Cancer in the family: risks and management

A recent NHMRC publication addresses the clinical implications of cancer genetics for Australian families

MJA 2000; 172: 529-530

	A family history of cancer is widely recognised as an important risk factor for common cancers, with 5%-10% of cancers considered attributable to genetic predisposition. A recent National Health and Medical Research Council (NHMRC) publication for health professionals, Familial aspects of cancer: a guide to clinical practice,1 addresses the clinical implications of cancer genetics. Why do we need such a guide, and what does it cover?
Cancer genetics
	Knowledge of the genetic basis of cancer has increased dramatically in the past decade. It is now clear that cancers evolve in Darwinian fashion, exploiting mutations in genes that regulate cellular growth, death and differentiation. The cumulative acquisition of defects in a number of these genes facilitates the progressive selection of cells towards a highly malignant and uncontrolled state of cellular proliferation and immortality. In the majority of cancers, these mutations are acquired in particular cells over a lifetime (somatic mutations). There are, however, families displaying clear inherited predisposition to certain common cancers, including breast, ovarian, colorectal and prostate cancer and melanoma. The affected members of these families carry an inherited (germline) mutation in one of their "cellular fitness" genes. Germline mutations affect all body cells, but give certain tissues a genetic head start down the cascade of genetic errors that results in cancer. Genes prone to such inherited abnormalities are called "cancer susceptibility" genes. The individuals carrying mutations in these genes often carry a very high lifetime chance (> 50%) of developing cancer.
Implications for clinical practice
	The improved ability to detect individuals at high risk of cancer through analysis of family history and/or genetic testing has fortunately been accompanied by major advances in screening, surveillance and prevention. The clinical usefulness of such advances is exemplified in the management of familial adenomatous polyposis (FAP), a condition caused by a dominantly inherited mutation in the adenomatous polyposis coli (APC) gene. Individuals with FAP develop hundreds of adenomatous polyps, of which one or more may, if untreated, become malignant, often at an early age. Until recently, all at-risk individuals required regular screening sigmoidoscopy from the early teenage years. Now, after being genetically tested, only those family members found to carry the mutation need to undergo intensive cancer screening and eventually prophylactic colectomy.2 Similarly, genetic testing for hereditary non-polyposis colorectal cancer has proved to be acceptable to families, and may reduce the cost of unnecessary screening colonoscopy in those family members found not to carry a mutation.3 Familial cancer clinics have now been set up in response to the growing public and professional awareness of family history as a risk factor for cancer. These clinics provide pedigree analysis, risk assessment and advice to those at high risk of cancer, and may also carry out genetic testing (if appropriate) in association with genetic counselling. The NHMRC document1 stratifies risk categories for people with a family history of diseases such as breast and colorectal cancer. It identifies those who may benefit from referral to familial cancer clinics and the role of general practitioners and specialists in managing high risk families. In the context of a detailed ethical discussion, an attempt is made to designate those who may benefit from genetic testing (see Box).
Why national guidelines?
	A coordinated national policy on cancer genetics has arisen in response to a number of factors: In recent years there has been heightened public awareness of the problem and increased demand for access to familial cancer services from those at perceived risk of cancer. (At the Familial Cancer Service at Westmead Hospital, for example, referrals, carefully screened for adherence to eligibility criteria, increased from 120 new families in 1996 to almost 300 in 1999); Health authorities have understandable concerns about the potential for proliferation of unregulated, unevaluated genetic testing facilities for cancer, as has occurred in the United States, and the need for public education and guidance in this area; Scientists face considerable challenges in assuring quality for complex, new and constantly evolving diagnostic tests, overcoming difficulties in resource management, and ensuring the timely and appropriate translation of relevant technologies from a research to a diagnostic environment. While similar documents have been produced by other international groups,4-7 these issues need to be addressed in a manner relevant to the Australian population. Guidelines based on US data for breast cancer, for example, may be quite inappropriate for Australia, and specific mutations in melanoma susceptibility genes may be more highly penetrant under the influence of Australian sunlight.8,9 In 1995 the Australian Cancer Network (ACN), in joint sponsorship with the NHMRC National Breast Cancer Centre (NBCC) and the Human Genetics Society of Australasia, convened the ACN Cancer Genetics Working Party to draft national guidelines for clinical practice. The current guidelines are the culmination of an extensive consultation and collaboration process.
