Carmen Maria Morales Alvarez

Scopus Publications

Validation of ITPR2, DPF3, EPAS1, and PVT1-associated SNPs as biomarkers for RCC in an independent case-control cohort
C. M. Morales-Álvarez, A. C. Jiménez-Domínguez, R. M. Rios-Pelegrina, E. Arance, F. Marín-Benesiu, et al.
Frontiers in Medicine, 2026
Introduction Renal cell carcinoma (RCC) is a heterogeneous malignancy influenced by genetic and environmental factors. Previous genome-wide association studies (GWAS) have identified risk single nucleotide polymorphisms (SNPs) associated with RCC susceptibility, particularly within genes such as ITPR2 , DPF3 , EPAS1 , PVT1 , and MYC . These SNPs are in regions implicated in key cellular processes like calcium signaling, chromatin remodeling, hypoxia response and oncogenesis. These pathways are highly relevant to RCC pathogenesis, although the functional significance of these genetic variations in sporadic RCC remains insufficiently characterized. Methods This study analyzed five GWAS-identified SNPs—rs1049380 and rs10771279 ( ITPR2 ), rs4903064 ( DPF3 ), rs7579899 ( EPAS1 ), and rs35252396 ( PVT1/MYC )—in a Spanish case-control cohort comprising 168 RCC patients and 259 healthy controls. Genotyping was performed from buccal swabs, and gene expression levels were assessed in 33 paired formalin-fixed paraffin-embedded (FFPE) tumor and adjacent normal kidney tissue samples. Associations between SNPs, overall survival, and expression of quantitative trait loci (eQTLs) were evaluated in relation to RCC risk and RCC progression in the case of survival curves. Results The C/C genotype of ITPR2 rs10771279 was nominally associated with a protective effect (OR: 0.41), with higher ITPR2 expression observed in healthy tissues than in RCC. The C/C genotype of DPF3 rs4903064 was nominally correlated with increased RCC risk (OR: 2.21) and higher DPF3 expression, potentially linked to hypoxia-inducible pathways. Similarly, EPAS1 rs7579899 A/A genotype was nominally associated with RCC risk (OR: 1.78) While PVT1/MYC rs35252396 did not show susceptibility relation, both genes showed upregulated expression in RCC tissue. In survival analyses, the G allele of rs1049380 ( ITPR2 ) was significantly associated with reduced 5-year survival in metastic and non-metastatic patients. Additionally, the AC genotype of rs35252396 showed nominal associations with highest risk in 5-year survival models. Conclusion This study provides independent evidence supporting the biological relevance of GWAS-identified loci in RCC. While several variants showed nominal associations with disease risk, ITPR2 rs1049380 emerged as a variant of potential prognostic relevance for five-year overall survival. Overall, these findings highlight the differential contribution of genetic variants to RCC susceptibility and progression and should be considered hypothesis-generating, warranting validation in larger, independent cohorts.
A model including CD15, ACE2 and age efficiently predicts COVID-19 severity
Sergio Cuenca-López, Ana Pozo-Agundo, Carmen María Morales-Álvarez, Verónica Arenas-Rodríguez, Silvia Martínez-Diz, et al.
Scientific Reports, 2025
Analyzing the role of ACE2, AR, MX1 and TMPRSS2 genetic markers for COVID-19 severity
Silvia Martinez-Diz, Carmen Maria Morales-Álvarez, Yarmila Garcia-Iglesias, Juan Miguel Guerrero-González, Catalina Romero-Cachinero, et al.
