Abstract
BackgroundHistological grade (HG) is commonly adopted as a prognostic factor for ER-positive breast cancer patients. However, HG evaluation methods, such as the pathological Nottingham grading system, are highly subjective with only 50–85% inter-observer agreements. Specifically, the subjectivity in the pathological assignment of the intermediate grade (HG2) breast cancers, comprising of about half of breast cancer cases, results in uncertain disease outcomes prediction. Here, we developed a qualitative transcriptional signature, based on within-sample relative expression orderings (REOs) of gene pairs, to define HG1 and HG3 and reclassify pathologically-determined HG2 (denoted as pHG2) breast cancer patients.ResultsFrom the gene pairs with significantly stable REOs in pathologically-determined HG1 (denoted as pHG1) samples and reversely stable REOs in pathologically-determined HG3 (denoted as pHG3) samples, concordantly identified from seven datasets, we extracted a signature which could determine the HG state of samples through evaluating whether the within-sample REOs match with the patterns of the pHG1 REOs or pHG3 REOs. A sample was classified into the HG3 group if at least a half of the REOs of the 10 gene pairs signature within this sample voted for HG3; otherwise, HG1. Using four datasets including samples of early stage (I–II) ER-positive breast cancer patients who accepted surgery only, we validated that this signature was able to reclassify pHG2 patients into HG1 and HG3 groups with significantly different survival time. For the original pHG1 and pHG3 patients, the signature could also more accurately and objectively stratify them into distinct prognostic groups. And the up-regulated and down down-regulated genes in HG1 compared with HG3 involved in cell proliferation and extracellular signal transduction pathways respectively. By comparing with existing signatures, 10-GPS was with prognostic significance and was more aligned with survival of patients especially for pHG2 samples.ConclusionsThe transcriptional qualitative signature can provide an objective assessment of HG states of ER-positive breast cancer patients, especially for reclassifying patients with pHG2, to assist decision making on clinical therapy.
Highlights
Histological grade (HG) is commonly adopted as a prognostic factor for estrogen receptor (ER)-positive breast cancer patients
Genomics analysis indicates that HG1 and HG3 breast carcinomas develop independently along different genetic pathways [10, 11], while HG2 patients contain a blend of histological features, some of which are common to both HG1 and HG3 tumors, and exhibit a mixed gene expression profiles of HG1 and HG3 [12, 13]
Using gene expression profiles of 932 ER-positive early stage breast cancer patients, we developed a qualitative signature to allocate each patient into the pathologically-determined HG1 or HG3 group
Summary
Histological grade (HG) is commonly adopted as a prognostic factor for ER-positive breast cancer patients. The subjectivity in the pathological assignment of the intermediate grade (HG2) breast cancers, comprising of about half of breast cancer cases, results in uncertain disease outcomes prediction. Genomics analysis indicates that HG1 and HG3 breast carcinomas develop independently along different genetic pathways [10, 11], while HG2 patients (comprising ~ 50% of breast cancer cases) contain a blend of histological features, some of which are common to both HG1 and HG3 tumors, and exhibit a mixed gene expression profiles of HG1 and HG3 [12, 13]. The heterogeneity of the HG2 breast cancers resulted in uncertain disease outcome prediction and there is no standard treatment protocol for clinical decision making [7, 16]
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