Ruiz Espejo, Francisco

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Ruiz Espejo, Francisco

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Ruiz Espejo, Francisco

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Universidad de Murcia. Departamento de Bioquímica y Biología Molecular"B" e Inmunología

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Novel BRCA1 deleterious mutation (c.1918C>T) in familial breast and ovarian cancer syndrome who share a common ancestry
(Springer, 2014-03-16) Gabaldó Barrios, Xavier; Alonso-Romero, José Luis; Marín Vera, Miguel; Marín Zafra, Gema; Sánchez Henarejos, Pilar; Sánchez Bermúdez, Ana Isabel; Ruiz Espejo, Francisco; Sarabia Meseguer, María Desamparados; Medicina
Mutations in breast cancer susceptibility (BRCA) genes lead to defects in DNA repair processes resulting in elevated genome instability and predisposing to breast and ovarian cancer. We report a novel mutation (c.1918C>T) in the exon 11 of the BRCA1 gene that consists of a nonsense mutation that causes a stop codon downstream in the 640 position of the protein. The mutation was present in two Spanish unrelated families and was associated with four breast cancer cases, including two bilateral breast cancer (one of them synchronous). The median age/mean age (range) was 48.5/44.25 years (27–53). This finding led us to perform haplotype analysis in all family carriers. Four highly polymorphic microsatellite markers were used (17-3858, 17-3930, D17S855, D17S1326) to establish whether or not all these families had a common ancestor. This analysis showed that all mutation carriers of these families had a common haplotype. None of the noncarriers of the mutation or of the 24 healthy controls showed this haplotype. Therefore, the c.1918C>T mutation carriers from these two families allows us to assert that all analyzed mutation carriers share a common ancestry.
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Molecular characterization and clinical interpretation of BRCA1/BRCA2 variants in families from Murcia (south-eastern Spain) with hereditary breast and ovarian cancer: clinical–pathological features in BRCA carriers and non-carriers
(Springer, 2017-05-05) Gabaldó Barrios, Xavier; Marín Vera, Miguel; Sánchez Bermúdez, Ana Isabel; Macías Cerrolaza, José Antonio; Sánchez Henarejos, Pilar; Zafra Poves, Marta; García Hernández, María Rosario; Cuevas Tortosa, Encarna; Aliaga Baño, Ángeles; Castillo Guardiola, Verónica; Martínez Hernández, Pedro; Tovar Zapata, Isabel; Martínez Barba, Enrique; Ayala de la Peña, Francisco; Alonso-Romero, José Luis; Noguera Velasco, José Antonio; Ruiz Espejo, Francisco; Sarabia Meseguer, María Desamparados; Medicina
This is the first study performed in Murcia (south-eastern Spain) in which 592 families with hereditary breast and ovarian cancer were identified thanks to Genetic Counselling Units from this area over 6 years. Diagnostic performance was 18.1% and 194 different genetic variants were obtained. Variants with uncertain significance accounted for only 5.6% of the total number of reports, so our population has been well characterised. In BRCA1 gene, two novel variants were found (c.1859delT and c.3205C > T) and the most frequently detected mutations were c.68_69delAG, c.212 + 1G > A, c.5123C > A, c.211A > G and c.1918C > T, which together represented 56.67% of total pathogenic mutations. In BRCA2 gene, four recurrent variants were described (deletion of entire exon 2, c.9117G > A, c.3264dupT and c.3455T > G) representing 43.5% of the mutations in this gene. Mutation c.68_69delAG and deletion of entire exon 2 in BRCA1 and BRCA2 genes respectively were the most prevalent variants in our population. Regarding the genotype-phenotype relation, mutation c.212 + 1G > A appeared in an important percentage of breast and ovarian cancer cases, c.5123C > A in bilateral breast cancer and c.9117G > A in bilateral breast cancer and ovarian cancer. With respect to clinical–pathological characteristic, BRCA1/BRCA2 mutation carriers showed earlier onset age of breast tumour and higher risk of developing contra lateral breast cancer than non-informative cases. Moreover, association between either molecular subtype triple negative breast cancer or ovarian cancer and BRCA1 carriers was obtained.
