LUCAS SANTOS DE SANTANA

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Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina

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  • article
    Evidence for a Founder Effect of SDHB Exon 1 Deletion in Brazilian Patients With Paraganglioma
    (2023) FAGUNDES, Gustavo F. C.; FREITAS-CASTRO, Felipe; SANTANA, Lucas S.; AFONSO, Ana Caroline F.; PETENUCI, Janaina; FUNARI, Mariana F. A.; GUIMARAES, Augusto G.; LEDESMA, Felipe L.; PEREIRA, Maria Adelaide A.; VICTOR, Carolina R.; FERRARI, Marcela S. M.; COELHO, Fernando M. A.; SROUGI, Victor; TANNO, Fabio Y.; CHAMBO, Jose L.; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; V, Maria Candida B. Fragoso; HOFF, Ana O.; ALMEIDA, Madson Q.
    Context Limited information is available concerning the genetic spectrum of pheochromocytoma and paraganglioma (PPGL) patients in South America. Germline SDHB large deletions are very rare worldwide, but most of the individuals harboring the SDHB exon 1 deletion originated from the Iberian Peninsula. Objective Our aim was to investigate the spectrum of SDHB genetic defects in a large cohort of Brazilian patients with PPGLs. Methods Genetic investigation of 155 index PPGL patients was performed by Sanger DNA sequencing, multiplex ligation-dependent probe amplification, and/or target next-generation sequencing panel. Common ancestrality was investigated by microsatellite genotyping with haplotype reconstruction, and analysis of deletion breakpoint. Results Among 155 index patients, heterozygous germline SDHB pathogenic or likely pathogenic variants were identified in 22 cases (14.2%). The heterozygous SDHB exon 1 complete deletion was the most frequent genetic defect in SDHB, identified in 8 out of 22 (36%) of patients. Haplotype analysis of 5 SDHB flanking microsatellite markers demonstrated a significant difference in haplotype frequencies in a case-control permutation test (P = 0.03). More precisely, 3 closer/informative microsatellites were shared by 6 out of 8 apparently unrelated cases (75%) (SDHB-GATA29A05-D1S2826-D1S2644 | SDHB-186-130-213), which was observed in only 1 chromosome (1/42) without SDHB exon 1 deletion (X-2 = 29.43; P < 0.001). Moreover, all cases with SDHB exon 1 deletion had the same gene breakpoint pattern of a 15 678 bp deletion previously described in the Iberian Peninsula, indicating a common origin. Conclusion The germline heterozygous SDHB exon 1 deletion was the most frequent genetic defect in the Brazilian PPGL cohort. Our findings demonstrated a founder effect for the SDHB exon 1 deletion in Brazilian patients with paragangliomas.
  • article 1 Citação(ões) na Scopus
    The performance of the MODY calculator in a non-Caucasian, mixed-race population diagnosed with diabetes mellitus before 35 years of age
    (2023) SANTOMAURO, Augusto Cezar; MAGALHAES, aurea Luiza Fernandes; MOTTA, Flavia Tedesco; SANTANA, Lucas Santos de; FRANCO, Pedro Campos; FREITAS, Silvia Maria de; SANCHEZ, Jeniffer Johana Duarte; COSTA-RIQUETTO, Aline Dantas; TELES, Milena G. G.
    BackgroundA maturity-onset diabetes of the young (MODY) calculator has been described and validated for use in European Caucasians. This study evaluated its performance in Brazilians diagnosed with diabetes mellitus (DM) before 35 years of age.MethodsThe electronic records of 391 individuals were reviewed in 2020 at the diabetes clinic of a quaternary hospital in Sao Paulo were analyzed: 231 with type 1 DM (T1DM), 46 with type 2 (T2DM) and 114 with MODY. The MODY calculator was applied to the three groups. A receiver operating characteristic curve was calculated to obtain cut-off points for this population.ResultsThe principal differences between the MODY and the T1DM and T2DM groups were body mass index, a positive family history of diabetes and mean HbA1c level. Age at diagnosis in the MODY group was only significantly different compared to the T2DM group. Specificity and sensitivity were good for the cut-off points of 40%, 50% and 60%, with the accuracy of the model for any of these cut-off points being > 95%.ConclusionThe capacity of the calculator to identify Brazilian patients with MODY was good. Values >= 60% proved useful for selecting candidates for MODY genetic testing, with good sensitivity and specificity.
