1. Estimating the penetrances of breast and ovarian cancer in the carriers of BRCA1/2 mutations Silvano Presciuttini University of Pisa, Italy

2. Accurate estimates of breast and ovarian cancer penetrance in BRCA1/2 mutation carriers are crucial in genetic counseling. We estimated the penetrances of breast and ovarian cancers in carriers of BRCA1/2 mutations in 568 Italian families screened for germline mutations. Our approach could lead to country-customized versions of the BRCAPRO software by providing appropriate population-specific estimates.

3. Content of the presentation Introduction: 1)Hereditary cancer 2)BRCA1 and BRCA2 The problem: 1)Predicting the presence of a germline mutation in a proband 2)Performances of extant predictive models How to improve predictions 1)Our results 2)Comparison with previous penetrance estimates 3)Consequences at the population level

4. Sporadic vs hereditary tumors In most cases, cancer-causing mutations in somatic cells occur by chance, or as a result of damage to DNA by environmental factors such as chemicals in cigarette smoke, or UV radiation in sunlight. Cancer in these cases is said to be sporadic. However, a small percentage of cancers arise in families that show a very strong, hereditary susceptibility to a particular type of cancer. The cancer-susceptibility in these families is usually highly penetrant. Affected individuals in these families carry a germ-line (i.e. inherited) mutation - which is therefore present in every cell of their body - that makes it much more likely that their somatic cells will become cancerous.

5. BRCA1 and BRCA2  Mutations in the two genes BRCA1 and BRCA2 account for 30– 40% of the families with multiple breast cancer cases and for the vast majority of families with multiple breast and ovarian cancers cases.  Taken together, these genes may be responsible for 5–10% of early-onset breast cancers and about 10% of all ovarian cancers.  Initial studies of multiple-case families with four or more cancer cases suggested that the lifetime risk (penetrance) of breast cancer in BRCA1 mutation carriers was 71–85%, and that of ovarian cancer was 42–63% at age 70.  Similarly, early penetrance evaluations in BRCA2 led to an 84% risk of breast cancer and 27% for ovarian cancer at age 70.

6. How can the presence of a germline mutation predicted in a proband? In other words, the questions are: 1.Given a proband, what is the probability that a mutation in BRCA1/2 is present? 2.What is the chance of the DNA laboratory finding a mutation?

7. A rather complicated problem...

8. Two well-known predictive models  The Myriad mutation prevalence tables display the proportion of probands, stratified in 42 possible groups, with identified mutations in BRCA1 or BRCA2 in the analyses performed at Myriad, which include more than 10,000 tests  BRCAPRO is a Mendelian model that incorporates mutated allele frequencies and cancer specific penetrances derived from published studies and uses Bayesian updating methods to compute carrier probabilities in pedigrees

9. Evaluating model performances BRCAPRO: (sensitivity of molecular techniques set to 70%) Myriad Tables:

10. Including five other models in the analysis For each model, probands were stratified by risk in three groups: 40% The figure shows, for each model, a plot of the proportion of expected vs observed proportion of mutations in the three groups. All models show a similar pattern, underestimating mutation detection probability at lower risks (<10%), and overestimating it at higher risks.

11. How to improve predictions  We estimated cancer- and gene-specific penetrances in a large sample of Italian families (568) screened for both genes, 83 harboring a BRCA1 mutation, and 50 a BRCA2 mutation.  We used the software BRCAPRO as a probability calculation tool. Since the prediction made by this program is based on a specific genetic model (the set of parameter values, allele frequencies and penetrances that define the risk of disease in the population), it is possible to reverse the approach, that is, estimating some of the parameters from the family data.  This is accomplished by iteratively exploring new parameter values until the best genetic model is found, for which the prediction made by BRCAPRO is more accurate.

12. STUDY DESIGN GENETIC MODEL Stop when convergence criteria are met Individual prediction for all families Calculation of total log-likelihood Explore new Parameter values MODIFIED MODEL Re-calculation of total log-likelihood Compare log-likelihoods Accept/Reject modified model

13. The new penetrance curves

14. Performance of the modified model Observed and expected number of mutations in the families stratified by cancer profile, considering BRCA1 and BRCA2 together HBC: hereditary breast cancer. HBOC: hereditary breast-ovarian cancer. HOC: hereditary ovarian cancer. MBC: male breast cancer.

15. Risk of disease for women with BRCA1 or BRCA2 mutations Cancer specific penetrances translate into cumulative risks of being affected by either disease

16. Proportion of breast cancers occurring in carriers The fraction of breast cancers occurring in gene carriers can be computed either by five-year intervals or as cumulative proportion

17. Conclusions  Our new penetrance functions are appropriate for predicting breast cancer risk, and for determining the probability of carrying BRCA1/2 mutations, in people who are presently referred to genetic counseling in Italy.  Our approach could lead to country-customized versions of the BRCAPRO software by providing appropriate population-specific estimates.