Earlier age of onset of BRCA mutation-related cancers in subsequent generations

Hereditary breast and ovarian cancer syndrome (HBOC) related to the breast cancer (BRCA) genes initially was identified in families with the use of genetic linkage analysis.1–3 Since then, over 5000 different mutations in these genes have been identified that are inherited in an autosomal-dominant fashion and are responsible for approximately 5% to 10% of breast cancer diagnoses.4 Carriers of this mutation have an elevated risk of developing both breast and/or ovarian cancer, and a meta-analysis estimate of the lifetime risk of breast cancer was 47% to 66% in BRCA1 carriers and 40% to 57% in the BRCA2 carriers, and the risk of developing ovarian cancer was 35% to 46% and 13% to 23%, respectively, in the same analysis.5 One of the major risk factors for HBOC is the development of breast cancer at a very young age, Thus, the National Comprehensive Cancer Network (NCCN) guidelines panel has recommend initiating screening at ages 20 to 25 years, or 5 to 10 years earlier than the youngest age at diagnosis in the family.6 Implementing screening techniques is meant to identify cancers at the earliest time possible; therefore, estimating the onset of disease is vital in timing the initiation of screening and interventions. Anticipation has been described as a phenomenon observed in inherited diseases such as Fragile X syndrome and Huntington disease, in which the disease occurs at younger ages or with increased severity of disease in subsequent generations.7,8 The cause of this anticipation has been identified as DNA instability, such as nucleotide repeats that change in length in subsequent generations, altering the phenotype of the disease. However, changes in disease phenotype in subsequent generations also have been identified in other disorders, such as in colon cancer, Alzheimer disease, and diabetes.9,10 With the increase in BRCA1 and BRCA2 testing, there also has been an increase in families being evaluated and screened for HBOC. There have been several reports of anticipation in breast cancer. To date, these reports have been based on very small cohorts; those studies indicated an earlier age at diagnosis and examined the absolute differences between matched pairs. Dagan and Gershoni-Baruch reported a statistically significant difference of approximately 4 years in BRCA2 mutation carriers and a statistically nonsignificant numerical difference in BRCA1 carriers.11 In addition, Peixoto et al and Paltiel et al also observed similar patterns of earlier age of diagnosis for subsequent generations in breast cancer registries.12,13 When discussing appropriate screening interventions for women with a known deleterious BRCA1 or BRCA2 mutation, potential interventions include clinical breast examination, magnetic resonance imaging, and mammography.14 Evaluating for patterns of inheritance like anticipation in families with known deleterious BRCA mutations may help promote understanding of these genes and provide further insight into the timing of screening initiation and starting other interventions. The objective of the current analysis was to evaluate any trends in age at diagnoses in families with known deleterious BRCA mutations at a single institution to add to the growing evidence of genetic anticipation in patients with HBOC. We evaluated families who were referred to the Clinical Cancer Genetic Program at our institution and analyzed age at diagnosis across 2 generations.