  • article 14 Citação(ões) na Scopus
    Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing
    (2018) CARVALHO, Rafael A.; URTREMARI, Betsaida; JORGE, Alexander A. L.; SANTANA, Lucas S.; QUEDAS, Elisangela P. S.; SEKIYA, Tomoko; LONGUINI, Viviane C.; MONTENEGRO, Fabio L. M.; LERARIO, Antonio M.; TOLEDO, Sergio P. A.; MARX, Stephen J.; TOLEDO, Rodrigo A.; JR, Delmar M. Lourenco
    Background: Loss-of-function germline MEN1 gene mutations account for 75-95% of patients with multiple endocrine neoplasia type 1 (MEN1). It has been postulated that mutations in non-coding regions of MEN1 might occur in some of the remaining patients; however, this hypothesis has not yet been fully investigated. Objective: To sequence for the entire MEN1 including promoter, exons and introns in a large MEN1 cohort and determine the mutation profile. Methods and patients: A target next-generation sequencing (tNGS) assay comprising 7.2 kb of the full MEN1 was developed to investigate germline mutations in 76 unrelated MEN1 probands (49 familial, 27 sporadic). tNGS results were validated by Sanger sequencing (SS), and multiplex ligation-dependent probe amplification (MLPA) assay was applied when no mutations were identifiable by both tNGS and SS. Results: Germline MEN1 variants were verified in coding region and splicing sites of 57/76 patients (74%) by both tNGS and SS (100% reproducibility). Thirty-eight different pathogenic or likely pathogenic variants were identified, including 13 new and six recurrent variants. Three large deletions were detected by MLPA only. No mutation was detected in 16 patients. In untranslated, regulatory or in deep intronic MEN1 regions of the 76 MEN1 cases, no point or short indel pathogenic variants were found in untranslated, although 33 benign/likely benign and three new VUS variants were detected. Conclusions: Our study documents that point or short indel mutations in non-coding regions of MEN1 are very rare events. Also, tNGS proved to be a highly effective technology for routine genetic MEN1 testing.
  • conferenceObject
    Maxillary myxomas associated with MEN1 syndrome
    (2014) LOURENCO, D. M.; TOLEDO, R. A.; SEKIYA, T.; MORAES, M. B.; SANTANA, L. S.; TOLEDO, S. P. A.
  • article 17 Citação(ões) na Scopus
    Clinical application of ACMG-AMP guidelines in HNF1A and GCK variants in a cohort of MODY families
    (2017) SANTANA, L. S.; CAETANO, L. A.; COSTA-RIQUETTO, A. D.; QUEDAS, E. P. S.; NERY, M.; COLLETT-SOLBERG, P.; BOGUSZEWSKI, M. C. S.; VENDRAMINI, M. F.; CRISOSTOMO, L. G.; FLOH, F. O.; ZARABIA, Z. I.; KOHARA, S. K.; GUASTAPAGLIA, L.; PASSONE, C. G. B.; SEWAYBRICKER, L. E.; JORGE, A. A. L.; TELES, M. G.
    Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. GCK-MODY and HNF1A-MODY are the prevalent subtypes. Currently, there is growing concern regarding the correct interpretation of molecular genetic findings. The American College of Medical Genetics and Genomics (ACMG) updated guidelines to interpret and classify molecular variants. This study aimed to determine the prevalence of MODY (GCK/HNF1A) in a large cohort of Brazilian families, to report variants related to phenotype, and to classify them according to ACMG guidelines. One hundred and nine probands were investigated, 45% with clinical suspicion of GCK-MODY and 55% with suspicion of HNF1A-MODY. Twenty-five different variants were identified in GCK gene (30 probands61% of ositivity), and 7 variants in HNF1A (10 probands17% of positivity). Fourteen of them werenovel (12GCK/2HNF1A). ACMG guidelines were able to classify a large portion of variants as athogenic (36%GCK/86%HNF1A) and likely pathogenic (44%GCK/14%HNF1A), with 16% (5/32) as uncertain significance. This allows us to determine the pathogenicity classification more efficiently, and also reinforces the suspected associations with the phenotype among novel variants.
