Revealing the Molecular Portrait of Triple Negative Breast Tumors in an Understudied Population through Omics Analysis of Formalin-Fixed and Paraffin-Embedded Tissues

Vaca-Paniagua, Felipe; Álvarez-Gómez, Rosa María; Maldonado-Martínez, Héctor Aquiles; Pérez‐Plasencia, Carlos; Fragoso-Ontiveros, Verónica; Lasa-Gonsebatt, Federico; Cantú, David; Bargalló-Rocha, Enrique; Mohar, Alejandro; Durand, G.; Forey, Nathalie; Voegele, Catherine; Vallée, Maxime; Calvez-Kelm, Florence Le; McKay, James; Ardin, Maude; Villar, Stéphanie; Zavadil, Jiří; Olivier, Magalí

doi:10.1371/journal.pone.0126762

Cited by 18 publications

(19 citation statements)

References 56 publications

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“…Pathway analysis of potentially functional mutations across all genes showed enrichment of signal transduction pathways including EGFR, PDGF and IGF1R, and mutational signatures showed a large contribution of DNA repair defects to the mutation load. These overall results on TN cases fit with our previous analyses of another series of TN cases from Mexico where transcriptomics analyses showed an overexpression of growth-promoting signals (including EGFR, PDGFR and PIK3CA), a repression of cell cycle control pathways (TP53, RB1) and a deregulation of DNA-repair pathways [46].…”

Section: Discussionsupporting

confidence: 90%

Molecular features of premenopausal breast cancers in Latin American women: pilot results from the PRECAMA study

Olivier

Bouaoun

Villar

et al. 2018

Preprint

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on behalf of the PRECAMA team. List of abbreviationsBC, breast cancer; preBC, premenauposal breast cancer; postBC, postmenauposal breast cancer; TN, triple negative; TNBC, triple negative breast cancer; ER, estogen receptor; PR, progesterone receptor; WES, whole exome sequencing; IHC, immunohistochemistry; HR, homologous recombination; DMR, DNA mismatch repair. AbstractBackground In Latin America (LA), there is a high incidence rate of breast cancer (BC) in premenopausal women, and the genomic features of these BC remain unknown. Here, we aim to characterize the molecular features of BC in young LA women within the framework of the PRECAMA study, a multicenter population-based case-control study on breast cancer in premenopausal women.Methods Pathological tumor tissues were collected from incident cases from four LA countries. Immunohistochemistry (IHC) was performed centrally for ER, PR, HER2, Ki67, EGFR, CK5/6 and p53 protein markers. Targeted deep sequencing was done on genomic DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissues and their paired blood samples to screen for somatic mutations in eight genes frequently mutated in BC. A subset of samples was analyzed by exome sequencing to identify somatic mutational signatures. ResultsThe majority of cases were positive for ER or PR (168/233; 72%) and there were 21% triple negative (TN) cases, mainly of basal type. Most tumors were positive for Ki67 (189/233; 81%). In 126 sequenced cases, TP53 and PIK3CA were the most frequently mutated genes (32.5% and 21.4%, respectively), followed by AKT1 (9.5%). TP53 mutations were more frequent in HER2enriched and TN IHC subtypes, while PIK3CA/AKT1 mutations were more frequent in ER positive tumors, as expected. Interestingly, a higher proportion of G:C>T:A mutations was observed in TP53 gene in PRECAMA cases compared to TCGA and METABRIC breast cancer series (27% vs 14%).Exome-wide mutational patterns in 10 TN cases revealed alterations in signaling transduction pathways and major contributions of mutational signatures caused by altered DNA repair pathways. ConclusionsThis pilot results on PRECAMA tumors gives a preview of the molecular features of premenopausal BC in LA. Although, the overall mutation burden was as expected from data in other populations, mutational patterns observed in TP53 and exome-wide suggested possible differences in mutagenic processes giving rise to these tumors compared to other populations. Further omics analyses of a larger number of cases in the near future will allow investigating relationships between these molecular features and risk factors.

