool NSW 2170 Tel: 02 9828 4589 Western Sydney Clinical Genetics Service Clinical Genetics Unit, Westmead Hospital Westmead NSW 2145 Tel: 02 9845 3273 Hunter Genetics PO Box 84 Waratah NSW 2298 Tel: 02 4985 3132 Queensland Qld Clinical Genetics Service Herston Hospital Complex Herston Qld 4029 Tel: 07 3253 1686 South Australia The Familial Cancer Unit SA Clinical Genetics Service Women's and Children's Hospital North Adelaide SA 5006 Tel: 08 8204 7375

Tasmania Tasmanian Clinical Genetics Service Royal Hobart Hospital GPO Box 1061L Hobart, Tasmania, 7001 Tel: 03 6222 8296


Peter MacCallum Familial Cancer Centre Peter Mac Callum Cancer Institute St Andrew's Place East Melbourne Vie 3002

Tel: 03 9656 1199

Genetic Health Services Victoria Royal Children's Hospital 10th Roor, Remington Road Parkville Vie 3052 Tel: 03 8341 6201 Monash Familial Cancer Clinic Monash Medical Centre 246 Clayton Road Clayton Vie 3168 Tel: 03 9594 2026 Royal Melbourne Hospital Familial Cancer Clinic Royal Melbourne Hospital Parkville Vie 3052

Tel: 03 9342 7151

Western Australia Genetic Services of Western Australia King Edward Memorial Hospital 374 Bagot Road Subiaco WA 6008 Tel: 08 9340 1525

Familial cancers — an overview

Case 2. (HNPCC)

Case 1. (BRCA1)


•"-•jp Ovarian cancer


O uUnaffected

60 years


teral ast cer

3ars/ ears


V Affected

Affected Endometrial cancer 58 years


r~t i

Rectal cancer 52 years



Susan breast cancer 39 years


Alison and Susan were referred to the familial cancer clinic by their GP after Alison requested a prophylactic mastectomy following the diagnosis of breast cancer in her sister Susan at age 39 years. Alison was very worried that she would be 'next' in the family to develop breast cancer. The family history was suggestive of a BRCA1 or BRCA2 gene mutation, and blood was collected from Susan for mutation detection. Four months later, genetic testing revealed that Susan carried a mutation in the BRCA1 gene. In the light of this information, Susan was informed that she was at an increased risk of developing a second breast cancer and also at increased risk of ovarian cancer, and preventative measures were discussed. After counselling, Alison decided to be tested for the BRCA1 mutation, and was found not to carry the mutation. Her personal risk of breast cancer was therefore the same as for the general population.


Colorectal cancer 34 years Stomach cancer 50 years



Andrew presented to his GP at age 34 years after seeing a television program about familial cancer. The GP referred Andrew to the familial cancer clinic and also arranged a colonoscopy, at which a large adenomatous polyp was removed. When Andrew attended the familial cancer clinic, the possible diagnosis of HNPCC was discussed. Andrew's father later attended the clinic, and blood was taken for genetic testing for HNPCC. Later, a mutation in the HNPCC gene MLH1 was detected in Andrew's father. Predictive genetic testing for HNPCC was then offered to Andrew, his two siblings and two cousins. Andrew was found to carry the MLH1 mutation, and regular colonoscopic surveillance was commenced. His two siblings were found not to carry the mutation, and therefore did not require further colonoscopies.

member who has not been affected by cancer. Predictive testing is therefore only available in families where a mutation has been identified during the mutation detection phase. Predictive testing is technically simpler than mutation detection, because only the family specific mutation needs to be tested, but it carries significant medical and psychological implications for the individual and detailed counselling is required. Some individuals may choose not to undergo predictive testing, and testing is not usually performed in children unless there is a clear health benefit to the child.

ventive strategies to be better targeted to those truly at risk, and may assist individuals in making important life choices. In individuals who test negative for a known familial cancer mutation, anxiety can be relieved and invasive surveillance tests are no longer necessary.15 Potentially adverse consequences of testing include fear, anxiety, depression, guilt and disruption to family relationships, and these complications must be anticipated in the counselling process. There may also be concerns about the confidentiality of the test result and its potential effect on life insurance and employment.

