Publications by authors named "Leandro M Colli"

18 Publications

  • Page 1 of 1

Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident.

Science 2021 May 22;372(6543):725-729. Epub 2021 Apr 22.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20892, USA.

Effects of radiation exposure from the Chernobyl nuclear accident remain a topic of interest. We investigated germline de novo mutations (DNMs) in children born to parents employed as cleanup workers or exposed to occupational and environmental ionizing radiation after the accident. Whole-genome sequencing of 130 children (born 1987-2002) and their parents did not reveal an increase in the rates, distributions, or types of DNMs relative to the results of previous studies. We find no elevation in total DNMs, regardless of cumulative preconception gonadal paternal [mean = 365 milligrays (mGy), range = 0 to 4080 mGy] or maternal (mean = 19 mGy, range = 0 to 550 mGy) exposure to ionizing radiation. Thus, we conclude that, over this exposure range, evidence is lacking for a substantial effect on germline DNMs in humans, suggesting minimal impact from transgenerational genetic effects.
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http://dx.doi.org/10.1126/science.abg2365DOI Listing
May 2021

Relative expression of KLK5 to LEKTI is associated with aggressiveness of oral squamous cell carcinoma.

Transl Oncol 2021 Jan 28;14(1):100970. Epub 2020 Nov 28.

Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil. Electronic address:

Background: Oral squamous cell carcinoma (OSCC) remains a challenging cancer to treat despite all the advances of the last 50 years. Kallikrein 5 (KLK5) is among the serine proteases implicated in OSCC development. However, whether the activity of KLK5 promotes carcinogenesis is still controversial. Moreover, knowledge regarding the role of the KLK5 cognate inhibitor, Lympho-Epithelial Kazal-Type related Inhibitor (LEKTI), in OSCC is scarce. We have, thus, sought to investigate the importance of KLK5 and LEKTI expression in premalignant and malignant lesions of the oral cavity.

Methods: KLK5 and LEKTI protein expression was evaluated in 301 human samples, which were comprised of non-malignant and malignant lesions of the oral cavity. Moreover, a bioinformatic analysis of the overall survival rate from 517 head and neck squamous cell carcinoma (HNSCC) samples was performed. Additionally, to mimic the uncovered KLK5 to serine peptidase inhibitor (SPINK5) imbalance, the KLK5 gene was abrogated in an OSCC cell line using CRISPR-Cas9 technology. The generated cell line was then used for in vivo and in vitro carcinogenesis related experiments.

Results: LEKTI was found to be statistically downregulated in OSCCs, with increased KLK5/SPINK5 mRNA ratio being associated with a shorter overall survival (p = 0.091). Indeed, disruption of KLK5 to SPINK5 balance through the generation of KLK5 null OSCC cells led to smaller xenografted tumors and statistically decreased proliferation rates following multiple time points of BrdU treatment in vitro.

Conclusion: The association of increased enzyme/inhibitor ratio with poor prognosis indicates KLK5 to SPINK5 relative expression as an important prognostic marker in OSCC.
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http://dx.doi.org/10.1016/j.tranon.2020.100970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708696PMC
January 2021

Common variants in signaling transcription-factor-binding sites drive phenotypic variability in red blood cell traits.

Nat Genet 2020 12 23;52(12):1333-1345. Epub 2020 Nov 23.

Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Genome-wide association studies identify genomic variants associated with human traits and diseases. Most trait-associated variants are located within cell-type-specific enhancers, but the molecular mechanisms governing phenotypic variation are less well understood. Here, we show that many enhancer variants associated with red blood cell (RBC) traits map to enhancers that are co-bound by lineage-specific master transcription factors (MTFs) and signaling transcription factors (STFs) responsive to extracellular signals. The majority of enhancer variants reside on STF and not MTF motifs, perturbing DNA binding by various STFs (BMP/TGF-β-directed SMADs or WNT-induced TCFs) and affecting target gene expression. Analyses of engineered human blood cells and expression quantitative trait loci verify that disrupted STF binding leads to altered gene expression. Our results propose that the majority of the RBC-trait-associated variants that reside on transcription-factor-binding sequences fall in STF target sequences, suggesting that the phenotypic variation of RBC traits could stem from altered responsiveness to extracellular stimuli.
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http://dx.doi.org/10.1038/s41588-020-00738-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876911PMC
December 2020

Massively parallel reporter assays of melanoma risk variants identify MX2 as a gene promoting melanoma.