  • article 0 Citação(ões) na Scopus
    Clonagem molecular do oncogene EZH2 de leucemia mieloide crônica e perspectivas terapêuticas
    (2015) GASPAR, Juliana Costa; SANTANA, Lucas Santos de; SOUZA, Camila Menezes Freire de; CASEIRO, Marcos Montani; GIULIANI, Rosane Rezende de Souza; SOUZA, Cleide Barbieri de
    Chronic myeloid leukemia (CML) is a myeloproliferative neoplasia, caused in 95 % of the cases by a cytogenetic abnormality characterized by the reciprocal translocation between chromosomes 9 and 22 t(9; 22) (q34; q11), resulting in Philadelphia chromosome (Ph). Considering that CML cure is only possible with a successful bone marrow transplantation and that there are resistance cases to the tyrosine kinase inhibitor Imatinib Mesylate, prescribed in first line drug treatment; it is important to know in detail the genes and proteins that are possibly altered in CML, favoring effective therapeutic strategies, optimized diagnosis and minimal residual disease detection. Among the new therapeutic approaches to CML is gene therapy, which, depending on the target gene, can be efficient to other neoplasms treatment. In this context, the aims of this work were: to proceed the molecular cloning of a DNA fragment from EZH2 gene, potential target for gene therapy, that promotes epigenetic alteration in CML and in many neoplasms; as well as to contribute to studies related to interspecies gene transfer that have high contribution to health. For this reason, the EZH2 gene was isolated from peripheral blood genomic DNA from CML patients and cloned in prokaryotic systems. Therefore, in this study, we proceed, defined and proved the interspecies gene transfer procedures and discussed the future of biotechnology in researches and treatments, especially in CML.
  • article 17 Citação(ões) na Scopus
    Phosphodiesterase 2A and 3B variants are associated with primary aldosteronism
    (2021) RASSI-CRUZ, Marcela; MARIA, Andrea G.; FAUCZ, Fabio R.; LONDON, Edra; VILELA, Leticia A. P.; SANTANA, Lucas S.; BENEDETTI, Anna Flavia F.; GOLDBAUM, Tatiana S.; TANNO, Fabio Y.; SROUGI, Vitor; CHAMBO, Jose L.; PEREIRA, Maria Adelaide A.; CAVALCANTE, Aline C. B. S.; CARNEVALE, Francisco C.; PILAN, Bruna; BORTOLOTTO, Luiz A.; DRAGER, Luciano F.; LERARIO, Antonio M.; LATRONICO, Ana Claudia; V, Maria Candida B. Fragoso; MENDONCA, Berenice B.; ZERBINI, Maria Claudia N.; STRATAKIS, Constantine A.; ALMEIDA, Madson Q.
    Familial primary aldosteronism (PA) is rare and mostly diagnosed in early-onset hypertension (HT). However, 'sporadic' bilateral adrenal hyperplasia (BAH) is the most frequent cause of PA and remains without genetic etiology in most cases. Our aim was to investigate new genetic defects associated with BAH and PA. We performed whole-exome sequencing (paired blood and adrenal tissue) in six patients with PA caused by BAH that underwent unilateral adrenalectomy. Additionally, we conducted functional studies in adrenal hyperplastic tissue and transfected cells to confirm the pathogenicity of the identified genetic variants. Rare germline variants in phosphodiesterase 2A (PDE2A) and 3B (PDE3B) genes were identified in three patients. The PDE2A heterozygous variant (p.Ile629Val) was identified in a patient with BAH and early-onset HT at 13 years of age. Two PDE3B heterozygous variants (p.Arg217Gln and p.Gly392Val) were identified in patients with BAH and HT diagnosed at 18 and 33 years of age, respectively. A strong PDE2A staining was found in all cases of BAH in zona glomerulosa and/or micronodules (that were also positive for CYP11B2). PKA activity in frozen tissue was significantly higher in BAH from patients harboring PDE2A and PDE3B variants. PDE2A and PDE3B variants significantly reduced protein expression in mutant transfected cells compared to WT. Interestingly, PDE2A and PDE3B variants increased SGK1 and SCNN1G/ENaCg at mRNA or protein levels. In conclusion, PDE2A and PDE3B variants were associated with PA caused by BAH. These novel genetic findings expand the spectrum of gene tic etiologies of PA.
  • article 6 Citação(ões) na Scopus
    Pathogenesis of Primary Aldosteronism: Impact on Clinical Outcome
    (2022) SANTANA, Lucas S.; GUIMARAES, Augusto G.; ALMEIDA, Madson Q.
