scholarly journals Functional Exploration of Copy Number Alterations in a Drosophila Model of Triple Negative Breast Cancer

2020 ◽  
Author(s):  
Jennifer E. L. Diaz ◽  
Vanessa Barcessat ◽  
Christian Bahamon ◽  
Ross L. Cagan
Keyword(s):  
Breast Cancer ◽  
Copy Number ◽  
Triple Negative ◽  
Standard Of Care ◽  
Chemotherapeutic Drug ◽  
Copy Number Alterations ◽  
Drosophila Model ◽  
Genetic Complexity ◽  
Disproportionate Number ◽  
Tumor Types

AbstractAccounting for 10-20% of breast cancer cases, TNBC is associated with a disproportionate number of breast cancer deaths. Despite recent progress, many patients fail to respond to current targeted therapies. Responses to chemotherapy are variable, and the tumor characteristics that determine response are poorly understood. One challenge in studying TNBC is its genomic profile: outside of TP53 loss, most cases are characterized by copy number alterations (CNAs), making modeling the disease in whole animals challenging. We analyzed 186 previously identified CNA regions in breast cancer to rank genes within each region by likelihood of acting as a tumor driver. We characterized a Drosophila p53-Myc model of TNBC, demonstrating aspects of transformation. We then used this model to assess highly ranked genes, identifying 48 as functional drivers. To demonstrate the utility of this functional database, we combined six of these drivers with p53-Myc to generate six 3-hit genotypes. These 3-hit models showed increased aspects of transformation as well as resistance to the standard-of-care chemotherapeutic drug fluorouracil. Our work provides a functional database of CNA-associated TNBC drivers, and uses this database to support the model that increased genetic complexity leads to increased therapeutic resistance. Further, we provide a template for an integrated computational/whole animal approach to identify functional drivers of transformation and drug resistance within CNAs for other tumor types.

DNA copy number alterations and expression of relevant genes in triple-negative breast cancer

2008 ◽  
Vol 47 (6) ◽  
pp. 490-499 ◽  
Author(s):  
Wonshik Han ◽  
Eun-Mi Jung ◽  
Jihyoung Cho ◽  
Jong Won Lee ◽  
Ki-Tae Hwang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Copy Number ◽  
Triple Negative ◽  
Copy Number Alterations ◽  
Dna Copy Number ◽  
Dna Copy Number Alterations

scholarly journals Importance of Copy Number Alterations of FGFR1 and C-MYC Genes in Triple Negative Breast Cancer

2018 ◽  
Vol 0 (0) ◽  
Author(s):  
Milica Nedeljković ◽  
Nikola Tanić ◽  
Tatjana Dramićanin ◽  
Zorka Milovanović ◽  
Snežana Šušnjar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prognostic Marker ◽  
Triple Negative Breast Cancer ◽  
Copy Number ◽  
Triple Negative ◽  
Clinical Course ◽  
Copy Number Gain ◽  
Gene Copy ◽  
Copy Number Alterations ◽  
The Impact

Summary Background: Triple negative breast cancer (TNBC) is characterized by aggressive clinical course and is unresponsive to anti-HER2 and endocrine therapy. TNBC is difficult to treat and is often lethal. Given the need to find new targets for therapy we explored clinicopathological significance of copy number gain of FGFR1 and c-MYC. Our aim was to determine the impact of FGFR1 and c-MYC copy number gain on clinical course and outcome of TNBC. Methods: FGFR1 and c-MYC gene copy number alterations were evaluated in 78 archive TNBC samples using TaqMan based quantitative real time PCR assays. Results: 50% of samples had increased c-MYC copy number. c-MYC copy number gain was associated with TNBC in contrast to ER positive cancers. Our results showed significant correlation between c-MYC copy number gain and high grade of TNBCs. This suggests that c-MYC copy number could be an useful prognostic marker for TNBC patients. c-MYC copy number gain was associated with high pTNM stage as well as lobular and medullary tumor subtypes. 43% of samples had increased FGFR1 copy number. No correlations between FGFR1 copy number gain and clinicopathological variables were observed. Conclusions: We identified c-MYC copy number gain as a prognostic marker for TNBC. Our results indicate that c- MYC may contribute to TNBC progression. We observed no significant association between c-MYC and/or FGFR1 copy number status and patient survival.