Nat Commun 2020 06 1;11(1):2718. Epub 2020 Jun 1.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.

Genome-wide association studies (GWAS) have identified ~20 melanoma susceptibility loci, most of which are not functionally characterized. Here we report an approach integrating massively-parallel reporter assays (MPRA) with cell-type-specific epigenome and expression quantitative trait loci (eQTL) to identify susceptibility genes/variants from multiple GWAS loci. From 832 high-LD variants, we identify 39 candidate functional variants from 14 loci displaying allelic transcriptional activity, a subset of which corroborates four colocalizing melanocyte cis-eQTL genes. Among these, we further characterize the locus encompassing the HIV-1 restriction gene, MX2 (Chr21q22.3), and validate a functional intronic variant, rs398206. rs398206 mediates the binding of the transcription factor, YY1, to increase MX2 levels, consistent with the cis-eQTL of MX2 in primary human melanocytes. Melanocyte-specific expression of human MX2 in a zebrafish model demonstrates accelerated melanoma formation in a BRAF background. Our integrative approach streamlines GWAS follow-up studies and highlights a pleiotropic function of MX2 in melanoma susceptibility.
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http://dx.doi.org/10.1038/s41467-020-16590-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264232PMC
June 2020

Detectible mosaic truncating PPM1D mutations, age and breast cancer risk.

J Hum Genet 2019 Jun 8;64(6):545-550. Epub 2019 Mar 8.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Mosaic protein truncating variants (PTVs) in the phosphatase, Mg2+/Mn2+dependent 1D (PPM1D) gene in blood-derived DNA have been associated with increased risk of breast cancer. We analyzed PPM1D PTVs in blood from 3817 breast cancer cases and 3058 controls by deep sequencing of a previously defined region in exon 6 of PPM1D. We identified 50 of 6875 (0.73%) participants having a mosaic PPM1D PTV. We observed a higher frequency of mosaic PPM1D PTVs with increasing age (P = 2.9 × 10). We did not observe an overall association between PPM1D PTVs and increased breast cancer risk (OR = 1.51, 95% CI = 0.84-2.71). Evidence for an association was observed in a subset of cases with DNA collected 1-year or more before breast cancer diagnosis (OR = 3.44, 95% CI = 1.62-7.30, P-value = 0.001); however, no significant association was observed for the larger series of cases with DNA collected post diagnosis (OR = 1.01, 95% CI = 0.51-2.01, P-value = 0.98). Our study indicates that the PPM1D PTVs are present at higher rates than previously reported and the frequency of PPM1D PTVs increases with age. We observed limited evidence for an association between mosaic PPM1D PTVs and breast cancer risk, suggesting mosaic PPM1D PTVs in the blood likely do not influence risk of breast cancer.
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http://dx.doi.org/10.1038/s10038-019-0589-1DOI Listing
June 2019

The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study.

PLoS Med 2019 01 3;16(1):e1002724. Epub 2019 Jan 3.

National Institute of Public Health, Bucharest, Romania.

Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.

Methods And Findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.

Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.
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http://dx.doi.org/10.1371/journal.pmed.1002724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317776PMC
January 2019

Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia.

