An Integrative Genomics Approach for Associating GWAS Information with Triple-Negative Breast Cancer

Hicks, Chindo; Kumar, Ranjit; Pannuti, Antonio; Backus, Kandis; Brown, Alexandra S.; Monico, Jesus; Miele, Lucio

doi:10.4137/cin.s10413

Cited by 16 publications

(29 citation statements)

References 69 publications

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“… 98 PTEN SNPs have also been associated with TNBC incidence. 99 PTEN loss, which can occur through multiple mechanisms, has been associated with breast cancer tumor size, grade, reoccurrence, drug resistance, and worse prognosis. 100 …”

Section: Tnbc Biomarkers In the Cell Cytoplasmmentioning

confidence: 99%

Current advances in biomarkers for targeted therapy in triple-negative breast cancer

Fleisher¹,

Clarke²,

Ait‐Oudhia³

2016

BCTT

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Triple-negative breast cancer (TNBC) is a complex heterogeneous disease characterized by the absence of three hallmark receptors: human epidermal growth factor receptor 2, estrogen receptor, and progesterone receptor. Compared to other breast cancer subtypes, TNBC is more aggressive, has a higher prevalence in African-Americans, and more frequently affects younger patients. Currently, TNBC lacks clinically accepted targets for tailored therapy, warranting the need for candidate biomarkers. BiomarkerBase, an online platform used to find biomarkers reported in clinical trials, was utilized to screen all potential biomarkers for TNBC and select only the ones registered in completed TNBC trials through clinicaltrials.gov. The selected candidate biomarkers were classified as surrogate, prognostic, predictive, or pharmacodynamic (PD) and organized by location in the blood, on the cell surface, in the cytoplasm, or in the nucleus. Blood biomarkers include vascular endothelial growth factor/vascular endothelial growth factor receptor and interleukin-8 (IL-8); cell surface biomarkers include EGFR, insulin-like growth factor binding protein, c-Kit, c-Met, and PD-L1; cytoplasm biomarkers include PIK3CA, pAKT/S6/p4E-BP1, PTEN, ALDH1, and the PIK3CA/AKT/mTOR-related metabolites; and nucleus biomarkers include BRCA1, the gluco-corticoid receptor, TP53, and Ki67. Candidate biomarkers were further organized into a “cellular protein network” that demonstrates potential connectivity. This review provides an inventory and reference point for promising biomarkers for breakthrough targeted therapies in TNBC.

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Section: Tnbc Biomarkers In the Cell Cytoplasmmentioning

confidence: 99%

Current advances in biomarkers for targeted therapy in triple-negative breast cancer

Fleisher¹,

Clarke²,

Ait‐Oudhia³

2016

BCTT

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“…Previous genome-wide association investigations have identified genetic variants, which are associated with an increased risk of developing breast cancer. Furthermore, gene expression profile analyses have provided multi-gene signatures associated with TNBC carcinogenesis ( 11 , 12 ). Although investigations are increasingly focussing on the recurrence ( 5 , 6 , 13 ) and treatment ( 7 ) of TNBC, the molecular profiles of paired specimens obtained from patients with and without subsequent recurrence require further investigation.…”

