Lara P Fernandez

Hospital General Universitario Gregorio Marañón, Madrid, Madrid, Spain

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Publications (15)51.26 Total impact

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    ABSTRACT: Seven genetic biomarkers previously associated with melanoma were analysed in a meta-analysis conducted in three South European populations: five red hair colour (RHC) MC1R alleles, one SLC45A2 variant (p.Phe374Leu) and one thermosensitive TYR variant (p.Arg402Gln). The study included 1639 melanoma patients and 1342 control subjects. The estimated odds ratio (OR) associated with carrying at least one MC1R RHC variant was 2.18 (95% confidence interval (CI): 1.86-2.55; p-value=1.02×10(-21)), with an additive effect for carrying two RHC variants (OR: 5.02, 95% CI: 2.88-8.94, p-value=3.91×10(-8)). The SLC45A2 variant, p.Phe374Leu, was significantly and strongly protective for melanoma in the three South European populations studied, with an overall OR value of 0.41 (95% CI: 0.33-0.50; p-value=3.50×10(-17)). The association with melanoma of the TYR variant p.Arg402Gln was also statistically significant (OR: 1.50; 95% CI: 1.11-2.04; p-value=0.0089). Adjustment for all clinical potential confounders showed that melanoma risks attributable to MC1R and SLC45A2 variants strongly persisted (OR: 2.01 95% CI: 1.49-2.72 and OR: 0.50, 95% CI: 0.31-0.80, respectively), while the association of TYR p.Arg402Gln was no longer significant. In addition, stratification of clinical melanoma risk factors showed that the risk of melanoma was strong in those individuals who did not have clinical risk factors. In conclusion, our results show without ambiguity that in South European populations, MC1R RHC and SCL45A2 p.Phe374Leu variants are strong melanoma risk predictors, notably in those individuals who would not be identified as high risk based on their phenotypes or exposures alone. The use of these biomarkers in clinical practice could be promising and warrants further discussion.
    European journal of cancer (Oxford, England: 1990) 03/2012; 48(14):2183-91. · 4.12 Impact Factor
  • European Journal of Cancer 03/2012; · 5.06 Impact Factor
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    ABSTRACT: Background The melanocortin-1 receptor (MC1R) is an important risk factor for melanoma due to its role in the production of melanin in response to sun exposure.
    Aorn. 01/2012;
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    ABSTRACT: The melanocortin-1 receptor (MC1R) is an important risk factor for melanoma due to its role in the production of melanin in response to sun exposure. To analyze the phenotypic and histologic characteristics of cutaneous melanoma in patients carrying mutations in MC1R and assess the influence of sun exposure on the occurrence of melanoma. A total of 224 patients with a diagnosis of melanoma seen in the Department of Dermatology at Hospital General Universitario Gregorio Marañón in Madrid, Spain between September 2004 and December 2009 were included in the study. The genomic sequence of MC1R was analyzed by polymerase chain reaction. At least one of the following MC1R variants was present in 58% of the patients: V60L, V92M, I155T, R160W, D294H, and R163Q. Carriers of those variants had a history of sunburn (P=.018) and melanomas located on areas with intermittent sun exposure (P=.019), and the majority had a diagnosis of superficial spreading melanoma. These associations were especially significant in patients with the R160W and D294H variants. Carriers of R160W also had melanomas associated with melanocytic nevi (P=.028). The results of our study suggest that there may be a relationship between the expression of certain MC1R variants and sun exposure, history of sunburn, and skin type. They also indicate a higher frequency of superficial spreading melanomas and melanomas associated with melanocytic nevi in patients carrying certain mutations in MC1R.
    Actas Dermo-Sifiliográficas 01/2012; 103(1):44-50.
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    ABSTRACT: The melanocortin-1 receptor (MC1R) is an important risk factor for melanoma due to its role in the production of melanin in response to sun exposure. To analyze the phenotypic and histologic characteristics of cutaneous melanoma in patients carrying mutations in MC1R and assess the influence of sun exposure on the occurrence of melanoma. A total of 224 patients with a diagnosis of melanoma seen in the Department of Dermatology at Hospital General Universitario Gregorio Marañón in Madrid, Spain between September 2004 and December 2009 were included in the study. The genomic sequence of MC1R was analyzed by polymerase chain reaction. At least one of the following MC1R variants was present in 58% of the patients: V60L, V92M, I155T, R160W, D294H, and R163Q. Carriers of those variants had a history of sunburn (P=.018) and melanomas located on areas with intermittent sun exposure (P=.019), and the majority had a diagnosis of superficial spreading melanoma. These associations were especially significant in patients with the R160W and D294H variants. Carriers of R160W also had melanomas associated with melanocytic nevi (P=.028). The results of our study suggest that there may be a relationship between the expression of certain MC1R variants and sun exposure, history of sunburn, and skin type. They also indicate a higher frequency of superficial spreading melanomas and melanomas associated with melanocytic nevi in patients carrying certain mutations in MC1R.