J Endocrinol 2017 Nov;235(2):123-136

Department of UrologyUniversity of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

Elongation factor, RNA polymerase II, 2 (ELL2) is an RNA Pol II elongation factor with functional properties similar to ELL that can interact with the prostate tumor suppressor EAF2. In the prostate, is an androgen response gene that is upregulated in benign prostatic hyperplasia (BPH). We recently showed that ELL2 loss could enhance prostate cancer cell proliferation and migration, and that gene expression was downregulated in high Gleason score prostate cancer specimens. Here, prostate-specific deletion of ELL2 in a mouse model revealed a potential role for ELL2 as a prostate tumor suppressor -knockout mice exhibited prostatic defects including increased epithelial proliferation, vascularity and PIN lesions similar to the previously determined prostate phenotype in -knockout mice. Microarray analysis of prostates from -knockout and wild-type mice on a C57BL/6J background at age 3 months and qPCR validation at 17 months of age revealed a number of differentially expressed genes associated with proliferation, cellular motility and epithelial and neural differentiation. OncoPrint analysis identified combined downregulation or deletion in prostate adenocarcinoma cases from the Cancer Genome Atlas (TCGA) data portal. These results suggest that ELL2 and its pathway genes likely play an important role in the development and progression of prostate cancer.
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http://dx.doi.org/10.1530/JOE-17-0112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679084PMC
November 2017

Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma.

Eur Urol 2017 11 7;72(5):747-754. Epub 2017 Aug 7.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services, Bethesda, MS, USA.

Background: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.

Objective: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.

Design, Setting, And Participants: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.

Outcome Measurements And Statistical Analysis: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.

Results And Limitations: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13).

Conclusions: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.

Patient Summary: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.
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http://dx.doi.org/10.1016/j.eururo.2017.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641242PMC
November 2017

Genome-wide association study identifies multiple risk loci for renal cell carcinoma.

Nat Commun 2017 06 9;8:15724. Epub 2017 Jun 9.

Clinical Center of Serbia (KCS), Clinic of Urology, University of Belgrade-Faculty of Medicine, 11000 Belgrade, Serbia.

Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10), 3p22.1 (rs67311347, P=2.5 × 10), 3q26.2 (rs10936602, P=8.8 × 10), 8p21.3 (rs2241261, P=5.8 × 10), 10q24.33-q25.1 (rs11813268, P=3.9 × 10), 11q22.3 (rs74911261, P=2.1 × 10) and 14q24.2 (rs4903064, P=2.2 × 10). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.
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http://dx.doi.org/10.1038/ncomms15724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472706PMC
June 2017

Landscape of Combination Immunotherapy and Targeted Therapy to Improve Cancer Management.

Cancer Res 2017 07 26;77(13):3666-3671. Epub 2017 Apr 26.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Cancer treatments composed of immune checkpoint inhibitors and oncogene-targeted drugs might improve cancer management, but there has been little investigation of their combined potential as yet. To estimate the fraction of cancer cases that might benefit from such combination therapy, we conducted an exploratory study of cancer genomic datasets to determine the proportion with somatic mutation profiles amenable to either immunotherapy or targeted therapy. We surveyed 13,349 genomic profiles from public databases for cases with specific mutations targeted by current agents or a burden of exome-wide nonsynonymous mutations (NsM) that exceed a proposed threshold for response to checkpoint inhibitors. Overall, 8.9% of cases displayed profiles that could benefit from combination therapy, which corresponded to approximately 11.2% of U.S. annual incident cancer cases. Frequently targetable mutations were in , and We also noted a high burden of NsM in cases with targetable mutations in , and Our results indicate that a significant proportion of solid tumor patients are eligible for immuno-targeted combination therapy, and they suggest prioritizing specific cancers for trials of certain targeted and checkpoint inhibitor drugs. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-3338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522610PMC
July 2017

Functional characterization of the 12p12.1 renal cancer-susceptibility locus implicates BHLHE41.

Nat Commun 2016 07 7;7:12098. Epub 2016 Jul 7.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 8717 Grovemont Circle, Bethesda, Maryland 20892, USA.