Section: Introductionmentioning

confidence: 99%

Molecular characteristics of recurrent triple-negative breast cancer

Tsai¹,

Chiu²,

Yang

et al. 2015

Molecular Medicine Reports

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Due to the fact that the treatment of breast cancer depends significantly on the molecular markers present in the cancer, including estrogen receptor (+), progesterone receptor (+) or erbB2 receptor (+), further investigation targeting triple-negative breast cancer (TNBC) subtypes may assist in elucidating the mechanisms of recurrence of TNBC and enable the identification of novel therapeutic strategies for patients with TNBC. The aim of the present study was to compare the gene expression profiles between TNBC samples that were identified as having recurrent and non-recurrent statuses. Between June 2011 and May 2012, a total of 30 patients with TNBC were examined using a follow-up period of at least 5 years. Their clinicopathological information was retrospectively reviewed and they were classified with a status either of recurrence [n=15 stage II (9), IIIA (2), IIIC (4)] or non-recurrence [n=15 stage II (6), IIIA (1), IIIC (8)]. The total RNA from tissue samples obtained from the recurrent and non-recurrent TNBC patients were used to performed oligonucleotide microarray analysis. The dataset was analyzed using GeneSpring software and validated using reverse transcription-quantitative polymerase chain reaction. Principal component analysis demonstrated that there was a marked difference in the gene expression distribution between the stage IIIc recurrent samples and early stage (stages IIa, IIb and IIIa) recurrent samples. In early stage recurrence, the significant pathway-associated upregulated genes were matrix metalloproteinases (MMPs) and genes associated with cancer cell migration (CDH2) and cell adhesion/motility (KRAS, CDC42, RAC1, ICAM and SRGAP2). By contrast, during stage IIIc recurrence, the significant pathway-associated upregulated genes in the recurrent samples were WNT signaling genes, including WNT 4 and WNT 16. It was concluded that there were markedly different distributions and gene expression profiles between stage IIIc recurrent TNBC tumors and early stage (IIa, IIb, IIIa) recurrent TNBC tumors, which provides important information for the development of effective treatment strategies for TNBC.

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“…We selected the three of the most studied SNPs of CCL5 located in the promoter region of the CCL5 gene. We also selected six SNPs from breast cancer GWAS studies (14). The six SNPs containing genes are all involved in signaling pathways that can regulate CCL5 levels.…”

Section: Snp Selection and Genotypingmentioning

confidence: 99%

“…Thus far, potential association between genetic variation in CCL5 and breast cancer has not been investigated. Integrative genomics analysis, combining information from GWAS studies on breast cancer involving over 400,000 cases and over 400,000 controls, was performed by Hicks et al (14) to determine whether genes containing SNPs associated with an increased risk of developing breast cancer are associated with TNBC. Twelve out the 34 large-effect SNPs associated with TNBC are located within genes involved in the JNK, p38 MAPK, NF-κB, and cAMP/PKA signaling pathways, all of which regulate CCL5 levels in immune cells (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Genetic Variation in CCL5 Signaling Genes and Triple Negative Breast Cancer: Susceptibility and Prognosis Implications

et al. 2019

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Triple-negative breast cancer (TNBC) accounts for ∼15-20% of breast cancer (BC) and has a higher rate of early relapse and mortality compared to other subtypes. The Chemokine (C-C motif) ligand 5 (CCL5) and its signaling pathway have been linked to TNBC. We aimed to investigate the susceptibility and prognostic implications of genetic variation in CCL5 signaling genes in TNBC in the present study. We characterized variants in CCL5 and that of six other CCL5 signaling genes (CCND1, ZMIZ1, CASP8, NOTCH2, MAP3K21, and HS6ST3) among 1,082 unrelated Tunisian subjects (544 BC patients, including 196 TNBC, and 538 healthy controls), assessed the association of the variants with BC-specific overall survival (OVS) and progression-free survival (PFS), and correlated CCL5 mRNA and serum levels with CCL5 genotypes. We found a highly significant association between the CCND1 rs614367-TT genotype (OR = 5.14; P = 0.004) and TNBC risk, and identified a significant association between the rs614367-T allele and decreased PFS in TNBC. A decreased risk of lymph node metastasis was associated with the MAP3K21 rs1294255-C allele, particularly in rs1294255-GC (OR = 0.47; P = 0.001). CCL5 variants (rs2107538 and rs2280789) were linked to CCL5 serum and mRNA levels. In the TCGA TNBC/Basal-like cohort the MAP3K21 rs1294255-G allele was associated with a decreased OVS. High expression of CCL5 in breast tumors was significantly associated with an increased OVS in all BC patients, but particularly in TNBC/Basal-like patients. In conclusion, genetic variation in CCL5 signaling genes may predict not only TNBC risk but also disease aggressiveness.

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An Integrative Genomics Approach for Associating GWAS Information with Triple-Negative Breast Cancer

Cited by 16 publications

References 69 publications

Current advances in biomarkers for targeted therapy in triple-negative breast cancer

Current advances in biomarkers for targeted therapy in triple-negative breast cancer

Molecular characteristics of recurrent triple-negative breast cancer

Genetic Variation in CCL5 Signaling Genes and Triple Negative Breast Cancer: Susceptibility and Prognosis Implications

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