The future	In such a rapidly changing field, future refinements of the guidelines will depend on the availability of high quality Australian data from national epidemiological studies. These studies will provide information on the frequency and penetrance of mutations in cancer susceptibility genes in the Australian population and the effect of local environmental factors on those mutations. A welcome spin-off of the endeavour to compile this guide has been the unification of diverse research interests throughout Australia in well organised, comprehensive consortia investigating the cancer genetics of breast cancer, melanoma and colorectal cancer.* In parallel with these exciting developments in research, we need to improve the accessibility of such information to general practitioners.10 The NBCC and the ACN have already moved toward the provision of more succinct information for GPs with their publications Current best advice about familial aspects of breast cancer11 (under current revision to incorporate familial ovarian cancer) and Advice about familial aspects of bowel cancer: a guide for general practitioners (ACN, in preparation). Consumer information has been developed to accompany these documents. The National Cancer Control Institute is also fostering a national approach to education and data management for families with a genetic predisposition to malignancy. The energy, goodwill and collaborative spirit associated with the preparation of these new guidelines provide a strong basis for the ongoing care of cancer families in Australia. Judy Kirk Senior Staff Specialist Familial Cancer Service and Westmead Institute for Cancer Research Westmead Hospital, Westmead, NSW Richard Kefford Professor of Medicine, Westmead Institute for Cancer Research Westmead Hospital, Westmead, NSW *Breast cancer: The Kathleen Cuningham Consortium for Research on Familial Breast Cancer (kConFab) research project (see <http://www.pmci.unimelb. edu.au/kconfab>), led by Joseph Sambrook, and the Australian Breast Cancer Family Study, led by John Hopper (j.hopperATgpph.unimelb.edu.au). Colorectal cancer: The Australasian Colorectal Cancer Study, led by Jeremy Jass (j.jassATmailbox.uq.edu.au). Melanoma: The Australian Melanoma Family Study, led by Graham Mann (gmannATmail.usyd.edu.au) National Health and Medical Research Council. Familial aspects of cancer: a guide to clinical practice. Endorsed Nov 1999. Available at: <http://www.nhmrc.health.gov.au/publicat/cp-home.htm>. Accessed 2 May 2000. (Catalogue No. 993839X.) Gardner M, St John J. Gene testing and genetic counselling in familial polyposis. Med J Aust 1995; 162: 457. Stanley AJ, Gaff CL, Attomaki AK, et al. Value of predictive genetic testing in management of hereditary non-polyposis colorectal cancer (HNPCC). Med J Aust 2000; 172: 313-316. Burke W, Daly M, Garber J, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. JAMA 1997; 277: 997-1003. Burke W, Petersen G, Lynch P, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA 1997; 277: 915-919. Eisinger F, Alby N, Bremond A, et al. Recommendations for medical management of hereditary breast and ovarian cancer: the French National Ad Hoc Committee. Ann Oncol 1998; 9: 939-950. Kefford RF, Newton Bishop JA, Bergman W, Tucker MA. Counseling and DNA testing for individuals perceived to be genetically predisposed to melanoma: a consensus statement of the Melanoma Genetics Consortium. J Clin Oncol 1999; 17: 3245-3251. Cannon-Albright LA, Meyer LJ, Goldgar DE, et al. Penetrance and expressivity of the chromosome 9p melanoma susceptibility locus (MLM). Cancer Res 1994; 54: 6041-6044. Bishop JA, Wachsmuth RC, Harland M, et al. Genotype/phenotype and penetrance studies in melanoma families with germline CDKN2A mutations. J Invest Dermatol 2000; 114: 28-33. Gupta L, Ward JE, Hayward RS. Clinical practice guidelines in general practice: a national survey of recall, attitudes and impact. Med J Aust 1997; 166: 69-72. National Breast Cancer Centre. Current best advice about familial aspects of breast cancer. Sydney: NBCC, 1997. Available at: <http://www.nbcc.org.au/ pages/info/resource/nbccpubs/advice.htm>. Accessed 2 May 2000. ©MJA 2000 Make a comment Home | Issues | eMJA shop | Terms of use | Classifieds | More... | Contact | Topics | Search The Medical Journal of Australia    eMJA   Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company. Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> © 2000 Medical Journal of Australia. We appreciate your comments.
	Familial aspects of cancer: a guide to clinical practice New NHMRC guidelines1 address the following key issues: Importance of an accurate, extended family history in assessing cancer risk Identification of rare families with a genetic predisposition to one of the common malignancies (eg, breast, ovarian, colorectal or prostate cancer, or melanoma) Role of familial cancer clinics in the management of families at risk Evolving role of genetic testing in risk assessment Requirement for genetic counselling in association with genetic testing Ethical issues relating to genetic counselling and testing for cancer predisposition Management, screening and cancer prevention for individuals found to be at high risk or potentially high risk of developing cancer Continued need for national collaborative research in this field
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