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DNA-damage related genes and clinical outcome in hormone receptor positive breast cancer.

ABSTRACT: Control of DNA damage is frequently deregulated in solid tumors. Upregulation of genes within this process can be indicative of a more aggressive phenotype and linked with worse outcome. In the present article we identify DNA damage related genes associated with worse outcome in breast cancer.2286 genes were differentially expressed between normal breast tissue and basal-like tumors, and 62 included in the DNA metabolic process function. Expression of RAD51, GINS1, TRIP13 and MCM2 were associated with detrimental relapse free survival (RFS) and overall survival (OS) in luminal tumors. The combined analyses of TRIP13+RAD51+MCM2 showed the worse association for RFS (HR 2.25 (1.51-3.35) log rank p= 4.1e-05) and TRIP13+RAD51 for OS (HR 5.13 (0.6-44.17) log rank p=0.098) in ER+/HER2- tumors. TRIP13 is amplified in 3.1% of breast cancers.Transcriptomic analyses using public datasets evaluating expression values between normal breast tissue and TNBC identified upregulated genes. Genes included in the DNA metabolic process were selected and confirmed using data contained at oncomine (www.oncomine.org). Evaluation of the selected genes with RFS and OS was performed using the KM Plotter Online Tool (http://www.kmplot.com). Evaluation of molecular alterations was performed using cBioportal (www.cbioportal.org).Expression of DNA metabolic related genes RAD51, GINS1, TRIP13 and MCM2 are associated with poor outcome. Combinations of some of these genes are linked to poor RFS or OS in luminal A, B and ER+HER2- tumors. Evaluation of its predictive capacity in prospective studies is required.

SUBMITTER: Nieto-Jimenez C

PROVIDER: S-EPMC5609884 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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DNA-damage related genes and clinical outcome in hormone receptor positive breast cancer.

Nieto-Jiménez Cristina C Alcaraz-Sanabria Ana A Páez Raquel R Pérez-Peña Javier J Corrales-Sánchez Verónica V Pandiella Atanasio A Ocaña Alberto A

Oncotarget 20160728 38

<h4>Background</h4>Control of DNA damage is frequently deregulated in solid tumors. Upregulation of genes within this process can be indicative of a more aggressive phenotype and linked with worse outcome. In the present article we identify DNA damage related genes associated with worse outcome in breast cancer.<h4>Results</h4>2286 genes were differentially expressed between normal breast tissue and basal-like tumors, and 62 included in the DNA metabolic process function. Expression of RAD51, GI ...[more]

PMID: 28968952

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Project description:Background99mTechnetium labeled methylene diphosphonate bone scans (BSs) are commonly used to monitor disease progression in bone for patients with metastatic breast cancer (MBC). However, new BS lesions may represent osteoblastic bone healing, which we now define as bone pseudoprogression. In this study, we aimed to assess the clinical significance and determination methods of bone pseudoprogression.MethodsThis retrospective analysis was conducted among 48 patients with hormone receptor-positive MBC treated with first-line endocrine therapy. Four months after initiating therapy, all the participants did not show extraosseous disease progression. Participants were divided into two groups according to the presence of new BS lesions. All the patients continued on treatment until explicit disease progression (extraosseous disease progression or progressive lysis on bone lesions). Explicit progression-free survival (PFS) and extraosseous objective response rate were analyzed between the two groups.ResultsNew BS lesions were observed in 11 of 48 (22.9%) patients. All the new BS lesions appeared as osteoblastic bone lesions on computed tomography. For patients with new BS lesions, the median PFS was 26.57 months [95% confidence interval (CI) 15.46-37.68], which was similar to that (29.57 months; 95% CI 19.24-39.90) in patients without new BS lesions [hazard ratio: 1.098 (95% CI 0.482-2.503), p = 0.818]. Notably, 82.9% of patients without new BS lesions showed an extraosseous objective response, whereas 85.7% of patients with new BS lesions demonstrated an extraosseous objective response [odds ratio: 0.806 (95% CI 0.061-5.682), p = 0.999]. The median interval between bone pseudoprogression and true disease progression was 21.26 months (95% CI 10.11-32.42).ConclusionsOsteoblastic new BS lesions detected on follow-up BSs may represent bone pseudoprogression. Clinicians should raise awareness of bone pseudoprogression, thereby avoiding premature discontinuation of therapy and maximizing the opportunity to benefit from endocrine therapy. Due to the small sample size and retrospective nature of the study, large prospective clinical trials are needed to confirm our findings.

Project description:The major changes in hormone levels that occur through the menstrual cycle have been postulated to affect the expression of hormone-regulated and proliferation-associated genes (PAGs) in premenopausal ER+ breast cancer. Whilst previous studies have demonstrated differences in gene expression, here, we investigated if there are within patient changes in the expression of oestrogen- and progesterone-regulated genes (ERGs and PRGs) and PAGs in ER+ breast cancer during the menstrual cycle. Samples from 96 patients in two independent prospective studies of the effect of menstrual cycle on ER+ breast cancer were used. Plasma hormone measurements were used to assign tumours to one of three pre-defined menstrual cycle windows: W1 (days 27-35 and 1-6; low oestradiol and low progesterone), W2 (days 7-16; high oestradiol and low progesterone) and W3 (days 17-26; intermediate oestradiol and high progesterone). RNA expression of 50 genes, including 27 ERGs, 11 putative PRGs and seven PAGs was measured. The AvERG (geomean of PGR, GREB1, TFF1 and PDZK1) was used as a composite measure of ERG expression and showed significant changes between the three windows of the menstrual cycle increasing over 2.2-fold between W1 and W2 and decreasing between W2 and W3 and between W3 and W1. Proliferation gene expression also varied significantly, following the same pattern of changes as ERG expression, but the changes were of lower magnitude (1.4-fold increase between W1 and W2). Significant changes in the expression of eight individual ERGs, including GREB1, PGR and TFF1, and two PAGs were observed between W1 and either W2 or W3 with all genes showing higher levels in W2 or W3 (1.3-2.4-fold; FDR 0.016-0.05). The AvProg, a composite measure of PRG expression, increased significantly (1.5-fold) in W3 compared to W1 or W2 but no significant changes were observed for individual PRGs. In conclusion, we observed significant changes in ERG, PRG and PAG expression in ER+ breast tumours during the menstrual cycle that may affect the assessment and interpretation of prominent biomarkers (e.g. PgR) and commonly used multigene prognostic signatures in premenopausal ER+ breast cancer.

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DNA-damage related genes and clinical outcome in hormone receptor positive breast cancer.

Publications

DNA-damage related genes and clinical outcome in hormone receptor positive breast cancer.

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