    Actas Dermo-Sifiliográficas 07/2011; 103(1):44-50.
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    ABSTRACT: Base excision repair (BER) and nucleotide excision repair (NER) pathways eliminate a wide variety of DNA damage, including UV photoproducts. The ability of each individual to repair DNA damage following different causes might explain at least in part the variability in cancer susceptibility. Moreover, inflammatory response to UV exposure may further contribute to skin carcinogenesis by oxidative stress mechanisms. Single nucleotide polymorphisms in genes encoding various DNA-repair enzymes and oxidative stress factors may be candidate low-penetrance variants with a role in susceptibility to different cancers, particularly in those with aetiologies linked to environmental exposure, such as malignant melanoma (MM). In this case-control study, 684 Spanish sporadic MM patients and 406 cancer-free control subjects were included and the role of 46 polymorphisms belonging to 16 BER and NER genes as well as 11 genes involved in oxidative stress processes were investigated. One polymorphism was identified to be individually associated with MM in the Spanish population. The variant was found in the NOS1 oxidative stress gene (rs2682826; p-value=0.01). These results suggest a putative role of oxidative stress processes in the genetic predisposition to melanoma. To the authors' knowledge, this is the largest DNA repair-related SNP study in melanoma risk conducted in the Spanish population up to now. Furthermore, it also represents a comprehensive genetic study of several oxidative stress polymorphisms tested in relation to MM susceptibility.
    European journal of cancer (Oxford, England: 1990) 06/2011; 47(17):2618-25. · 4.12 Impact Factor
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    ABSTRACT: As the incidence of Malignant Melanoma (MM) reflects an interaction between skin colour and UV exposure, variations in genes implicated in pigmentation and tanning response to UV may be associated with susceptibility to MM. In this study, 363 SNPs in 65 gene regions belonging to the pigmentation pathway have been successfully genotyped using a SNP array. Five hundred and ninety MM cases and 507 controls were analyzed in a discovery phase I. Ten candidate SNPs based on a p-value threshold of 0.01 were identified. Two of them, rs35414 (SLC45A2) and rs2069398 (SILV/CKD2), were statistically significant after conservative Bonferroni correction. The best six SNPs were further tested in an independent Spanish series (624 MM cases and 789 controls). A novel SNP located on the SLC45A2 gene (rs35414) was found to be significantly associated with melanoma in both phase I and phase II (P<0.0001). None of the other five SNPs were replicated in this second phase of the study. However, three SNPs in TYR, SILV/CDK2 and ADAMTS20 genes (rs17793678, rs2069398 and rs1510521 respectively) had an overall p-value<0.05 when considering the whole DNA collection (1214 MM cases and 1296 controls). Both the SLC45A2 and the SILV/CDK2 variants behave as protective alleles, while the TYR and ADAMTS20 variants seem to function as risk alleles. Cumulative effects were detected when these four variants were considered together. Furthermore, individuals carrying two or more mutations in MC1R, a well-known low penetrance melanoma-predisposing gene, had a decreased MM risk if concurrently bearing the SLC45A2 protective variant. To our knowledge, this is the largest study on Spanish sporadic MM cases to date.
    PLoS ONE 01/2011; 6(4):e19271. · 3.73 Impact Factor
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    ABSTRACT: The CDKN2A gene is regarded as the major familial malignant melanoma (MM) susceptibility gene. Human pigmentation is one of the main modulators of individual risk of developing MM. Therefore, the genes involved in the determination of skin colour and tanning response are potentially implicated in MM predisposition and may be useful predictors of MM risk in the general population. The human melanocortin-1 receptor gene (MC1R) plays a crucial role in pigmentation and also appears to be important in MM. The OCA2 gene has emerged as a new and significant determinant of human iris colour variation. We present a case-control study in Spanish population including 390 consecutive patients with melanoma and 254 control subjects. Sequence analysis of the entire coding region and genotyping of 5 tag-SNPs in the genomic region of MC1R was performed. We identified 27 variants, two reaching statistical significance [R160W (OR: 4.18, 95% CI: 1.24-14.04, P = 0.02) and D294H (OR: 3.10, 95% CI: 1.37-7.01, P = 0.01)] and we detected two novel non-synonymous changes: V92L and T308M. Odds ratio for carrying two functional variants was 4.25 (95% CI: 2.30-7.84, P = 3.63 x 10(-6)). Haplotypes of the entire MC1R region have been established, and we observed an enrichment of a rare European haplotype similar to African values carrying variants V92M and I155T. In addition, three potentially functional SNPs were selected in p16/CDKN2A and in the promoter region of OCA2/HERC2. Our data for CDKN2A gene did not reach statistically significant results for any of the two studied alleles. We found that the variant allele A > G of OCA2/HERC2 (rs12913832) was associated with pigmentation features: eye, hair and skin colour; P-values = 1.8 x 10(-29), 9.2 x 10(-16), 1.1 x 10(-3), respectively, validating previous results.
