Dataset Information

A qualitative transcriptional signature to reclassify histological grade of ER-positive breast cancer patients.

ABSTRACT:

Background

Histological 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.

Results

From 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.

Conclusions

The 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.

SUBMITTER: Li J

PROVIDER: S-EPMC7132979 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Publications

A qualitative transcriptional signature to reclassify histological grade of ER-positive breast cancer patients.

Li Jing J Jiang Wenbin W Liang Qirui Q Liu Guanghao G Dai Yupeng Y Zheng Hailong H Yang Jing J Cai Hao H Zheng Guo G

BMC genomics 20200406 1

<h4>Background</h4>Histological 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 develo ...[more]

PMID: 32252627

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Project description:BACKGROUND:Targeted therapy for non-small cell lung cancer is histology dependent. However, histological classification by routine pathological assessment with hematoxylin-eosin staining and immunostaining for poorly differentiated tumors, particularly those from small biopsies, is still challenging. Additionally, the effectiveness of immunomarkers is limited by technical inconsistencies of immunostaining and lack of standardization for staining interpretation. RESULTS:Using gene expression profiles of pathologically-determined lung adenocarcinomas and squamous cell carcinomas, denoted as pADC and pSCC respectively, we developed a qualitative transcriptional signature, based on the within-sample relative gene expression orderings (REOs) of gene pairs, to distinguish ADC from SCC. The signature consists of two genes, KRT5 and AGR2, which has the stable REO pattern of KRT5 > AGR2 in pSCC and KRT5 < AGR2 in pADC. In the two test datasets with relative unambiguous NSCLC types, the apparent accuracy of the signature were 94.44 and 98.41%, respectively. In the other integrated dataset for frozen tissues, the signature reclassified 4.22% of the 805 pADC patients as SCC and 12% of the 125 pSCC patients as ADC. Similar results were observed in the clinical challenging cases, including FFPE specimens, mixed tumors, small biopsy specimens and poorly differentiated specimens. The survival analyses showed that the pADC patients reclassified as SCC had significantly shorter overall survival than the signature-confirmed pADC patients (log-rank p = 0.0123, HR = 1.89), consisting with the knowledge that SCC patients suffer poor prognoses than ADC patients. The proliferative activity, subtype-specific marker genes and consensus clustering analyses also supported the correctness of our signature. CONCLUSIONS:The non-subjective qualitative REOs signature could effectively distinguish ADC from SCC, which would be an auxiliary test for the pathological assessment of the ambiguous cases.

Project description:For estrogen receptor (ER)-negative breast cancer patients, paclitaxel (P), doxorubicin (A) and cyclophosphamide (C) neoadjuvant chemotherapy (NAC) is the standard therapeutic regimen. Pathologic complete response (pCR) and residual disease (RD) are common surrogate measures of chemosensitivity. After NAC, most patients still have RD; of these, some partially respond to NAC, whereas others show extreme resistance and cannot benefit from NAC but only suffer complications resulting from drug toxicity. Here we developed a qualitative transcriptional signature, based on the within-sample relative expression ordering (REO) of gene pairs, to identify extremely resistant samples to PAC NAC. Using gene expression data for ER-negative breast cancer patients including 113 pCR samples and 137 RD samples from four datasets, we selected 61 gene pairs with reversal REO patterns between the two groups as the resistance signature, denoted as NR61. Samples with more than 37 signature gene pairs that had the same REO patterns within the extremely resistant group were defined as having extreme resistance; otherwise, they were considered responders. In the GSE25055 and GSE25065 dataset, the NR61 signature could correctly identify 44 (97.8%) of the 45 pCR samples and 22 (95.7%) of the 23 pCR samples as responder samples, respectively; it also identified 13 (16.9%) of 77 RD samples and 8 (21.1%) of 38 RD samples as extremely resistant samples, respectively. Survival analysis showed that the distant relapse-free survival (DRFS) time of the 14 extremely resistant cases was significantly shorter than that of the 108 responders (P < 0.01; HR = 3.84; 95% CI = 1.91-7.70) in GSE25055. Similar results were obtained in GSE25065. Moreover, in the integrated data of the two datasets with 94 responders and 21 extremely resistant samples identified from RD patients, the former had significantly longer DRFS than the latter (P < 0.01; HR = 2.22; 95% CI = 1.26-3.90). In summary, our signature could effectively identify patients who completely respond to PAC NAC, as well as cases of extreme resistance, which can assist decision-making on the clinical therapy for these patients.

Dataset Information

A qualitative transcriptional signature to reclassify histological grade of ER-positive breast cancer patients.

Background

Results

Conclusions

Publications

A qualitative transcriptional signature to reclassify histological grade of ER-positive breast cancer patients.

Similar Datasets

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