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Section: Discussionsupporting

confidence: 90%

Molecular features of premenopausal breast cancers in Latin American women: pilot results from the PRECAMA study

Olivier

Bouaoun

Villar

et al. 2018

Preprint

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“…In Mexico, Vaca-Paniagua et al (41) reported TP53 and RB1 as the most frequently mutated genes in TNBC by complete exome sequencing. Differences in the results found in our work with respect to RB1 could be attributed to the design of the study.…”

Section: Discussionmentioning

confidence: 99%

Genetic alterations of triple negative breast cancer (TNBC) in women from Northeastern Mexico

et al. 2019

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Triple negative breast cancer (TNBC) is a subtype of breast cancer of heterogeneous nature that is negative for estrogen receptor (ER), progesterone receptor (PR) and growth factor human epidermal 2 (HER2) following immunohistochemical analysis. TNBC is frequently characterized by relapse and reduced survival. To date, there is no targeted therapy for this type of cancer. Chemotherapy, radiotherapy, and surgery remain as the standard treatments options. The lack of a target therapy and the heterogeneity of TNBC highlight the need to seek new therapeutic options. In this study, fresh tissue samples of TNBC were analyzed with a panel of 48 driver genes (212 amplicons) that are likely to be therapeutic targets. We found intron variants, missense, stop gained and splicing variants in TP53, PIK3CA and FLT3 genes. Interestingly, all the analyzed samples had at least two variants in the TP53 gene, one being a drug response variant, rs1042522, found in 94% of our samples. We also found seven additional variants not previously reported in the TP53 gene, to the best of our knowledge, with probable deleterious characteristics of the tumor suppressor gene. We found four genetic variants in the PIK3CA gene, including two missense variants. The rs2491231 variant in the FLT3 gene was identified in 84% (16/19) of the samples, which not yet reported for TNBC, to the best of our knowledge. In conclusion, genetic variants in TP53 were found in all TNBC tumors, with rs1042522 being the most frequent (94% of TNBC biopsies), which had not been previously reported in TNBC. Also, we found two missense variants in the PIK3CA gene. These results justify the validation of these genetic variants in a large cohort, as well as the extensive study of their impact on the prognosis and therapy management of TBNC.

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“…It is well established that miRNAs play important roles in the initiation, development, metastasis and resistance to treatment of TNBC [31,32]. Tumor suppressive miRNAs mediate the degradation or post-transcriptional inhibition of transcripts encoding oncogenes and can target ZEB1/2, HMGB2, Bcl2 and HIF-1α, which contribute to the increased proliferation, invasion, and EMT and reduce the apoptosis of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

MiRNAs Predict the Prognosis of Patients with Triple Negative Breast Cancer: A Meta-Analysis

Liu

Zhang

et al. 2017

PLoS ONE

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PurposemiRNAs are stable and can be extracted from tissues, blood and other body fluid without degradation. miRNAs are abnormally expressed in the presence of a pathological status, including cancer. Therefore, miRNAs are ideal biomarkers for cancer diagnosis and prognosis. Patients with triple negative breast cancer (TNBC) suffer the worst prognosis, although great efforts have been made. Many studies have investigated the role of miRNAs in predicting the outcomes of TNBC patients for better adjustment of treatment. However, results were inconsistent. Thus, we performed a meta-analysis to summarize the published studies for conclusive results.MethodsEligible studies from different database were retrieved from the online databases, and we used STSTA 12.0 to analysis the prognostic role of miRNAs in triple negative breast cancer.ResultsOverall high miRNA expression indicated a worse survival with HR value of 1.78 (95% CI: 0.97–3.25). However, subtotal HRs of oncogenic miRNAs and tumor suppressive miRNAs were 2.73 (95% CI: 2.08–3.57; P<0.001) and 0.44 (95% CI: 0.21–0.90; P = 0.024), respectively, and no heterogeneity was observed within the subgroups.ConclusionsThe miRNAs showed a slightly stronger prognostic value for disease-free survival, relapse-free survival and distant metastasis-free survival compared to the overall survival of TNBC patients. Circulating miRNAs could serve as potential biomarkers for the prognosis of TNBC patients and need further investigation.

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Revealing the Molecular Portrait of Triple Negative Breast Tumors in an Understudied Population through Omics Analysis of Formalin-Fixed and Paraffin-Embedded Tissues

Cited by 18 publications

References 56 publications

Molecular features of premenopausal breast cancers in Latin American women: pilot results from the PRECAMA study

Molecular features of premenopausal breast cancers in Latin American women: pilot results from the PRECAMA study

Genetic alterations of triple negative breast cancer (TNBC) in women from Northeastern Mexico

MiRNAs Predict the Prognosis of Patients with Triple Negative Breast Cancer: A Meta-Analysis

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