Genomic profiling of breast tumours in relation to BRCAabnormalities and phenotypes

Stefansson, Olafur A.; Jonasson, Jón G.; Jóhannsson, Óskar Þór; Olafsdottir, Katrin; Steinarsdóttir, Margrét; Valgeirsdóttir, Sigrı́dur; Eyfjörd, Jórunn E.

doi:10.1186/bcr2334

Cited by 131 publications

(136 citation statements)

References 45 publications

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“…Nearly all of the cell lines with known mutations in BRCA1 and BRCA2 had GE patterns that correlated with the basal-like subtype, which is in agreement with the current view that BRCA-mutant tumors display a basal-like phenotype (44). A number of non-BRCAmutant cell lines that correlated with the basal-like TNBC subtypes contained nearly 2-fold the number of chromosome rearrangements as all other subtypes.…”

Section: Discussionsupporting

confidence: 77%

“…However, the synthetic lethal effects of PARP inhibition in homologous recombination-deficient cells may require multiple cell divisions and may be more appropriately tested in long-term survival assays. Other studies show that a subset of BRCA1-mutant tumors lack large-scale genomic alterations and these tumors represent a distinct disease entity and may not be susceptible to PARP inhibition (44). Previous analyses of PARP inhibitors in isogenic BRCA2 +/+ and BRCA2 -/-cell lines suggest that sensitivity to this targeted therapy is dependent on the molecular context of the DNA repair machinery and that DNA repair requiring homologous recombination involves multiple redundant pathways (9,10).…”

Section: Discussionmentioning

confidence: 99%

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Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies

Lehmann¹,

Bauer²,

Chen³

et al. 2011

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Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) profiles from 21 breast cancer data sets and identified 587 TNBC cases. Cluster analysis identified 6 TNBC subtypes displaying unique GE and ontologies, including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype. Further, GE analysis allowed us to identify TNBC cell line models representative of these subtypes. Predicted "driver" signaling pathways were pharmacologically targeted in these cell line models as proof of concept that analysis of distinct GE signatures can inform therapy selection. BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling. LAR cell lines were uniquely sensitive to bicalutamide (an AR antagonist). These data may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies

Lehmann¹,

Bauer²,

Chen³

et al. 2011

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“…Certain regions that are amplified (3q, 20q) or deleted (5q) and the corresponding genes (TM4SF1, BCAS4, RAD50) found in hereditary type tumors would suggest defects in the DNA repair system with a consequent installation of genomic instability (46,(56)(57)(58).…”

Section: Ovarian Dysplasiamentioning

confidence: 99%

Early Telomere Shortening and Genomic Instability in Tubo-Ovarian Preneoplastic Lesions

Chêne

Tchirkov

Pierre-Eymard

et al. 2013

Clinical Cancer Research

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Purpose: Genetic instability plays an important role in ovarian carcinogenesis. We investigated the level of telomere shortening and genomic instability in early and preinvasive stages of ovarian cancer, serous tubal intraepithelial carcinoma (STIC), and tubo-ovarian dysplasia (TOD).Experimental Design: Fifty-one TOD from prophylactic salpingo-oophorectomies with BRCA1 or 2 mutation, 12 STICs, 53 tubo-ovarian high-grade serous carcinoma, and 36 noncancerous controls were laser capture microdissected from formalin-fixed, paraffin-embedded sections, analyzed by comparative genomic hybridization (array CGH) and for telomere length (using quantitative real-time PCR based on the Cawthon's method). TOD and STICs were defined by morphologic scores and immunohistochemical expressions of p53, Ki67, and gH2AX.Results: TOD showed marked telomere shortening compared with noncancerous controls (P < 10 À7 ).STICs had even shorter telomeres than TOD (P ¼ 0.0008). Ovarian carcinoma had shorter telomeres than controls but longer than STICs and dysplasia. In TOD, telomeres were significantly shorter in those with BRCA1 mutation than in those with BRCA2 mutation (P ¼ 0.005). In addition, gH2AX expression in TOD and STIC groups with short telomeres was significantly increased (P < 10 À7 ). In dysplastic epithelium, we found subtle genomic alterations, in contrast to more important genomic imbalances in STICs. The total number of genetic alterations was the highest in ovarian cancers. Conclusions: These findings suggest that genetic instability occurs in early stages of ovarian tumorigenesis. STICs and noninvasive dysplasia are likely an important step in early serous ovarian neoplasia.

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“…The mechanism for synthetic lethality involving PARP1 and BRCA1 or 2 is considered to be an interplay between 2 DNA repair pathways (3,4,7,20), and thus to date, there has been considerable focus on the critical involvement of both proteins of a synthetic lethal partnership in DNA surveillance or repair (6,8,(20)(21)(22)(23)(24)(25). SHP-1 is a protein tyrosine phosphatase known to negatively regulate receptor tyrosine kinase signaling (18,26).…”

Section: Underlying Mechanism Of the Pnkp/shp-1 Synthetic Lethal Partmentioning

confidence: 99%

Genetic Screening for Synthetic Lethal Partners of Polynucleotide Kinase/Phosphatase: Potential for Targeting SHP-1–Depleted Cancers

et al. 2012

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A genetic screen using a library of 6,961 siRNAs led to the identification of SHP-1 (PTPN6), a tumor suppressor frequently mutated in malignant lymphomas, leukemias, and prostate cancer, as a potential synthetic lethal partner of the DNA repair protein polynucleotide kinase/phosphatase (PNKP). After confirming the partnership with SHP-1, we observed that codepletion of PNKP and SHP-1 induced apoptosis. A T-cell lymphoma cell line that is SHP-1 deficient (Karpas 299) was shown to be sensitive to a chemical inhibitor of PNKP, but resistance was restored by expression of wild-type SHP-1 in these cells. We determined that while SHP-1 depletion does not significantly impact DNA strand-break repair, it does amplify the level of reactive oxygen species (ROS) and elevate endogenous DNA damage. The ROS scavenger WR1065 afforded protection to SHP-1-depleted cells treated with the PNKP inhibitor. We propose that codisruption of SHP-1 and PNKP leads to an increase in DNA damage that escapes repair, resulting in the accumulation of cytotoxic double-strand breaks and induction of apoptosis. This supports an alternative paradigm for synthetic lethal partnerships that could be exploited therapeutically. Cancer Res; 72(22); 5934-44. Ó2012 AACR.

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Genomic profiling of breast tumours in relation to BRCAabnormalities and phenotypes

Cited by 131 publications

References 45 publications

Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies

Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies

Early Telomere Shortening and Genomic Instability in Tubo-Ovarian Preneoplastic Lesions

Genetic Screening for Synthetic Lethal Partners of Polynucleotide Kinase/Phosphatase: Potential for Targeting SHP-1–Depleted Cancers

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