Genome-wide association studies have identified multiple renal cell carcinoma (RCC) susceptibility loci. Here, we use regional imputation and bioinformatics analysis of the 12p12.1 locus to identify the single-nucleotide polymorphism (SNP) rs7132434 as a potential functional variant. Luciferase assays demonstrate allele-specific regulatory activity and, together with data from electromobility shift assays, suggest allele-specific differences at rs7132434 for AP-1 transcription factor binding. In an analysis of The Cancer Genome Atlas data, SNPs highly correlated with rs7132434 show allele-specific differences in BHLHE41 expression (trend P value=6.3 × 10(-7)). Cells overexpressing BHLHE41 produce larger mouse xenograft tumours, while RNA-seq analysis reveals that constitutively increased BHLHE41 induces expression of IL-11. We conclude that the RCC risk allele at 12p12.1 maps to rs7132434, a functional variant in an enhancer that upregulates BHLHE41 expression which, in turn, induces IL-11, a member of the IL-6 cytokine family.
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http://dx.doi.org/10.1038/ncomms12098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941055PMC
July 2016

Burden of Nonsynonymous Mutations among TCGA Cancers and Candidate Immune Checkpoint Inhibitor Responses.

Cancer Res 2016 07 18;76(13):3767-72. Epub 2016 May 18.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Immune checkpoint inhibitor treatment represents a promising approach toward treating cancer and has been shown to be effective in a subset of melanoma, non-small cell lung cancer (NSCLC), and kidney cancers. Recent studies have suggested that the number of nonsynonymous mutations (NsM) can be used to select melanoma and NSCLC patients most likely to benefit from checkpoint inhibitor treatment. It is hypothesized that a higher burden of NsM generates novel epitopes and gene products, detected by the immune system as foreign. We conducted an assessment of NsM across 7,757 tumor samples drawn from 26 cancers sequenced in the Cancer Genome Atlas (TCGA) Project to estimate the subset of cancers (both types and fractions thereof) that fit the profile suggested for melanoma and NSCLC. An additional independent set of 613 tumors drawn from 5 cancers were analyzed for replication. An analysis of the receiver operating characteristic curves of published data on checkpoint inhibitor response in melanoma and NSCLC data estimates a cutoff of 192 NsM with 74% sensitivity and 59.3% specificity to discriminate potential clinical benefit. Across the 7,757 samples of TCGA, 16.2% displayed an NsM count that exceeded the threshold of 192. It is notable that more than 30% of bladder, colon, gastric, and endometrial cancers have NsM counts above 192, which was also confirmed in melanoma and NSCLC. Our data could inform the prioritization of tumor types (and subtypes) for possible clinical trials to investigate further indications for effective use of immune checkpoint inhibitors, particularly in adult cancers. Cancer Res; 76(13); 3767-72. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-0170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930685PMC
July 2016

Regulation of aryl hydrocarbon receptor interacting protein (AIP) protein expression by MiR-34a in sporadic somatotropinomas.

PLoS One 2015 6;10(2):e0117107. Epub 2015 Feb 6.

Department of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom.

Introduction: Patients with germline AIP mutations or low AIP protein expression have large, invasive somatotroph adenomas and poor response to somatostatin analogues (SSA).

Methods: To study the mechanism of low AIP protein expression 31 sporadic somatotropinomas with low (n = 13) or high (n = 18) AIP protein expression were analyzed for expression of AIP messenger RNA (mRNA) and 11 microRNAs (miRNAs) predicted to bind the 3'UTR of AIP. Luciferase reporter assays of wild-type and deletion constructs of AIP-3'UTR were used to study the effect of the selected miRNAs in GH3 cells. Endogenous AIP protein and mRNA levels were measured after miRNA over- and underexpression in HEK293 and GH3 cells.

Results: No significant difference was observed in AIP mRNA expression between tumors with low or high AIP protein expression suggesting post-transcriptional regulation. miR-34a was highly expressed in low AIP protein samples compared high AIP protein adenomas and miR-34a levels were inversely correlated with response to SSA therapy. miR-34a inhibited the luciferase-AIP-3'UTR construct, suggesting that miR-34a binds to AIP-3'UTR. Deletion mutants of the 3 different predicted binding sites in AIP-3'UTR identified the c.*6-30 site to be involved in miR-34a's activity. miR-34a overexpression in HEK293 and GH3 cells resulted in inhibition of endogenous AIP protein expression.