scholarly journals 1q21.3 amplification modulates therapy sensitivity in Triple Negative Breast Cancer

2020 ◽  
Author(s):  
Ramakanth Chirravuri-Venkata ◽  
Dario Ghersi ◽  
Apar K. Ganti ◽  
Imayavaramban Lakshmanan ◽  
Sanjib Chaudary ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Risk Stratification ◽  
Genetic Marker ◽  
Triple Negative Breast Cancer ◽  
Copy Number ◽  
Triple Negative ◽  
Copy Number Alterations ◽  
Copy Number Status ◽  
Cytotoxic Therapies

AbstractThe contrast in therapy sensitivity and response across triple negative breast cancer (TNBC) patients suggest underlying genotypic heterogeneity. Using publicly available data, we found significant associations between DNA-level copy number alterations of 1q21.3 locus and therapy sensitivity. We show that in spite of their aggressive nature, 1q21.3 amplified tumors are more responsive to commonly used cytotoxic therapies, highlighting the relevance of 1q21.3 copy number status as a genetic marker for risk stratification, therapy selection and response.

scholarly journals Importance of Copy Number Alterations of FGFR1 and C-MYC Genes in Triple Negative Breast Cancer

2019 ◽  
Vol 38 (1) ◽  
pp. 63-70
Author(s):  
Milica Nedeljković ◽  
Nikola Tanić ◽  
Tatjana Dramićanin ◽  
Zorka Milovanović ◽  
Snežana Šušnjar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prognostic Marker ◽  
Triple Negative Breast Cancer ◽  
Copy Number ◽  
Triple Negative ◽  
Clinical Course ◽  
Copy Number Gain ◽  
Gene Copy ◽  
Copy Number Alterations ◽  
The Impact

Summary Background: Triple negative breast cancer (TNBC) is characterized by aggressive clinical course and is unresponsive to anti-HER2 and endocrine therapy. TNBC is difficult to treat and is often lethal. Given the need to find new targets for therapy we explored clinicopathological significance of copy number gain of FGFR1 and c-MYC. Our aim was to determine the impact of FGFR1 and c-MYC copy number gain on clinical course and outcome of TNBC. Methods: FGFR1 and c-MYC gene copy number alterations were evaluated in 78 archive TNBC samples using TaqMan based quantitative real time PCR assays. Results: 50% of samples had increased c-MYC copy number. c-MYC copy number gain was associated with TNBC in contrast to ER positive cancers. Our results showed significant correlation between c-MYC copy number gain and high grade of TNBCs. This suggests that c-MYC copy number could be an useful prognostic marker for TNBC patients. c-MYC copy number gain was associated with high pTNM stage as well as lobular and medullary tumor subtypes. 43% of samples had increased FGFR1 copy number. No correlations between FGFR1 copy number gain and clinicopathological variables were observed. Conclusions: We identified c-MYC copy number gain as a prognostic marker for TNBC. Our results indicate that c- MYC may contribute to TNBC progression. We observed no significant association between c-MYC and/or FGFR1 copy number status and patient survival.

scholarly journals Association of Cell-Free DNA Tumor Fraction and Somatic Copy Number Alterations With Survival in Metastatic Triple-Negative Breast Cancer

2018 ◽  
Vol 36 (6) ◽  
pp. 543-553 ◽  
Author(s):  
Daniel G. Stover ◽  
Heather A. Parsons ◽  
Gavin Ha ◽  
Samuel S. Freeman ◽  
William T. Barry ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Copy Number ◽  
Triple Negative ◽  
Copy Number Alterations ◽  
Cell Free Dna ◽  
Primary Tumors ◽  
Free Dna ◽  
Genome Wide ◽  
Somatic Copy Number Alterations