Human Genomics, 2023
Background The use of molecular biomarkers for COVID-19 remains unconclusive. The application of a molecular biomarker in combination with clinical ones that could help classifying aggressive patients in first steps of the disease could help clinician and sanitary system a better management of the disease. Here we characterize the role of ACE2, AR, MX1, ERG, ETV5 and TMPRSS2 for trying a better classification of COVID-19 through knowledge of the disease mechanisms. Methods A total of 329 blood samples were genotyped in ACE2, MX1 and TMPRSS2. RNA analyses were also performed from 258 available samples using quantitative polymerase chain reaction for genes: ERG, ETV5, AR, MX1, ACE2, and TMPRSS2. Moreover, in silico analysis variant effect predictor, ClinVar, IPA, DAVID, GTEx, STRING and miRDB database was also performed. Clinical and demographic data were recruited from all participants following WHO classification criteria. Results We confirm the use of ferritin (p < 0.001), D-dimer (p < 0.010), CRP (p < 0.001) and LDH (p < 0.001) as markers for distinguishing mild and severe cohorts. Expression studies showed that MX1 and AR are significantly higher expressed in mild vs severe patients (p < 0.05). ACE2 and TMPRSS2 are involved in the same molecular process of membrane fusion (p = 4.4 × 10–3), acting as proteases (p = 0.047). Conclusions In addition to the key role of TMPSRSS2, we reported for the first time that higher expression levels of AR are related with a decreased risk of severe COVID-19 disease in females. Moreover, functional analysis demonstrates that ACE2, MX1 and TMPRSS2 are relevant markers in this disease. Graphical abstract
Development of stromal differentiation patterns in heterotypical models of artificial corneas generated by tissue engineering
Cristina Blanco-Elices, Carmen Morales-Álvarez, Jesús Chato-Astrain, Carmen González-Gallardo, Paula Ávila-Fernández, et al.
Frontiers in Bioengineering and Biotechnology, 2023
Purpose: We carried out a histological characterization analysis of the stromal layer of human heterotypic cornea substitutes generated with extra-corneal cells to determine their putative usefulness in tissue engineering.Methods: Human bioartificial corneas were generated using nanostructured fibrin-agarose biomaterials with corneal stromal cells immersed within. To generate heterotypical corneas, umbilical cord Wharton’s jelly stem cells (HWJSC) were cultured on the surface of the stromal substitutes to obtain an epithelial-like layer. These bioartificial corneas were compared with control native human corneas and with orthotypical corneas generated with human corneal epithelial cells on top of the stromal substitute. Both the corneal stroma and the basement membrane were analyzed using histological, histochemical and immunohistochemical methods in samples kept in culture and grafted in vivo for 12 months in the rabbit cornea.Results: Our results showed that the stroma of the bioartificial corneas kept ex vivo showed very low levels of fibrillar and non-fibrillar components of the tissue extracellular matrix. However, in vivo implantation resulted in a significant increase of the contents of collagen, proteoglycans, decorin, keratocan and lumican in the corneal stroma, showing higher levels of maturation and spatial organization of these components. Heterotypical corneas grafted in vivo for 12 months showed significantly higher contents of collagen fibers, proteoglycans and keratocan. When the basement membrane was analyzed, we found that all corneas grafted in vivo showed intense PAS signal and higher contents of nidogen-1, although the levels found in human native corneas was not reached, and a rudimentary basement membrane was observed using transmission electron microscopy. At the epithelial level, HWJSC used to generate an epithelial-like layer in ex vivo corneas were mostly negative for p63, whereas orthotypical corneas and heterotypical corneas grafted in vivo were positive.Conclusion: These results support the possibility of generating bioengineered artificial corneas using non-corneal HWJSC. Although heterotypical corneas were not completely biomimetic to the native human corneas, especially ex vivo, in vivo grafted corneas demonstrated to be highly biocompatible, and the animal cornea became properly differentiated at the stroma and basement membrane compartments. These findings open the door to the future clinical use of these bioartificial corneas.
Genetic variants of antioxidant enzymes and environmental exposures as molecular biomarkers associated with the risk and aggressiveness of bladder cancer
D. Martin-Way, I. Puche-Sanz, J. Cózar, A. Zafra-Gómez, María del Carmen Gómez-Regalado, et al.
Science of the Total Environment, 2022