Abstract | BACKGROUND: METHODS: One-hundred-forty-four TNBC tumor specimens were analysed by the MLPA-based "BRCA1-like" test. Classification into BRCA1-like vs. non-BRCA1-like samples was performed by our formerly established nearest shrunken centroids classifier. Data were subsequently compared with the BRCA1-mutation/methylation status of the samples. T-lymphocyte infiltration and expression of the main target of PARP inhibitors, PARP1, were assessed on a subset of samples by immunohistochemistry. Data acquisition and interpretation was performed in a blinded manner. RESULTS: In the studied TNBC cohort, 63 out of 144 (44 %) tumors were classified into the BRCA1-like category. Among these, the MLPA test correctly predicted 15 out of 18 (83 %) samples with a pathogenic BRCA1-mutation and 20 of 22 (91 %) samples exhibiting BRCA1-promoter methylation. Five false-negative samples were observed. We identified high lymphocyte infiltration as one possible basis for misclassification. However, two falsely classified BRCA1-mutated tumors were also characterized by rather non-BRCA1-associated histopathological features such as borderline ER expression. The BRCA1-like vs. non-BRCA1-like signature was specifically enriched in high-grade (G3) cancers (90 % vs. 58 %, p = 0.0004) and was also frequent in tumors with strong (3+) nuclear PARP1 expression (37 % vs. 16 %; p = 0.087). CONCLUSIONS: This validation study confirmed the good performance of the initial MLPA assay which might thus serve as a valuable tool to select patients for platinum-based chemotherapy regimens. Moreover, frequent PARP1 upregulation in BRCA1-like tumors may also point to susceptibility to treatment with PARP inhibitors. Limitations are the requirement of high tumor content and high-quality DNA.
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Authors | Eva Gross, Harm van Tinteren, Zhou Li, Sandra Raab, Christina Meul, Stefanie Avril, Nadja Laddach, Michaela Aubele, Corinna Propping, Apostolos Gkazepis, Manfred Schmitt, Alfons Meindl, Petra M Nederlof, Marion Kiechle, Esther H Lips |
Journal | BMC cancer
(BMC Cancer)
Vol. 16
Issue 1
Pg. 811
(10 19 2016)
ISSN: 1471-2407 [Electronic] England |
PMID | 27756336
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- BRCA1 Protein
- BRCA1 protein, human
- Biomarkers, Tumor
- Poly (ADP-Ribose) Polymerase-1
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Topics |
- Adult
- Aged
- BRCA1 Protein
(genetics, metabolism)
- Biomarkers, Tumor
- Chromosome Mapping
- Combined Modality Therapy
- DNA Methylation
- Female
- Humans
- Immunohistochemistry
- Middle Aged
- Multiplex Polymerase Chain Reaction
- Mutation
- Neoplasm Grading
- Poly (ADP-Ribose) Polymerase-1
(metabolism)
- Promoter Regions, Genetic
- Reproducibility of Results
- Sensitivity and Specificity
- Triple Negative Breast Neoplasms
(diagnosis, genetics, metabolism, therapy)
- Tumor Burden
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