Purpose Cell-free DNA (cfDNA) offers the potential for minimally invasive genome-wide profiling of tumor alterations without tumor biopsy and may be associated with patient prognosis. Triple-negative breast cancer (TNBC) is characterized by few mutations but extensive somatic copy number alterations (SCNAs), yet little is known regarding SCNAs in metastatic TNBC. We sought to evaluate SCNAs in metastatic TNBC exclusively via cfDNA and determine if cfDNA tumor fraction is associated with overall survival in metastatic TNBC. Patients and Methods In this retrospective cohort study, we identified 164 patients with biopsy-proven metastatic TNBC at a single tertiary care institution who received prior chemotherapy in the (neo)adjuvant or metastatic setting. We performed low-coverage genome-wide sequencing of cfDNA from plasma. Results Without prior knowledge of tumor mutations, we determined tumor fraction of cfDNA for 96.3% of patients and SCNAs for 63.9% of patients. Copy number profiles and percent genome altered were remarkably similar between metastatic and primary TNBCs. Certain SCNAs were more frequent in metastatic TNBCs relative to paired primary tumors and primary TNBCs in publicly available data sets The Cancer Genome Atlas and METABRIC, including chromosomal gains in drivers NOTCH2, AKT2, and AKT3. Prespecified cfDNA tumor fraction threshold of ≥ 10% was associated with significantly worse metastatic survival (median, 6.4 v 15.9 months) and remained significant independent of clinicopathologic factors (hazard ratio, 2.14; 95% CI, 1.4 to 3.8; P < .001). Conclusion We present the largest genomic characterization of metastatic TNBC to our knowledge, exclusively from cfDNA. Evaluation of cfDNA tumor fraction was feasible for nearly all patients, and tumor fraction ≥ 10% is associated with significantly worse survival in this large metastatic TNBC cohort. Specific SCNAs are enriched and prognostic in metastatic TNBC, with implications for metastasis, resistance, and novel therapeutic approaches.

Genome-wide copy number analysis of cell-free DNA from patients with chemotherapy-resistant metastatic triple-negative breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1092-1092
Author(s):  
Daniel G. Stover ◽  
Heather Anne Parsons ◽  
Gavin Ha ◽  
Samuel Freeman ◽  
William Thomas Barry ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Copy Number ◽  
Triple Negative ◽  
Plasma Samples ◽  
Copy Number Alterations ◽  
Copy Number Analysis ◽  
Blood Draw ◽  
Genome Wide ◽  
Line Of Therapy ◽  
Low Coverage

1092 Background: Triple-negative breast cancer (TNBC) is a poor prognosis breast cancer subset characterized by relatively few mutations but extensive copy number alterations (CNAs). Cell-free DNA (cfDNA) offers the potential to overcome infrequent tumor biopsies in metastatic TNBC (mTNBC) and interrogate the genomics of chemotherapy resistance. Methods: 506 archival or fresh plasma samples were identified from 164 patients with mTNBC who had previously received chemotherapy. We performed low coverage sequencing to determine genome-wide copy number and estimate ‘tumor fraction’ of cfDNA (TFx). In patient samples with TFx >10%, we identified regions that were significantly gained or lost using GISTIC2.0. We compared CNAs of mTNBCs with primary TNBCs from a publicly-available dataset, METABRIC (TNBC n=277). Results: We successfully obtained high quality, low coverage whole genome sequencing data for 478 (94.5%) plasma samples from 158 patients, with 1 to 14 samples per patient. Archival samples had significantly higher average cfDNA per mL plasma and TFx than fresh samples, potentially due to later average line of therapy. Average TFx of first blood draw was significantly higher in patients with liver metastases (TFx 28.3% vs. 14.4%, p=1.1e-7). 101/158 patients (63.9%) had at least one sample with TFx >10%, our threshold for high confidence CNA calls. Most alterations significantly enriched in chemotherapy-resistant mTNBCs were chromosomal gains, including NOTCH2 and ERCC1. Median overall survival from time of first blood draw was 9 months, and TFx was highly correlated independent of metastatic line of therapy, age at metastatic diagnosis, BRCA status, and primary stage: adjusted hazard ratio between 4th and 1stquartiles = 4.29 (95% CI 1.66-11.1; p=0.0008). Conclusions: It is feasible to perform genome-level copy number analysis from cfDNA in both archival and fresh samples from patients with mTNBC. Copy number alterations enriched in mTNBC may have implications in the understanding of metastasis, therapeutic resistance, and novel therapeutic targets. ‘Tumor fraction’ of cfDNA is correlated with overall survival and may be an independent prognostic marker in mTNBC.

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