Molecular analysis of TCGA breast cancer histologic types

Thennavan, Aatish; Beça, Francisco; Xia, Youli; García-Recio, Susana; Allison, Kimberly H.; Collins, Laura C.; Tse, Gary M.; Chen, Yunn-Yi; Schnitt, Stuart J.; Hoadley, Katherine A.; Beck, Andrew H.; Perou, Charles M.

doi:10.1016/j.xgen.2021.100067

Cited by 41 publications

(19 citation statements)

References 50 publications

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“…TCGA breast cancer PAM50 subtypes were obtained from Du et al [ 20 ]. ER, PR, and HER2 status for TCGA breast cancer was obtained from Thennavan et al [ 21 ]. Differential expression (DE) analysis was performed with the R package DESeq2 (version 1.30.0) [ 22 ], and genes with fold change > 4 and false discovery rate (FDR) < 0.05 were selected as upregulated DE genes.…”

Section: Methodsmentioning

confidence: 99%

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Matrix Gla protein (MGP), GATA3, and TRPS1: a novel diagnostic panel to determine breast origin

Zheng

et al. 2022

Breast Cancer Res

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Background Metastatic breast carcinoma is commonly considered during differential diagnosis when metastatic disease is detected in females. In addition to the tumor morphology and documented clinical history, sensitive and specific immunohistochemical (IHC) markers such as GCDFP-15, mammaglobin, and GATA3 are helpful for determining breast origin. However, these markers are reported to show lower sensitivity in certain subtypes, such as triple-negative breast cancer (TNBC). Materials and methods Using bioinformatics analyses, we identified a potential diagnostic panel to determine breast origin: matrix Gla protein (MGP), transcriptional repressor GATA binding 1 (TRPS1), and GATA-binding protein 3 (GATA3). We compared MGP, TRPS1, and GATA3 expression in different subtypes of breast carcinoma of (n = 1201) using IHC. As a newly identified marker, MGP expression was also evaluated in solid tumors (n = 2384) and normal tissues (n = 1351) from different organs. Results MGP and TRPS1 had comparable positive expression in HER2-positive (91.2% vs. 92.0%, p = 0.79) and TNBC subtypes (87.3% vs. 91.2%, p = 0.18). GATA3 expression was lower than MGP (p < 0.001) or TRPS1 (p < 0.001), especially in HER2-positive (77.0%, p < 0.001) and TNBC (43.3%, p < 0.001) subtypes. TRPS1 had the highest positivity rate (97.9%) in metaplastic TNBCs, followed by MGP (88.6%), while only 47.1% of metaplastic TNBCs were positive for GATA3. When using MGP, GATA3, and TRPS1 as a novel IHC panel, 93.0% of breast carcinomas were positive for at least two markers, and only 9 cases were negative for all three markers. MGP was detected in 36 cases (3.0%) that were negative for both GATA3 and TRPS1. MGP showed mild-to-moderate positive expression in normal hepatocytes, renal tubules, as well as 31.1% (99/318) of hepatocellular carcinomas. Rare cases (0.6–5%) had focal MGP expression in renal, ovarian, lung, urothelial, and cholangiocarcinomas. Conclusions Our findings suggest that MGP is a newly identified sensitive IHC marker to support breast origin. MGP, TRPS1, and GATA3 could be applied as a reliable diagnostic panel to determine breast origin in clinical practice.

