Hereditary cancer syndromes: opportunities and challenges

Prevention offers the most cost-effective long-term strategy for the control of cancer and at least one-third of all malignancies are preventable. A number of strategies have been developed over the last decades to provide opportunities for cancer prevention at different levels: primary prevention by reducing levels of exposure to high risk factors or causative agents, secondary prevention through establishment of cancer screening programs and tertiary prevention with interventions aimed at the modification of cancer outcomes, such as clinical trials and tailored therapies. In this scenario, the identification of individuals at high risk of developing certain cancers can provide an important opportunity for prevention, at different levels. The example of breast cancer will be used to further explore this concept. Breast cancer is a significant health care problem worldwide. Among women with this diagnosis, a subset of patients with previously identifiable risk factors can be easily recognized. Two main groups of high-risk women can be described. The first is composed of women with a significantly increased lifetime risk of developing the disease when compared to the general population, and this is due to a combination of reproductive, behavioral and low-penetrance, common genetic risk factors. Several mathematical models have been developed to identify this subset of women, and specific risk-reducing interventions have been proposed (i.e. annual magnetic resonance imaging of the breast for women with estimated lifetime risks of breast cancer over 20% and chemoprevention for women with and estimated breast cancer risk greater than 1,66% in five years). A significant proportion of women, at the populational level may benefit from cancer risk assessment. In Southern Brazil, for instance, a population-based study of 9,128 women from the public primary health care system identified a lifetime breast cancer risk estimate > 20% in 8% of women in that cohort [1]. On the other hand, a study from the same region, involving 3,665 cancer-unaffected women between the ages of 40 and 69 years undergoing screening mammography, identified a significant 5-year breast cancer risk in approximately 7% [2]. Breast cancer risk estimation is important not only to direct the medical management of the patients, but has also been described as an important and independent predictor of adherence to mammographic breast cancer screening. Although the benefits of chemoprevention have been demonstrated in several large prospective clinical trials, less than one in every 10 women at high risk for breast cancer discussed her risk with a physician or was considered for risk reducing chemotherapy [3]. Thus, an effort should be undertaken not only to increase the identification of high risk patients, but also to further investigate risk reducing interventions for this group. The second group of women at high risk for breast cancer are those who carry a germline mutation related to hereditary predisposition to the disease. Hereditary cancer syndromes underly 5-20% of all breast tumors and carriers have a significantly increased risk of developing multiple tumors at an early age [4]. The identification of hereditary cancer patients and families is essential to ensure accurate risk assessment, implementation of appropriate risk-reducing interventions and effective genetic counseling. Several hereditary breast cancer syndromes have been identified to date and mutations in many different genes have been described with these forms of the disease including those in BRCA1, BRCA2, TP53, PTEN, ATM, among others. The magnitude of risk associated with mutation carriage is significant, i.e. carriers of mutations in the BRCA1 and BRCA2 genes have an estimated lifetime risk of 70-85%, compared to the lifetime risk of women in the general population which is Correspondence: [email protected] Post-Graduate Program in Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Brazil Ashton-Prolla BMC Proceedings 2013, 7(Suppl 2):K14 http://www.biomedcentral.com/1753-6561/7/S2/K14