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Gene Commanding Height (GCH) hierarchy in the cancer nucleus and cancer-free resection margins from a surgically removed prostatic adenocarcinoma of a 47y old white man

ABSTRACT: We profiled the transcriptomes of the cancer nucleus (Gleason score 4+5=9) and of the cancer free resection margins of a surgically removed prostate tumor from a 47y old white man. Normalized to the median of valid spots expression data where used to determine the Gene Commanding Height (GCH) Score for every coding and non-coding transcript adequately quantified in all four cancer and four normal tissue samples. The analysis proved that cancer and normal tissue have distinct gene hiearchies. The top three genes in the cancer region were: LOC145474 (uncharacterized long non-coding RNA), PRRG1 (proline rich Gla (G-carboxyglutamic acid) 1) and ASAP3 (ArfGAP with SH3 domain, ankyrin repeat and PH domain 3), while the top three genes in the cancer-free region were: SFR1 (SWI5-dependent recombination repair 1 ), EDF1 (endothelial differentiation-related factor 1) and RHOD (ras homolog family member D).

ORGANISM(S): Homo sapiens

PROVIDER: GSE133891 | GEO | 2019/07/06

REPOSITORIES: GEO

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Project description:PURPOSE: Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant TOP trial, in which patients with estrogen receptor (ER)-negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase IIα (TOP2A) and to develop a gene expression signature to identify those patients who do not benefit from anthracyclines. METHODS: The TOP trial included 149 patients, of which 141 were evaluable for response prediction analyses. The primary endpoint was pathological complete response (pCR). TOP2A and gene expression profiles were evaluated using pre-epirubicin biopsies. Gene expression data from ER-negative samples of the EORTC 10994/BIG 00-01 and MDACC 2003-0321 neoadjuvant trials were used for validation purposes. RESULTS: A pCR was obtained in 14% of the evaluable TOP patients. TOP2A amplification, but not protein overexpression, was significantly associated with pCR (p=0.001 and 0.22). We developed an “anthracycline-based score (A-Score)” that combines three signatures: a TOP2A gene signature and two previously published signatures related to tumor invasion and immune response. The A-Score was characterized by a high negative predictive value (NPV=0.98 [95% CI: 0.90-1.00]) overall, and in the HER2-negative and HER2-positive subpopulations. Its performance was independently confirmed in the anthracycline-based (FAC/FEC) arms of the two validation trials (BIG 00-01: 0.80 [0.61-0.92] and MDACC 2003-0321: 1.00 [0.80-1.00]). CONCLUSION: Given its high NPV, the A-Score could become, if further validated, a useful clinical tool to identify those patients who do not benefit from anthracyclines and could therefore be spared the non-negligible side effects. Predicting the efficacy of anthracyclines (epirubicin) in breast cancer (BC) patients (TOP trial) 120 microarray experiments from primary ER-negative breast tumors of anthracycline-treated patients. No replicate, no reference sample.

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Gene Commanding Height (GCH) hierarchy in the cancer nucleus and cancer-free resection margins from a surgically removed prostatic adenocarcinoma of a 47y old white man

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