    Primary aldosteronism (PA) is the most common form of secondary arterial hypertension, with a prevalence of approximately 20% in patients with resistant hypertension. In the last decade, somatic pathogenic variants in KCNJ5, CACNA1D, ATP1A1 and ATP2B3 genes, which are involved in maintaining intracellular ionic homeostasis and cell membrane potential, were described in aldosterone-producing adenomas (aldosteronomas). All variants in these genes lead to the activation of calcium signaling, the major trigger for aldosterone production. Genetic causes of familial hyperaldosteronism have been expanded through the report of germline pathogenic variants in KCNJ5, CACNA1H and CLCN2 genes. Moreover, PDE2A and PDE3B variants were associated with bilateral PA and increased the spectrum of genetic etiologies of PA. Of great importance, the genetic investigation of adrenal lesions guided by the CYP11B2 staining strongly changed the landscape of somatic genetic findings of PA. Furthermore, CYP11B2 staining allowed the better characterization of the aldosterone-producing adrenal lesions in unilateral PA. Aldosterone production may occur from multiple sources, such as solitary aldosteronoma or aldosterone-producing nodule (classical histopathology) or clusters of autonomous aldosterone-producing cells without apparent neoplasia denominated aldosterone-producing micronodules (non-classical histopathology). Interestingly, KCNJ5 mutational status and classical histopathology of unilateral PA (aldosteronoma) have emerged as relevant predictors of clinical and biochemical outcome, respectively. In this review, we summarize the most recent advances in the pathogenesis of PA and discuss their impact on clinical outcome.
  • article 22 Citação(ões) na Scopus
    PDX1-MODY and dorsal pancreatic agenesis: New phenotype of a rare disease
    (2018) CAETANO, L. A.; SANTANA, L. S.; COSTA-RIQUETTO, A. D.; LERARIO, A. M.; NERY, M.; NOGUEIRA, G. F.; ORTEGA, C. D.; ROCHA, M. S.; JORGE, A. A. L.; TELES, M. G.
    Maturity-Onset Diabetes of the Young (MODY) type 4 or PDX1-MODY is a rare form of monogenic diabetes caused by heterozygous variants in PDX1. Pancreatic developmental anomalies related to PDX1 are reported only in neonatal diabetes cases. Here, we describe dorsal pancreatic agenesis in 2 patients with PDX1-MODY. The proband presented with diabetes since 14 years of age and maintained regular glycemic control with low doses of basal insulin and detectable C-peptide levels after 38 years with diabetes. A diagnosis of MODY was suspected. Targeted next-generation sequencing identified a heterozygous variant in PDX1: c.188delC/p. Pro63Argfs*60. Computed tomography revealed caudal pancreatic agenesis. Low fecal elastase indicated exocrine insufficiency. His son had impaired glucose tolerance, presented similar pancreatic agenesis, and harbored the same allelic variant. The unusual presentation in this Brazilian family enabled expansion upon a rare disease phenotype, demonstrating the possibility of detecting pancreatic malformation even in cases of PDX1-related diabetes diagnosed after the first year of life. This finding can improve the management of MODY4 patients, leading to precocious investigation of pancreatic dysgenesis and exocrine dysfunction.
  • article 9 Citação(ões) na Scopus
    Evaluation of SHOX defects in the era of next-generation sequencing
    (2019) FUNARI, Mariana F. A.; BARROS, Juliana S. de; SANTANA, Lucas S.; LERARIO, Antonio M.; FREIRE, Bruna L.; HOMMA, Thais K.; VASQUES, Gabriela A.; MENDONCA, Berenice B.; NISHI, Mirian Y.; JORGE, Alexander A. L.
    Short stature homeobox (SHOX) haploinsufficiency is a frequent cause of short stature. Despite advances in sequencing technologies, the identification of SHOX mutations continues to be performed using standard methods, including multiplex ligation-dependent probe amplification (MLPA) followed by Sanger sequencing. We designed a targeted panel of genes associated with growth impairment, including SHOX genomic and enhancer regions, to improve the resolution of next-generation sequencing for SHOX analysis. We used two software packages, CONTRA and Nexus Copy Number, in addition to visual analysis to investigate the presence of copy number variants (CNVs). We evaluated 15 patients with previously known SHOX defects, including point mutations, deletions and a duplication, and 77 patients with idiopathic short stature (ISS). The panel was able to confirm all known defects in the validation analysis. During the prospective evaluation, we identified two new partial SHOX deletions (one detected only by visual analysis), including an intragenic deletion not detected by MLPA. Additionally, we were able to determine the breakpoints in four cases. Our results show that the designed panel can be used for the molecular investigation of patients with ISS, and it may even detect CNVs in SHOX and its enhancers, which may be present in a significant fraction of patients.