Genetic testing for familial cancer syndromes allows the provision of a more accurate estimate of the risk of developing cancer than is possible on the basis of family history alone. This enables pre-

Preventive strategies

Benefits and adverse consequences

6 • Reprinted from Australian Family Physician Vol. 30, No. 10, October 2001, pages 937-945

The process of genetic testing for familial cancer syndromes is, to a large extent, predicated on the availability of preventive strategies to eliminate or

Familial cancers — an overview

reduce the risk of cancer in those found to carry familial cancer gene mutations. Preventive strategies must be tailored to the individual patient and require a multidisciplinary approach and cooperation between the familial cancer clinic and the GP. It must be stated that firm evidence for the effectiveness of many preventive strategies in familial cancer syndromes is lacking, and recommendations may need to be updated as new evidence becomes available. Broadly speaking, preventive strategies can be divided into four categories: patient awareness, screening tests, prophylactic surgery and chemoprophylaxis. These may be utilised individually or collectively in a given patient (Table 4). Conclusion Familial cancer syndromes caused by single highpenetrance genes are now recognised to be responsible for 5-10% of all cancers. Recognition of such families by GPs may allow preventative strategies to be instituted with the aim of reducing the morbidity and mortality of cancer in a particular family. In some families genetic testing will be possible, with appropriate counselling, to further clarify the risk of cancer and to allow preventative strategies to be better targeted.







15. 16.



Cancer Linkage Consortium. Lancet 1994; 343:692-695. Ozcelik H, Schmocker B, Di Nicola N, et al. Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. Nat Genet 1997; 16:17-18. Lynch H T, de la Chapelle A. Genetic susceptibility to nonpolyposis colorectal cancer. J Med Genet 1999; 36:801-818. Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 1999; 81:214-218. King J E, Dozois R R, Lindor N M, Ahlquist D A. Care of patients and their families with familial adenomatous polyposis. Mayo Clin Proc 2000; 75:57-67. NH&MRC. Guidelines for the prevention, early detection and management of colorectal caner. A guide for general practitioners. NHMRC, 2000. NH&MRC National Breast Cancer Centre. Advice about familial aspects of breast canSer and ovarian cancer. A guide for health professionals. NHMRC, 2000. NH&MRC. Familial aspects of cancer: a guide to clinical practice. NHMRC, 1999. Narod S A, Risch H, Moslehi R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med 1998; 339:424-428. Fisher B, Costantino J P, Wickerham D L, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90:1371-1388. Janne P A, Mayer R J. Chemoprevention of colorectal cancer. N Engl J Med 2000; 342:1960-1968.

References 1.

Offit K. Clinical cancer genetics: risk counselling and management. New York: Wiley-Liss, 1998. 2. Peto J, Collins N, Barfoot R, et al. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early onset breast cancer. J Natl Cancer Inst 1999; 91:943-949. 3. Ford D, Easton D F, Stratton M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 1998; 62:676-689. 4. Scott C L, Jenkins M A, Phillips K A, Hopper J L. Average age specific risk of breast cancer in women who carry a germline mutation in BRCA1 or BRCA2. (submitted). 5. Hopper J L, Southey M C, Dite G S, et al. Population based estimate of the average age specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2. Australian Breast Cancer Family Study. Cancer Epidemiol Biomarkers Prev 1999; 8:741-747. 6. Struewing J P, Hartge P, Wacholder S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 1997; 336:1401-1408. 7. Easton D F, Steele L, Fields P, et al. Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12-13. Am J Hum Genet 1997; 61:120-128. 8. Ford D, Easton D F, Bishop D T, Narod S A, Goldgar D E. Risks of cancer in BRCA1-mutation carriers. Breast





A family history of cancer should be taken in all individuals. Features suggestive of familial cancer syndromes include early age of onset, multiple cancers in one individual, two or more family members with the same type of cancer, or the presence of different cancers that fit the spectrum of a known familial cancer syndrome. The identification of families with an inherited predisposition to cancer allows preventive strategies to be implemented to decrease morbidity and mortality from cancer. Genetic testing for hereditary breast-ovarian cancer syndrome, HNPCC and FAP is available to some families through familial cancer clinics. Genetic testing is currently only available to families where there is a strong suspicion that a familial cancer syndrome is present, and must be initiated in a family member who has been diagnosed with cancer. Genetic testing for familial cancer syndromes has significant medical and psychological implications for the individual and genetic counselling is mandatory.