Open Access
Acetyl-and butyrylcholinesterase activities decrease in human colon adenocarcinoma
(Springer, 2006-02) Montenegro Arce, María Fernanda; Ruiz Espejo, Francisco; Campoy Menéndez, Francisco Javier; Muñoz Delgado, Encarnación; Páez de la Cadena, María; Cabezas Herrera, Juan; Vidal, Cecilio J.; Bioquímica y Biología Molecular A
Apart from the hydrolysis of acetylcholine (ACh), acetyl- (AChE) and butyrylcholinesterase (BChE), through noncatalytic mechanisms, intervene in hematopoiesis, morphogenesis, and neurogenesis (Layer and Willbold, 1995; Soreq and Seidman, 2001). Cholinesterase (ChE) molecules occur as globular (G1, G2, and G4) and asymmetric (A4, A8, and A12) forms (Legay, 2000; Massoulié, 2002). The G species might display amphiphilic (GA) or hydrophilic (GH) properties (Perrier et al., 2002). The involvement of ChEs in tumorigenesis is supported by the measurement of ChE activity in tumors (García-Ayllón et al., 2001; Ruiz-Espejo et al., 2003), the amplification of ChE genes in leukemias and ovarian tumors, and the relationship between the expression of AChE and the aggressiveness of astrocytomas(Perry et al., 2002). This research was undertaken to determine whether ChE activity is altered in gut carcinomas.
Open Access
Insights into genotype-phenotype correlation in hypertrophic cardiomyopathy. Findings from 18 Spanish families with a single mutation in MYBPC3
(BMJ Publishing Group, 2010-11-23) Oliva Sandoval, María José; Monserrat, Lorenzo; Hermida Prieto, Manuel; Sabater Molina, María; García Molina, Esperanza; Ortiz, Martín; Rodríguez García, María Isabel; Núñez, Lucía; Gimeno, Juan Ramón; Castro Beiras, Alfonso; Valdés, Mariano; Ruiz Espejo, Francisco; Ciencias Sociosanitarias
Background: Mutations in the cardiac myosin-binding protein C (MYBPC3) gene are frequently found as a cause of hypertrophic cardiomyopathy (HCM). However, only a few studies have analysed genotype-phenotype correlations in small series of patients. The present study sought to determine the clinical characteristics, penetrance and prognosis of HCM with an identical mutation in MYBPC3. Methods: 154 non-related patients with HCM (aged 55±16 years, 100 (64.9%) males) were studied. 18 (11.7%) were found to have an identical mutation in the MYBPC3 gene (IVS23+1G→A). Pedigree analysis, including both clinical evaluation and genotyping, was performed. Results: 152 individuals (mean age 37±18 years, 53.3% males) from 18 families were evaluated. 65 carriers of the IVS23+1G→A mutation were identified, 61.5% of whom met HCM diagnostic criteria. Penetrance of the disease increased with age, with 50% affected at 46 years of age. Males tended to develop the disease earlier than females. 7 (15.6%) had systolic dysfunction. Compared with the rest of the HCM cohort, probands with the mutation had more hypertrophy and were younger at diagnosis. There was a trend towards a reduced survival free from sudden death (SD) (HR 1.71; 95% CI 0.98 to 2.98, p=0.059). There were 17 SD cases in 12 families with the mutation. Conclusions: The MYBPC3 IVS23+1G→A mutation is associated with middle-age onset disease and poor outcome, with a significant proportion of patients developing systolic impairment and a high SD risk profile
Open Access
Barth syndrome in adulthood: a clinical case.
