Incorporating truncating variants in PALB2, CHEK2, and ATM into the BOADICEA breast cancer risk model

Abstract

Purpose: The proliferation of gene panel testing precipitates the need for a breast cancer (BC) risk model that incorporates the effects of mutations in several genes and family history (FH). We extended the BOADICEA model to incorporate the effects of truncating variants in PALB2, CHEK2, and ATM.

Methods: The BC incidence was modeled via the explicit effects of truncating variants in BRCA1/2, PALB2, CHEK2, and ATM and other unobserved genetic effects using segregation analysis methods.

Results: The predicted average BC risk by age 80 for an ATM mutation carrier is 28%, 30% for CHEK2, 50% for PALB2, and 74% for BRCA1 and BRCA2. However, the BC risks are predicted to increase with FH burden. In families with mutations, predicted risks for mutation-negative members depend on both FH and the specific mutation. The reduction in BC risk after negative predictive testing is greatest when a BRCA1 mutation is identified in the family, but for women whose relatives carry a CHEK2 or ATM mutation, the risks decrease slightly.

Conclusions: The model may be a valuable tool for counseling women who have undergone gene panel testing for providing consistent risks and harmonizing their clinical management. A Web application can be used to obtain BC risks in clinical practice (http://ccge.medschl.cam.ac.uk/boadicea/).Genet Med 18 12, 1190-1198.

Figure 1. BOADICEA Breast Cancer Risk by Mutation Status and Family History

BOADICEA risk by mutation status for a female in the UK age 20 born in 1975: (a) with unknown family history (i.e. for the average female in the population); (b) with her mother affected at age 40; (c) with her mother and sister unaffected at ages 70 and 50 respectively. No testing assumed in other family members, in all cases.

Figure 2. BOADICEA Mutation Carrier Probabilities

BOADICEA mutation carrier probabilities for a female in the UK, born in 1975: (a) with unknown family history as a function of her breast cancer diagnosis age; (b) who was diagnosed with breast cancer at age 30 and whose mother was diagnosed with breast cancer, as a function of her mother’s age at diagnosis.

Figure 3. BOADICEA Breast Cancer Risk for Negative Testing by Family History

The predicted risk of breast cancer for a 20 year old female in the UK, born in 1975 by her mother’s mutation status, for different family histories. The predicted risk is shown for four different family histories. The graphs on the right hand side correspond to the pedigrees on the left hand side. The figures show the predicted risks for a proband (shown with an arrow) in families without any mutation testing in the five genes i.e. this corresponds to the predicted risk on the basis of family history information alone (black curves). The rest of the curves correspond to the cases where the proband is assumed to be negative for the mutation identified in the family. To enable direct comparisons, the proband is assumed to be 20 years old in all examples.