    Experimental Dermatology 09/2010; 19(9):836-44. · 3.58 Impact Factor
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    ABSTRACT: An abstract is unavailable. This article is available as HTML full text and PDF.
    Melanoma research 11/2009; 19(5):340-1. · 2.06 Impact Factor
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    ABSTRACT: Human pigmentation appears to be one of the main modulators of individual risk of developing malignant melanoma (MM). A large number of genes are known to be involved in rare pigmentary disorders and explain most of the variation in pigmentation phenotypes seen in human populations. This Spanish case-control study included 205 patients with melanoma and 245 control subjects. Thirty-one single nucleotide polymorphisms (SNPs) in genes that had been mainly associated with congenital pigmentation syndromes (ADTB3A, ATRN, CHS1, EDNRB, HPS, KIT, MGRN1, MITF, MLANA, MYO5A, MYO7A, OA1, OCA2, PAX3 and SOX10) were selected. We found that the variant allele of OCA2 R419Q (rs1800407) was associated with increased risk of MM (OR 1.55, 95% CI 1.04-2.31, P = 0.03). This effect on melanoma risk appeared to be stronger among individuals with solar lentigines, or at least 50 nevi. We also describe, for the first time, an association with the variant S1666C (rs2276288) in the MYO7A gene (OR 1.35; 95% CI 1.04-1.76; P = 0.03). Again, this association appeared to be stronger in several phenotypic groups such as individuals with fair skin and those with childhood sunburns. We also found that several variants in the pigmentation genes considered were associated with intermediate phenotypic characteristics. Our findings highlight the potential importance of pigmentation genes in sporadic MM susceptibility.
    Experimental Dermatology 04/2009; 18(7):634-42. · 3.58 Impact Factor
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    ABSTRACT: Vitamin D serum levels have been found to be related to sun exposure and diet, together with cell differentiation, growth control and consequently, cancer risk. Vitamin D receptor (VDR) genotypes may influence cancer risk; however, no epidemiological studies in sporadic breast cancer (BC) or malignant melanoma (MM) have been performed in a southern European population. In this study, the VDR gene has been evaluated in two epithelial cancers BC and MM. We have conducted an analysis in 549 consecutive and non-related sporadic BC cases and 556 controls, all from the Spanish population, and 283 MM cases and 245 controls. Genotyping analyses were carried out on four putatively functional SNPs within the VDR gene. An association with the minor allele A of the non-synonymous SNP rs2228570 (rs10735810, FokI, Met1Thr) was observed for BC, with an estimated odds ratio (OR) of 1.26 (95% CI = 1.02-1.57; p = 0.036). The synonymous variant rs731236 (TaqI) appeared to be associated with protection from BC (OR = 0.80, 95%CI = 0.64-0.99; p = 0.047). No statistically significant associations with MM were observed for any SNP. Nevertheless, sub-group analyses revealed an association between rs2228570 (FokI) and absence of childhood sunburns (OR = 0.65, p = 0.003), between the 3'utr SNP rs739837 (BglI) and fair skin (OR = 1.31, p = 0.048), and between the promoter SNP rs4516035 and the more aggressive tumour location in head-neck and trunk (OR = 1.54, p = 0.020). In summary, we observed associations between SNPs in the VDR gene and BC risk, and a comprehensive analysis using clinical and tumour characteristics as outcome variables has revealed potential associations with MM. These associations required confirmation in independent studies.
    BMC Cancer 01/2009; 8:385. · 3.33 Impact Factor
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    ABSTRACT: Human pigmentation appears to be one of the strongest risk factors for malignant melanoma (MM). In humans, there is a long list of genes known to be involved in rare pigmentary disorders such as albinism. These genes explain most of the variation in pigmentation phenotypes seen in human populations, and they do this by regulating the level of synthesis, chemical composition, packaging, and distribution of melanin. This Spanish case-control study included 131 consecutive melanoma patients and 245 control subjects frequency-matched for sex and age. A total of 23 SNPs in six candidate genes (ASP, OCA2, TYR, TYRP1, SILV, and SLC45A) belonging to the pigmentation pathway were genotyped. We found that the variant allele of c.1122C>G, p.Phe374Leu (NCBI dbSNP rs16891982) in SLC45A2 (membrane associated transporter previously known as MATP) was associated with protection from MM (OR, 0.41; 95% CI, 0.24-0.70; P=0.008 after adjustment for multiple testing). This association was validated by the consistent link observed with dark hair, dark skin, dark eye color, and the presence of solar lentigins and childhood sunburns. This is the first time SLC45A2 has been described as a melanoma susceptibility gene in a light-skinned population.