(Elsevier, 2013-01) Sabater Molina, María; Guillén Navarro, Encarna; García Molina, Esperanza; Ballesta Martínez, Maria juliana; Escudero, Fuensanta; Ruiz Espejo, Francisco; Ciencias Sociosanitarias
Open Access
Desmoplakin truncations and arrhythmogenic left ventricular cardiomyopathy: characterizing a phenotype
(Oxford University Press, 2014-06-17) López Ayala-José María; Gómez-Milanés, Iván; Sánchez Muñoz, Juan José; Ruiz Espejo, Francisco; Ortíz, Martín; González-Carrillo, Josefa; López-Cuenca, David; Monserrat, Lorenzo; Valdés, Mariano; Gimeno Blanes, Juan Ramón; Medicina; Facultad de Medicina
Aims: Risk stratification for sudden death in arrhythmogenic right ventricular cardiomyopathy (ARVC) is challenging in clinical practice. We lack recommendations for the risk stratification of exclusive left-sided phenotypes. The aim of this study was to investigate genotype–phenotype correlations in patients carrying a novel DSP c.1339C>T, and to review the literature on the clinical expression and the outcomes in patients with DSP truncating mutations. Methods and results: Genetic screening of the DSP gene was performed in 47 consecutive patients with a phenotype of either an ARVC (n = 24) or an idiopathic dilated cardiomyopathy (DCM), who presented with ventricular arrhythmias or a family history of sudden death (n = 23) (aged 40 ± 19 years, 62% males). Three unrelated probands with DCM were found to be carriers of a novel mutation (c.1339C>T). Cascade family screening led to the identification of 15 relatives who are carriers. Penetrance in c.1339C>T carriers was 83%. Sustained ventricular tachycardia was the first clinical manifestation in six patients and nine patients were diagnosed with left ventricular impairment (two had overt severe disease and seven had a mild dysfunction). Cardiac magnetic resonance revealed left ventricular involvement in nine cases and biventricular disease in three patients. Extensive fibrotic patterns in six and non-compaction phenotype in five patients were the hallmark in imaging. Conclusion: DSP c.1339C>T is associated with an aggressive clinical phenotype of left-dominant arrhythmogenic cardiomyopathy and left ventricular non-compaction. Truncating mutations in desmoplakin are consistently associated with aggressive phenotypes and must be considered as a risk factor of sudden death. Since ventricular tachycardia occurs even in the absence of severe systolic dysfunction, an implantable cardioverter-defibrillator should be indicated promptly.
Open Access
Recurrent genetic variants and prioritization of variants of uncertain clinical significance associated with hereditary breast and ovarian cancer in families from the Region of Murcia
(De Gruyter, 2023-09-22) Rosado-Jiménez, Laura; Mestre-Terkemani, Younes; García-Aliaga, Ángeles; Marín-Vera, Miguel; Macías-Cerrolaza, José Antonio; García-Hernández, María Rosario; Zafra-Poves, Marta; Sánchez-Henarejos, Pilar; Ayala de la Peña, Francisco; Alonso-Romero, José Luis; Noguera Velasco, José Antonio; Ruiz Espejo, Francisco; Sarabia Meseguer, María Desamparados; Medicina
Objectives Hereditary breast and ovarian cancer (HBOC) follows an autosomal dominant inheritance pattern of cancer susceptibility genes. The risk of developing this disease is primarily associated with germline mutations in the BRCA1 and BRCA2 genes. The advent of massive genetic sequencing technologies has expanded the mutational spectrum of this hereditary syndrome, thereby increasing the number of variants of uncertain clinical significance (VUS) detected by genetic testing. Methods A prevalence study of HBOC was performed within 2,928 families from the Region of Murcia, in southeastern Spain. Genetic testing enabled the identification of recurrent pathogenic variants and founder mutations, which were mainly related to the BRCA1 and BRCA2 genes. VUS testing was performed using a prioritization algorithm designed by our working group. Results Variants c.68_69del, c.212+1G>A, and c.5123C>A were detected in 30 % of BRCA1 carriers, whereas exon 2 deletion concurrent with c.3264dupT, c.3455T>G and c.9117G>A variants were found in 30 % of BRCA2 carriers. A total of 16 VUS (15 %) were prioritized. Conclusions The genotype-phenotype correlation observed in our study is consistent with the scientific literature. Furthermore, the founder effect of c.1918C>T (BRCA1) and c.8251_8254del (ATM) was verified in the Murcian population, whereas exon 2 deletion (BRCA2) was proven to be a Spanish founder mutation. Our algorithm enabled us to prioritize potentially pathogenic VUS that required further testing to determine their clinical significance and potential role in HBOC.
