Genetics and molecular biology in breast cancer

1. Genetics and molecular biology in breast cancer Mahfoudh Wijden , Hassen Elham and Chouchane Lotfi. Laboratoire d’Immuno-Oncologie Moléculaire, Faculté de Medecine de Monastir, Université du Centre, Tunisia

2. Introduction • Breast cancer is a common malignancy affecting women around the world. • It occurs in sporadic and hereditary forms.

4. RISK FACTORS • Uncontrollablerisk factors : being female, age, early menarche, benign breast disease and family history. • Controllable risk factors : obesity, use of oral contraceptives and having 1st child after 30.

5. Cancers are Genetics Disease • Cancer is a collection of diseases that result from loss of control over cell division. • Because the cell cycle is controlled by proteins, and proteins are encoded by genes, cancers are genetic diseases.

6. Gene • A unit of heredity • A portion of DNA molecule • A DNA blueprint for a protein

7. Base Nucleotide (base+sugar+phosphate) DNA (Deoxyribonucleic acid) Polymer of nucleotides Chromosome Human Genome

8. Human Genome

9. Gene Functional protein

10. Disease-Associated Mutations Functional protein Nonfunctional protein A DNAmutationis a change in the normal base pair sequence Single Mutation can result in nonfunctional protein

11. Germline and Somatic changes Parent Child All cells affected in offspring Somatic mutation (eg, lung cancer) Mutation in egg or sperm Germline mutations Somatic mutations • Occur in cells during the woman's lifetime • Are nonheritable • Present in egg or sperm • Are heritable

12. Genes That Regulate Cell Division • Oncogenes: genes whose protein product functions to promotecell division • Tumor suppressor genes: genes whose protein product functions to block cell division. Oncogenes = gas pedal Tumor Suppressor Genes = brakes Dr Griend. 2004

13. HowDoes a Cell Lose Control? • Mutations in genes controlling cell division may change the proteins that control cell division. • Changes in oncogenes result in abnormal over-stimulation (i.e. gas pedal stuck down) of cell division. • Changes in tumor suppressor genes result in an inability to stop cell division (i.e. breaks disabled). Tumor Suppressor Genes Oncogenes Always On Disabled Dr Griend. 2004

14. Breast cancer occurs in sporadic and hereditary forms. • About 5-10% of all breast cancer is inherited as the result of highly penetrant germline mutation in cancer predisposing genes which leads to an autosomal dominant predisposition to the disease. Germline Mutations All cells affected in offspring

15. Major Susceptibilitygenes to breast cancer: BRCA1/2. 2 20 Mutations in either of these genes confer a high lifetime risk, of up to 87%, of developing breast cancer.

16. Genetic Risk Factors for Breast Cancer 5 to 10% (Balmain, Gray and Ponder, Nature Genetics, 2003)

17. A wide variety of genes is commonly mutated or incorrectly regulated in sporadic breast cancers • overexpression of the epidermal growth factor receptors EGFR, HER-2/neu, ERBB3 and ERBB4 • amplification of the MYC gene • mutation and overexpression of the intracellular signaling molecules h-Ras and c-Src • mutation and inactivation of p53 and RB1 • overexpression of cyclin D1 and reduced expression of the adhesion molecule E-cadherin.

18. Large Genome-wide association study (GWAS) 1500 breast cancers 1500 controls

19. Genome-wide association study (GWAS) • Common SNPs in several genes have been shown to be associated with breast cancer risk: • CASP8 • TGFB1 • FGFR2(fibroblast growth factor receptor 2) • TNRC9 • MAP3K1 • LSP1 • ECHDC1(which encodes a protein involved in mitochondrial fatty acid oxidation) • RNF146 (which encodes a ubiquitin protein ligase).

20. Conclusion • These studies illustrate the power of GWA studies in large sample sizes to identify gene variants that may increase risk of breast cancer, although these are not high-penetrance genes. • Perhaps the greater ramifications for these findings are that they identify pathways that have not been previously explored, and they open new doors for basic science and epidemiologic studies to identify additional causes of breast cancer.