Residual disease after neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) is related with poor prognosis; however, the risk of recurrence after 3 years from surgery, becomes similar to other breast cancer subtypes indicating that TNBC is composed of tumours of different prognosis. To evaluate genes related to TNBC aggressiveness in the outcome of TNBC resistant to NAC, we profiled 82 samples of residual tumours whose expression for 449 genes was quantified with NanoString. The validation set (GSE25066) consisted of 113 TNBC cases with residual disease. The stepwise multivariate survival analysis performed by the Cox proportional hazards mode selected CCL5, DDIT4 and POLR1C as independent prognostic factors for distant recurrence-free survival (DRFS). We developed a three-genes signature using the regression coefficients for each gene (−0.393×CCL5+0.443×DDIT4+0.490×POLR1C). The median score in the discovery set (0.1494) identified two subgroups with different DRFS (P<0.001). The median score in the validation set was 0.0024 and was able to discriminate patients with different DRFS (P=0.002). In addition, the three-genes signature was a prognostic factor in TNBC patients regardless their response to NAC (data set GSE58812; P=0.001) and in patients with oestrogen-receptor-negative tumours (data set GSE16446; P=0.041). Here we describe a prognostic signature based on expression levels of CCL5, DDIT4 and POLR1C. The knowledge about the involvement of these genes in chemotherapy resistance could improve the therapeutic strategies in TNBC.
There are different biological and clinical patterns of lung cancer between genders indicating intrinsic differences leading to increased sensitivity to cigarette smoke-induced DNA damage, mutational patterns of KRAS and better clinical outcomes in women while differences between genders at gene-expression levels was not previously reported. Here we show an enrichment of immune genes in NSCLC in women compared to men. We found in a GSEA analysis (by biological processes annotated from Gene Ontology) of six public datasets a repeated observation of immune gene sets enrichment in women. “Immune system process”, “immune response”, “defense response”, “cellular defense response” and “regulation of immune system process” were the gene sets most over-represented while APOBEC3G, APOBEC3F, LAT, CD1D and CCL5 represented the top-five core genes. Characterization of immune cell composition with the platform CIBERSORT showed no differences between genders; however, there were differences when tumor tissues were compared to normal tissues. Our results suggest different immune responses in NSCLC between genders that could be related with the different clinical outcome.
INTRODUCTION: There is different susceptibility to DNA damage induced by tobacco smoking between women and men. In despite of the great advances in the knowledge of the genomic landscape of lung cancer, is not explored the molecular differences between man and women. Our aim was to evaluate differentially enriched gene sets between the two genders. METHODS: We evaluated 03 public databases containing gene expression values from lung adenocarcinoma patients: GSE50081 (HG-U133_Plus_2; n = 181 samples), GSE47115 (Illumina HumanHT-12 WG-DASL V4.0 R2; n = 46 samples), GSE10072 (HG-U133A; n = 107 samples). We perform the Gene Set Enrichment Analysis (GSEA) to find differences between the genders. Each dataset was analyzed individually and was divided in cohorts of smokers and non-smokers (and healthy tissues by smoking status when it was included in the dataset). Cases with unknown smoking status and former smokers were excluded from the analysis. We use the Gene Ontology biological process terms to find similar enriched pathways between cohorts. We consider enriched process with statistical differences (p<0.05) or trends (P<0.08) in at least a cohort. RESULTS: The analysis did show immune genes enrichment in women such as cytokine production, defense response to bacteria and response to other organisms. In another hand, regulation of JNK and MAPKKK cascades was enriched in tumors and healthy tissues from non-smokers women. In men, the oxidoreductase activity acting on sulfur group of donors was enriched in smoking men. CONCLUSION: There are differences between tumors from women and men that should be deeply explored. Citation Format: Joseph A. Pinto, Jhajaira M. Araujo, Alexandra Prado, Claudio Flores, Nadezhda K. Cardenas, Mayer Zaharia, Gustavo Sarria, Alfredo Aguilar, Silvia Neciosup, Henry Gomez, Luis Mas. Different gene expression between men and women patients with lung adenoarcinoma reveals enrichment of immune gene sets. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2188. doi:10.1158/1538-7445.AM2015-2188
Background: The presence of tumor infiltrating lymphocytes (TILs) have been associated with a better outcome in triple negative breast cancer (TNBC). In the other hand, we have found that CCL5, a chemokine involved in the recruitment of immune cells to the tumor microenvironment is an independent prognostic marker for distant-recurrence free survival (DFRS) in TNBC. The aim of this work was to evaluate the relationship between these two immunological prognostic markers in chemotherapy-resistant TNBC. Material and Methods: We evaluated a retrospective cohort (n = 74) of TNBC patients with residual disease after neoadjuvante chemotherapy. Residual tumors were profiled with Nanostring for genes previously related to TNBC aggressiveness. Gene expression values for CCL5 were log2 transformed and median centered. TIL count was performed according to the methods published by Salgado et al (2015). Values of TILs count were log2 transformed (values with 0% were removed from the cohort; n = 1). Spearman's rank correlation analysis and proportional hazards regression was used to investigate the relationship and impact in the outcome between these two markers. Results: The median TIL count was 10% (interquartile range: 21.25). A total of 59.5% of cases had TILs <15%. There was a significant correlation between TILs and CCL5 (ñ = 0.345, P = 0.032). In univariate analysis (as continuous variable), TILs (HR = 0.968 per unit of change; 95%IC: 0.946-0.990; P = 0.006) and CCL5 (HR = 0.95 per unit of change; 95%IC: 0.635-0.996; P = 0.046) were both associated with outcome. After adjusting to CCL5 expression, TIL's count, was the only significant marker with a P-value = 0.007 (HR = 0.702 per unit of change; 95%IC: 0.54-0.909), in contrast to CCL5 (HR = 0.925, CI95%:0.717-1,194; P-value = 0.550). Conclusions: TILs and CCL5 gene expression are significantly correlated in chemotherapy-resistant TNBC. However, although CCL5 expression is strongly associated with the progression of BC, particularly TNBC, TIL assessment remains the stronger and more significant prognostic immunological marker. Citation Format: Joseph A. Pinto, Zaida D. Morante, Roberto Salgado, Nadezhda Cardenas, Jhajaira Araujo, Jaime Ponce, Franco Doimi, Justin Balko, Henry Gomez. Correlation between tumor infiltrating lymphocytes and CCL5 gene expression in chemotherapy-resistant triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 738.
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