Analysis of Copy-Number Variations and Feline Mammary Carcinoma Survival

Granados-Soler, José Luis; Bornemann-Kolatzki, Kirsten; Beck, Julia; Brenig, Bertram; Schütz, Ekkehard; Betz, Daniela Simon; Junginger, Johannes; Hewicker‐Trautwein, M.; Escobar, Hugo Murua; Nolte, Ingo

doi:10.1038/s41598-020-57942-7

Cited by 9 publications

(15 citation statements)

References 142 publications

(247 reference statements)

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“…By multivariate survival analysis, mammary cancer progression (disease-free interval) in feline patients of the present study was independently modulated by Sox2, tumor size, ER and AR, with larger tumor size associated with poor prognosis, as frequently reported in FMCs (19)(20)(21)(49)(50)(51)(52)(53)(54)(55), AR associated with decreased probabilities of cancer progression (20), and ER expression associated with shortened DFI. This unfavorable effect of ER could seem paradoxical, as ERpositive breast cancers are associated with better outcomes than ER-negative breast cancers (56).…”

Section: Discussionsupporting

confidence: 69%

Unfavorable Prognostic Effects of the Stem Cell Pluripotency Factor Sox2 in Feline Invasive Mammary Carcinomas

et al. 2021

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Background: Sex-determining Region Y (SRY)-box transcription factor-2 (Sox2) belongs to the “Yamanaka's factors,” necessary and sufficient to convert somatic cells into pluripotent stem cells. In breast cancers, Sox2 expression has been associated with poor prognosis, and resistance to therapy. The aims of this study were to determine the frequency of Sox2 positivity in feline invasive mammary carcinomas (FMCs), its relationships with other clinical-pathologic variables, and with patient outcomes.Materials and Methods: This study relies on a previously described retrospective cohort of 180 FMCs, diagnosed in female cats treated by mastectomy alone, with 2-year follow-up. Sox2 (clone SP76), Estrogen Receptor alpha (ER), Progesterone Receptor (PR), Ki-67, Human Epidermal growth factor Receptor 2 (HER2), Androgen Receptor (AR), Bcl-2, Forkhead box protein A1 (FOXA1), basal markers and FoxP3-positive regulatory T cells (Tregs) were detected by automated immunohistochemistry. Sox2 expression was quantitated as an index (percentage of neoplastic cells demonstrating a positive nuclear signal). The FMCs were considered Sox2-positive at threshold >42%.Results: Sox2 was not expressed in the normal mammary gland or in mammary hyperplasia without atypia, but was occasionally detected in atypical hyperplasia. In FMCs, the mean Sox2 index was 38 ± 30%, and 79/180 FMCs (44%) were Sox2-positive. Sox2 expression was associated with older age at diagnosis, lymphovascular invasion, high Ki-67 proliferation indexes, low PR and FOXA1 expression, and increased numbers of tumor-associated Tregs, but was not significantly associated with the clinical stage, histological types, and histological grade. By multivariate survival analysis, Sox2 was associated with poor cancer-specific survival (Hazard Ratio = 1.48, 95% confidence interval 1.04–2.11, p = 0.0292), independently of the pathologic tumor size, pathologic nodal stage, distant metastasis, and AR expression. A rare subgroup of FMCs characterized by an AR+Sox2–phenotype (19/180 cases, 11%) was associated with very favorable outcomes.Conclusion: Sox2 expression was associated with poor cancer-specific survival of female cats with invasive mammary carcinomas, as previously reported in human breast cancer, but was more commonly expressed in cats than reported in breast cancers. Sox2 showed complementarity with AR in FMC prognostication.

