Details

Autor(en) / Beteiligte

• Domagala, Pawel
• Hybiak, Jolanta
• Cybulski, Cezary
• Lubinski, Jan

Titel

BRCA1/2‐negative hereditary triple‐negative breast cancers exhibit BRCAness

Ist Teil von

• International journal of cancer, 2017-04, Vol.140 (7), p.1545-1550

Ort / Verlag

United States: Wiley Subscription Services, Inc

Erscheinungsjahr

2017

Link zum Volltext

Quelle

Wiley Online Library

Beschreibungen/Notizen

• BRCA1/2‐associated breast cancers are sensitive to poly(ADPribose) polymerase (PARP) inhibitors and platinum compounds mainly due to their deficiency in DNA repair via homologous recombination (HR). However, approximately only 15% of triple‐negative breast cancers (TNBCs) are BRCA1/2‐associated. TNBCs that exhibit BRCAness (a phenotype reflecting impaired HR in BRCA1/2‐negative tumors) are also regarded sensitive to PARP inhibitors and platinum compounds. Thus, we hypothesized that hereditary BRCA1/2‐negative TNBCs may exhibit BRCAness. To find a subset of hereditary BRCA1/2‐negative TNBCs among 360 TNBCs, we first identified a group of 41 hereditary TNBCs by analyzing the family histories of the patients. Next, we tested this group for the presence of germline BRCA1/2 mutations, and finally, we compared the expression levels of 120 genes involved in HR and five other major mechanisms of DNA damage repair between BRCA1/2‐associated and BRCA1/2‐negative subgroups of hereditary TNBCs using real‐time PCR arrays. Approximately 73% of the hereditary TNBCs were BRCA1/2‐associated and 27% were BRCA1/2‐negative. The expression levels of the analyzed genes showed no significant differences between these two subgroups indicating the BRCAness of the BRCA1/2‐negative hereditary TNBCs and thereby distinguishing a novel subset of TNBCs as a potential target for PARP inhibitors or platinum‐based therapy. The results show the significance of family history in selecting patients with TNBC for therapies directed at incompetent DNA repair (e.g., PARP inhibitors and/or platinum‐based therapies) and indicate that a relatively simple strategy for broadening the target group for these modes of treatment is to identify patients with hereditary TNBCs. What's new? Triple‐negative breast cancers (TNBCs) that are positive for BRCA1/2 mutations display impairments in DNA repair via homologous recombination (HR), rendering the tumors sensitive to poly(ADPribose) polymerase (PARP) inhibitors and DNA cross‐linking drugs. Only a minority of TNBC patients, however, carry germline BRCA1/2 aberrations. In the present study, 27% of hereditary TNBCs examined were found to be BRCA1/2‐negative, yet showed no significant differences in the expression of HR‐related genes or other DNA damage repair genes when compared with BRCA1/2‐associated tumors. The BRCAness phenomenon distinguishes a subset of BRCA1/2‐negative hereditary TNBCs, which may be susceptible to PARP inhibitors and platinum‐based therapies.