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

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.

KEYWORDS::

• BRCA mutation
• drug response
• homologous recombination
• ovarian cancer
• PARP inhibitor
• survival

Acknowledgements

The authors would like to thank A Sutton in the Department of Scientific Publications (The University of Texas MD Anderson Cancer Center, TX, USA) for editing this manuscript.

Financial & competing interests disclosure

This study was supported by a grant from the NIH (U24CA143835) to I Shmulevich and W Zhang, a grant from the Blanton-Davis Ovarian Cancer Research Program to W Zhang, an Ovarian Cancer SPORE grant (P50 CA083639) to AK Sood and a grant supported by National Natural Science Foundation of China (grant no. 81101673) to G Liu. D Yang is an Odyssey Fellow at MD Anderson Cancer Center, and supported by The Diane Denson Tobola Fellowship in Ovarian Cancer Research fellowship and The Harold C and Mary L Daily Endowment Fund. Y Sun is supported by The Linda K Manning Fellowship in Ovarian Cancer and The A Lavoy Moore Endowment Fund. G Liu is a New Century outstanding fellow at Tianjin Medical University General Hospital. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This study was supported by a grant from the NIH (U24CA143835) to I Shmulevich and W Zhang, a grant from the Blanton-Davis Ovarian Cancer Research Program to W Zhang, an Ovarian Cancer SPORE grant (P50 CA083639) to AK Sood and a grant supported by National Natural Science Foundation of China (grant no. 81101673) to G Liu. D Yang is an Odyssey Fellow at MD Anderson Cancer Center, and supported by The Diane Denson Tobola Fellowship in Ovarian Cancer Research fellowship and The Harold C and Mary L Daily Endowment Fund. Y Sun is supported by The Linda K Manning Fellowship in Ovarian Cancer and The A Lavoy Moore Endowment Fund. G Liu is a New Century outstanding fellow at Tianjin Medical University General Hospital. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.