Abstract
Triple-negative breast cancer (TNBC) is an aggressive form of breast carcinoma with a poor prognosis. Recent evidence suggests that some patients with TNBC harbour germ-line mutations in DNA repair genes which may render their tumours susceptible to novel therapies such as treatment with PARP inhibitors. In the present study, we have investigated a hospital-based series of 40 German patients with TNBC for the presence of germ-line mutations in BRCA1, BRCA2, PALB2, and BRD7 genes. Microfluidic array PCR and next-generation sequencing was used for BRCA1 and BRCA2 analysis while conventional high-resolution melting and Sanger sequencing was applied to study the coding regions of PALB2 and BRD7, respectively. Truncating mutations in BRCA1 were found in six patients, and truncating mutations in BRCA2 and PALB2 were detected in one patient each, whereas no truncating mutation was identified in BRD7. One patient was a double heterozygote for the PALB2 mutation, c.758insT, and a BRCA1 mutation, c.927delA. Our results confirm in a hospital-based setting that a substantial proportion of German TNBC patients (17.5%) harbour germ-line mutations in genes involved in homology-directed DNA repair, with a preponderance of BRCA1 mutations. Triple-negative breast cancer should be considered as an additional criterion for future genetic counselling and diagnostic sequencing.
Highlights
Triple-negative breast cancers (TNBCs) account for about 15% of all invasive breast cancers and are defined as tumors that lack expression of estrogen receptor (ER) and progesterone receptor (PR), and do not show overexpression of HER2/neu [1]
We investigated a hospital-based series of 40 consecutive patients with triple-negative breast cancer for mutations in the whole coding sequences of BRCA1 and BRCA2 as well as in the two genes PALB2 and bromodomain-containing protein 7 (BRD7), which encode interaction partners of the BRCA1 protein
Among new therapies that are under investigation [24], the most important one is PARP inhibition, which induces synthetic lethality in tumour cells deficient in homology-directed DNA double-strand break repair such as cells mutated in BRCA1 or BRCA2 [7,8]
Summary
Triple-negative breast cancers (TNBCs) account for about 15% of all invasive breast cancers and are defined as tumors that lack expression of estrogen receptor (ER) and progesterone receptor (PR), and do not show overexpression of HER2/neu [1]. There is some overlap with a basal-like pattern of gene expression [2,3]. Women with a breast cancer family history experience a significantly increased risk of triple-negative breast cancer [4]. Carriers of mutations in the breast cancer susceptibility gene 1, BRCA1, frequently have basal-like and/or triple-negative breast cancers [5]. Deleterious mutations of the second breast cancer susceptibility gene, BRCA2, have been reported to occur at a high frequency in German patients with triple-negative breast cancers [12]
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