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Section: Discussionsupporting

confidence: 69%

Unfavorable Prognostic Effects of the Stem Cell Pluripotency Factor Sox2 in Feline Invasive Mammary Carcinomas

et al. 2021

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“…Somatic CNAs are typically longer than 1 Kbp (100 Kbp on average [53,54]) and like germline CNAs, include duplications (known as Copy-Number Gains or CNGs), or deletions (representing Copy-Number Losses or CNLs) [55]. Both types of somatic CNVs (CNGs and CNLs) are prominent lesion types in tumors that are characterized by extreme Chromosomal INstability (CIN) [56].…”

Section: Structural Classification Of Mutations In Cancermentioning

confidence: 99%

Non-Coding Variants in Cancer: Mechanistic Insights and Clinical Potential for Personalized Medicine

Lange

Begolli

Giakountis

2021

ncRNA

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The cancer genome is characterized by extensive variability, in the form of Single Nucleotide Polymorphisms (SNPs) or structural variations such as Copy Number Alterations (CNAs) across wider genomic areas. At the molecular level, most SNPs and/or CNAs reside in non-coding sequences, ultimately affecting the regulation of oncogenes and/or tumor-suppressors in a cancer-specific manner. Notably, inherited non-coding variants can predispose for cancer decades prior to disease onset. Furthermore, accumulation of additional non-coding driver mutations during progression of the disease, gives rise to genomic instability, acting as the driving force of neoplastic development and malignant evolution. Therefore, detection and characterization of such mutations can improve risk assessment for healthy carriers and expand the diagnostic and therapeutic toolbox for the patient. This review focuses on functional variants that reside in transcribed or not transcribed non-coding regions of the cancer genome and presents a collection of appropriate state-of-the-art methodologies to study them.

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“…and B.C) according to well‐established criteria, 25‐28 while molecular classification of the FMCs was established from the immunoexpression of ER, PR, HER‐2, Ki‐67 and cytokeratin (CK) 5 biomarkers 29 evaluated according to the protocols described in Supplementary Table 1. The inclusion criterion was based on the worse outcomes and the poorest survival rates of HER‐2 + and triple‐negative molecular subtypes, 7,29 as some of these FMCs are associated with a more genetically aberrant profile 30 . Upon histological and molecular classification, nine female cats bearing HER‐2 + ‐or triple‐negative molecular subtypes of FMCs were selected.…”

Section: Germline Variantsa Healthy Patients (N = 6) Fmc‐bearing Cats (N = 9) Start_position Gene Symbol Exon_number Wt He Ho Wt He Homentioning

confidence: 99%

Genetic variants of BRCA1 and BRCA2 genes in cats with mammary gland carcinoma

Govoni

Silva

Guerra

et al. 2021

Vet Comparative Oncology

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Mammary tumours are the first and third most incident neoplasm in women and cats, respectively. Approximately 85% of feline mammary gland tumours are malignant and aggressive, especially the triple‐negative and HER‐2+ molecular subtypes. Triple‐negative basal‐like feline mammary carcinomas (FMCs) are considered suitable models due to the clinical and morphological similarities with human basal‐like triple‐negative breast cancer (TNBC). In women, TNBC has a poor prognosis and is often associated with mutations in the tumour suppressor genes BRCA1 and BRCA2. In light of this, the aim of the present investigation was to screen somatic and germline variants of BRCA1 and BRCA2 in nine female cats bearing FMCs. Matched whole blood and FMC samples were obtained for genetic analysis. Additional tumour samples were obtained for histopathological and immunohistochemical evaluation. Genomic DNA was isolated and 27 exonic regions of BRCA1 and BRCA2 genes were amplified and screened by next‐generation sequencing. A somatic variant with high functional impact was found in exon 11 of BRCA2 at a frequency of 4.34% in one FMC‐bearing cat. Four germline variants with moderate impact were detected in three of the nine FMC‐bearing cats and were restricted to exon 9 of BRCA1. It is concluded that the germline genetic variants found in one‐third of FMC‐bearing animals might be associated with a higher risk of hereditary mammary carcinogenesis.

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Analysis of Copy-Number Variations and Feline Mammary Carcinoma Survival

Cited by 9 publications

References 142 publications

Unfavorable Prognostic Effects of the Stem Cell Pluripotency Factor Sox2 in Feline Invasive Mammary Carcinomas

Unfavorable Prognostic Effects of the Stem Cell Pluripotency Factor Sox2 in Feline Invasive Mammary Carcinomas

Non-Coding Variants in Cancer: Mechanistic Insights and Clinical Potential for Personalized Medicine

Genetic variants of BRCA1 and BRCA2 genes in cats with mammary gland carcinoma

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