Differing Clinical Impact of BRCA1 and BRCA2 Mutations in Serous Ovarian Cancer

Guoyan Liu; Da Yang; Yan Sun; Ilya Shmulevich; Fengxia Xue; Anil K Sood; Wei Zhang

Disclosures

Pharmacogenomics. 2012;13(13):1523-1535. 

In This Article

Abstract and Introduction

Abstract

A key function of BRCA1 and BRCA2 is the participation in dsDNAbreak repair via homologous recombination. BRCA1 and BRCA2 mutations, which occur in most hereditary ovarian cancers (OCs) and approximately 10% of all OC cases, are associated with defects in homologous recombination and genomic instability, a phenotype termed 'BRCAness'. The clinical effects of BRCA1 and BRCA2 mutations have commonly been analyzed together; however, it is becoming increasingly apparent that these mutations do not have the same effects in OC. Recently, three major reports highlighted the unequal clinical characteristics of OCs with BRCA1 and BRCA2 mutations. All studies demonstrated that BRCA2-mutated patients are associated with better survival and therapeutic response than BRCA1-mutated and wild-type patients with serous OC. The differing prognostic effects of the BRCA2 and BRCA1 mutations is likely due to differing roles of BRCA1 and BRCA2 in homologous recombination repair and a stronger association between the BRCA2 mutation and a hypermutator phenotype. These new findings have potentially important implications for clinical management of patients with serous OC.

Introduction

Ovarian cancer (OC) is the second most common gynecological malignancy and the leading cause of death from gynecological cancer. Approximately 75–80% of patients present with advanced disease that is refractory to current therapies; the 5-year survival rate for advanced OC is approximately 30–40%. A family history of OC is one of the strongest risk factors for OC. To date, at least 16 genes have been associated with hereditary OC, and BRCA1 and BRCA2 (BRCA1/2) mutations are beleived to account for the majority of hereditary OC.[1] More than 90% of early-onset cancers in families with breast cancer and OC histories are associated with BRCA1 or BRCA2 mutations. The risk of developing OC by 70 years of age is 40–50% for BRCA1 mutation carriers and 10–20% for BRCA2 mutation carriers.[2,3]

The previous studies have demonstrated that BRCA1 and BRCA2 mutation-related OCs have distinct clinicopathological features; they tend to be more sensitive to platinum agents and possibly PARP inhibitors than wild-type BRCA OCs, and secondary BRCA1 and BRCA2 mutations that result in gain of BRCA1 and BRCA2 function are associated with platinum resistance.[4,5] Recently, three independent investigations have shown that among women with serous OC, BRCA2 mutation is more significantly associated with improved patient survival than BRCA1 mutation;[6–8] one study also showed that BRCA2 mutation was more strongly associated with chemotherapy response and genome instability.[6] In addition, two other studies demonstrated the trend of favorable outcomes in BRCA2 mutation patients[9,10] compared with BRCA1 mutation. This article reviews recent progress in our understanding of BRCA1 and BRCA2 mutations in OC and how these emerging findings affect synthetic lethality-based therapeutics in OC.

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