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Section: Methodsmentioning

confidence: 99%

“…ER/PR+ (ER/PR+ and HER−, n = 685), HER2+ (n = 168), and TNBC (n = 177). TCGA BRCA ER, PR, and HER2 status were retrieved from Thennavan et al [21]. S1.…”

Section: Supplementary Informationmentioning

confidence: 99%

Matrix Gla protein (MGP), GATA3, and TRPS1: a novel diagnostic panel to determine breast origin

Zheng

et al. 2022

Breast Cancer Res

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“…Identifying cell-of-origin allows further evaluation of signaling pathways activated in this cancer type and eventually development of targeted therapies. Metaplastic carcinomas of the breast are CD49f + /EpCAM - 63 and can be subdivided into metaplastic, claudin-(META-CLOW) and metaplastic-squamous, and metaplastic-non-CLOW, non-Squamous. PZP cells acquired CD49f + /EpCAM - phenotype upon transformation and tumors derived from these cells displayed squamous features, indicating PZP cells are the cell-of-origin of metaplastic-squamous subtype.…”

Section: Discussionmentioning

confidence: 99%

Influence of genetic ancestry on breast stromal cells provides biologic basis for increased incidence of metaplastic breast cancer in women of African descent

Kumar

Batic

Bhat‐Nakshatri

et al. 2022

Preprint

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The biologic basis of genetic ancestry-dependent variability in disease incidence and outcome is just beginning to be explored. We recently reported enrichment of a population of ZEB1-expressing cells located adjacent to the ductal epithelial cells in the normal breast of women of African Ancestry (AA) compared to European Ancestry (EA). By establishing and characterizing cell lines corresponding to these cells and validating in vitro findings with tissue microarrays of healthy breast tissue from AA, EA and Latina Ancestry (LA) women, we demonstrate that these cells have the properties of fibroadipogenic/mesenchymal stromal cells that express PROCR and PDGFRalpha;. PROCR+/ZEB1+/PDGFRalpha+ cells, hence renamed as PZP cells, are enriched in the normal breast tissues of AA compared to EA or LA women. In vitro, PZP cells trans-differentiated into adipocytes or osteocytes. In co-culture conditions, PZP:epithelial cell communication resulted in luminal epithelial cells acquiring basal/stem cell characteristics and increased expression of IL-6 suggesting the impact of this communication on breast epithelial hierarchy and the microenvironment. Consistent with this possibility, the level of phospho-STAT3, which is a downstream target of IL-6, was higher in the normal and cancerous breast tissues of AA compared to EA women. PZP cells transformed with HRasG12V with or without SV40-T/t antigens generated metaplastic carcinoma in NSG mice suggesting that these cells could be the cell-of-origin of metaplastic breast cancers. Collectively, these results identify a stromal cell component that could influence the biology of breast cancer in AA women.

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“…For clinical prediction of recurrence the University of Tennessee Nomogram 9 was computed for each patient in TCGA; grade is not available in the original TCGA annotations but has been assessed and reported in prior work 29 . Precise tumor size was not provided in TCGA but was estimated from tumor stage group.…”

Section: Methodsmentioning

confidence: 99%

Multimodal Prediction of Breast Cancer Recurrence Assays and Risk of Recurrence

Howard

Dolezal

Kochanny

et al. 2022

Preprint

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Gene expression-based recurrence assays are strongly recommended to guide the use of chemotherapy in hormone receptor-positive, HER2-negative breast cancer, but such testing is expensive, can contribute to delays in care, and may not be available in low-resource settings. Here, we describe the training and independent validation of a deep learning model that predicts recurrence assay result and risk of recurrence using both digital histology and clinical risk factors. We demonstrate that this approach outperforms an established clinical nomogram (area under the receiver operating characteristic curve of 0.833 versus 0.765 in the validation cohort, p = 0.003), and can identify a subset of patients with excellent prognoses who may not need further genomic testing.

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Molecular analysis of TCGA breast cancer histologic types

Cited by 41 publications

References 50 publications

Matrix Gla protein (MGP), GATA3, and TRPS1: a novel diagnostic panel to determine breast origin

Matrix Gla protein (MGP), GATA3, and TRPS1: a novel diagnostic panel to determine breast origin

Influence of genetic ancestry on breast stromal cells provides biologic basis for increased incidence of metaplastic breast cancer in women of African descent

Multimodal Prediction of Breast Cancer Recurrence Assays and Risk of Recurrence

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