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Mutational analysis of RAD51C and RAD51D genes in hereditary breast and ovarian cancer families from Murcia (southeastern Spain)
(Elsevier, 2018-02-02) Sánchez-Bermúdez, Ana Isabel; García-Aliaga, Ángeles; Marín-Vera, Miguel; Macías-Cerrolaza, José Antonio; Sánchez Henaréjos, Pilar; Guardiola-Castillo, Verónica; Ayala-de la Peña, Francisco; Alonso-Romero, José Luis; Noguera Velasco, José Antonio; Ruiz Espejo, Francisco; Sarabia Meseguer, María Desamparados; Medicina
RAD51C and RAD51D have been defined as susceptibility genes for hereditary breast and ovarian cancer syndrome in several studies. In the present study, a mutation analysis of these genes was performed on non BRCA1/2 families. RAD51C and RAD51D genes were analyzed in 141 and 77 families, respectively. The analysis included direct sequencing and multiple ligation probe analysis. The RAD51C pathogenic variant c.404G > A was identified in a breast and ovarian cancer family (0.7%), while the RAD51D pathogenic variant c.694C > T was described in an ovarian cancer family (1.3%). Moreover, three unknown clinical significance variants were detected: c.307T > G in RAD51C, and c.413A > G and c.715C > T in RAD51D. No large genomic rearrangements (LGRs) were found. RAD51D carriers suffered from premenopausal ovarian tumors. These results increase our knowledge about the RAD51C and RAD51D mutation spectrum and support the notion that these genes should be included in the gene panel testing performed on patients with hereditary breast and ovarian cancer syndrome.
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New insights into the performance of multigene panel testing: two novel nonsense variants in BRIP1 and TP53 in a young woman with breast cancer
(Elsevier, 2018-06-23) Castillo-Guardiola, Verónica; Marín-Vera, Miguel; Sánchez-Bermúdez, Ana Isabel; Alonso-Romero, José Luis; Noguera Velasco, José Antonio; Ruiz Espejo, Francisco; Sarabia Meseguer, María Desamparados; Medicina
Li-Fraumeni syndrome is an autosomal-dominant disorder caused by germline mutations in the tumour suppressor gene TP53. Here we report the case of a family whose index case was a woman diagnosed with bilateral breast cancer at the age of 18 and who had a non-informative result after BRCA1 and BRCA2 testing. After extending the study through multigene panel testing, two clinically relevant variants in the TP53 and BRIP1 genes, respectively, were found. Afterwards, the patient developed a glioblastoma. Both tumours were consistent with Li-Fraumeni syndrome. Thanks to the possibility of studying different genes related with hereditary breast and ovarian cancer, it was possible to find out the gene variant that caused the early onset cancers in the patient. Furthermore, genetic counselling was provided to the index case and her family.
Open Access
Cholinesterases are down-expressed in human colorectal carcinoma
(Springer, 2006-08-11) Montenegro Arce, María Fernanda; Ruiz Espejo, Francisco; Campoy, F. J.; Muñoz Delgado, Encarnación; Páez de la Cadena, M.; Rodríguez-Berrocal, F. J.; Vidal, C. J.; Bioquímica y Biología Molecular A
The aberrations of cholinesterase (ChE) genes and the variation of ChE activity in cancerous tissues prompted us to investigate the expression of ChEs in colorectal carcinoma. The study of 55 paired specimens of healthy (HG) and cancerous gut (CG) showed that acetylcholinesterase (AChE) activity fell by 32% and butyrylcholinesterase (BuChE) activity by 58% in CG. Abundant AChE-H, fewer AChE-T, and even fewer AChE-R and BuChE mRNAs were observed in HG, and their content was greatly diminished in CG. The high level of the AChE-H mRNA explains the abundance of AChE-H subunits in HG, which as glycosylphosphatidylinositol (GPI)-anchored amphiphilic AChE dimers (GA2 ) and monomers (GA1) account for 69% of AChE activity. The identification of AChE-T and BuChE mRNAs justifies the occurrence in gut of A12, GH4 and PRiMA-containing GA4 AChE forms, besides GH4 , GA4 and GH1 BuChE. The down-regulation of ChEs might contribute to gut carcinogenesis by increasing acetylcholine availability and overstimulating muscarinic receptors.