    Human Mutation 06/2008; 29(9):1161-7. · 5.21 Impact Factor
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    ABSTRACT: Several components of the Fanconi anaemia (FA) family of proteins allow the formation of the DNA repair complex foci formed by proteins such as BRCA1/2 and RAD51. Because the genes that participate in the DNA repair pathway have been described as low-penetrance breast cancer susceptibility genes, we postulated that variants in FA genes could also be associated with sporadic breast cancer risk. We studied seven SNPs in FANCA, FANCL and FANCD2 in a total of 897 consecutive and non-related sporadic breast cancer cases and 1033 unaffected controls from the Spanish population. We observed a statistically significant association with sporadic breast cancer for the variant rs2272125 (L1366L) located on FANCD2 (OR per allele=1.35; 95% C.I. 1.09-1.67; P=0.005). Both haplotype and diplotype analyses confirmed this association, where one haplotype and pooled diplotypes carrying it were associated with more than 4-fold risk (P=0.007 and P=0.006, respectively). Screening for potential causal variants in FANCD2 was performed, detecting one in the putative promoter region, which is located in a phylogenetically conserved motif with consensus binding sites for some transcriptional factors, suggesting a functional implication. Our data indicate that a relationship between FANCD2 and sporadic breast cancer risk may exist.
    Carcinogenesis 10/2006; 27(9):1930-7. · 5.64 Impact Factor
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    ABSTRACT: Estrogens, and to a lesser extent progesterones, influence the proliferation, differentiation and physiology of breast tissue as well as the development and progression of breast cancer. Genetic variants in the steroid hormone receptor genes ESR1 and PGR (belonging to the nuclear receptor superfamily) could therefore modify sporadic breast cancer susceptibility. Two studies have shown a protective effect associated with variants in ESR1 in 2 distinct populations. We studied 4 single nucleotide polymorphisms (SNPs) in ESR1 and 4 in PGR in 550 consecutive and unrelated sporadic Spanish breast cancer patients and 564 healthy Spanish controls. We observed a dominant protective effect for the S10S variant in ESR1, with an estimated odds ratio (OR) of 0.75 (95% CI = 0.58-0.97; p = 0.03) although functional studies did not show changes in the RNA stability. A small subset of individuals carried a haplotype combination that corroborates this protection. No other SNP considered in either gene was found to be associated with sporadic breast cancer. Our results obtained in a European population confirm the protective role of the S10S variant in ESR1, previously reported in an Asian and a European-American population.
    International Journal of Cancer 08/2006; 119(2):467-71. · 6.20 Impact Factor
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    ABSTRACT: One of the many potential uses of the HapMap project is its application to the investigation of complex disease aetiology among a wide range of populations. This study aims to assess the transferability of HapMap SNP data to the Spanish population in the context of cancer research. We have carried out a genotyping study in Spanish subjects involving 175 candidate cancer genes using an indirect gene-based approach and compared results with those for HapMap CEU subjects. Allele frequencies were very consistent between the two samples, with a high positive correlation (R) of 0.91 (P<1x10(-6)). Linkage disequilibrium patterns and block structures across each gene were also very similar, with disequilibrium coefficient (r (2)) highly correlated (R=0.95, P<1x10(-6)). We found that of the 21 genes that contained at least one block larger than 60 kb, nine (ATM, ATR, BRCA1, ERCC6, FANCC, RAD17, RAD50, RAD54B and XRCC4) belonged to the GO category "DNA repair". Haplotype frequencies per gene were also highly correlated (mean R=0.93), as was haplotype diversity (R=0.91, P<1x10(-6)). "Yin yang" haplotypes were observed for 43% of the genes analysed and 18% of those were identical to the ancestral haplotype (identified in Chimpazee). Finally, the portability of tagSNPs identified in the HapMap CEU data using pairwise r (2) thresholds of 0.8 and 0.5 was assessed by applying these to the Spanish and current HapMap data for 66 genes. In general, the HapMap tagSNPs performed very well. Our results show generally high concordance with HapMap data in allele frequencies and haplotype distributions and confirm the applicability of HapMap SNP data to the study of complex diseases among the Spanish population.
    Human Genetics 03/2006; 118(6):669-79. · 4.63 Impact Factor

Publication Stats

218 Citations
51.26 Total Impact Points

Institutions

  • 2011–2012
    • Hospital General Universitario Gregorio Marañón
      • Servicio de Dermatología
      Madrid, Madrid, Spain
    • Fundación de Investigación del Hospital Clínico Universitario de Valencia INCLIVA
      Valenza, Valencia, Spain
  • 2006–2012
    • Centro Nacional de Investigaciones Oncológicas
      • Human Cancer Genetics Programme
      Madrid, Madrid, Spain