Conclusion: Low AIP protein expression is associated with high miR-34a expression. miR-34a can down-regulate AIP-protein but not RNA expression in vitro. miR-34a is a negative regulator of AIP-protein expression and could be responsible for the low AIP expression observed in somatotropinomas with an invasive phenotype and resistance to SSA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0117107PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319742PMC
January 2016

Dopamine receptor subtype 2 expression profile in nonfunctioning pituitary adenomas and in vivo response to cabergoline therapy.

Clin Endocrinol (Oxf) 2015 May 8;82(5):739-46. Epub 2015 Jan 8.

Neuroendocrinology Research Center/Endocrinology Section, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Endocrinology Unit, Hospital Federal da Lagoa, Rio de Janeiro, Brazil.

Objectives: To determine the dopamine receptor subtype 2 (DR2) mRNA levels and protein expression and to evaluate the effect of adjuvant cabergoline therapy on tumour volume (TV) in patients with postoperative residual nonfunctioning pituitary adenoma (NFPA).

Methods: The mRNA expression was quantified by real-time RT-PCR (TaqMan(®)), and protein expression was evaluated by immunohistochemistry. Tumours were classified according to the percentage of immunostained cells for DR2 as scores 1 (<50% of stained cells) or 2 (≥50%). Cabergoline was started at least 6 months after surgery in nine patients with residual tumours (3 mg/week). The cabergoline effect was prospectively evaluated by magnetic resonance imaging using three-dimensional volume calculation. TV reduction >25% was considered significant.

Results: The DR2 mRNA expression was variable but was observed in 100% of the samples (N = 20). DR2 protein expression was also observed in all the tumours (N = 34). Twenty-nine tumours (85%) were classified as score 2. The median DR2 mRNA expression was higher in the tumours classified as score 2 compared with score 1 (P = 0·007). TV reduction with cabergoline therapy was observed in 67% of the patients (6/9). The median TV before and after 6 months of treatment was 1·90 cm(3) (0·61-8·74) and 1·69 cm(3) (0·36-4·20) [P = 0·02], respectively.

Conclusion: In conclusion, DR2 is expressed in all adenomas and the majority of the patients in this study displayed tumour shrinkage on cabergoline (CAB) therapy. Thus, CAB might be useful in adjuvant therapy in NFPA patients with residual tumours after surgery.
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http://dx.doi.org/10.1111/cen.12684DOI Listing
May 2015

Altered expression of noncanonical Wnt pathway genes in paediatric and adult adrenocortical tumours.

Clin Endocrinol (Oxf) 2014 Oct 19;81(4):503-10. Epub 2014 May 19.

Department of Internal Medicine, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.

Context: The role of planar cell polarity (Wnt/PCP) and calcium-dependent (Wnt/Ca) noncanonical Wnt pathways in adrenocortical tumours (ACTs) is unknown.

Objectives: To investigate the gene expression of Wnt/PCP and Wnt/Ca pathways and its association with TP53 p.R337H and CTNNB1 mutations in paediatric and adult ACTs and to correlate these findings with clinical outcome.

Patients: Expression of noncanonical Wnt-related genes was evaluated in 91 ACTs (66 children and 25 adults) by qPCR and the expression of beta-catenin, P53 and protein effectors of Wnt/Ca (NFAT) and Wnt/PCP (JNK) by immunohistochemistry. TP53 and CTNNB1 genes were sequenced.

Results: TP53 p.R337H mutation frequency was higher in children (86% vs 28%), while CTNNB1 mutation was higher in adults (32% vs 6%). Mortality was higher in adults harbouring TP53 p.R337H and in children with CTNNB1 mutations. Overexpression of WNT5A, Wnt/Ca ligand, was observed in children and adults. Overexpression of MAPK8 and underexpression of PRICKLE, Wnt/PCP mediators, were observed in paediatric but not in adult cases. Cytoplasmic/nuclear beta-catenin and P53 accumulation was observed in the majority of paediatric and adult ACTs as well as NFAT and JNK. Overexpression of MAPK8 and underexpression of PRICKLE were associated with mortality in children, while overexpression of WNT5A and underexpression of PRICKLE were associated with mortality in adults.

Conclusions: In our study, TP53 p.R337H and CTNNB1 mutations correlated with poor prognosis in adults and children, respectively. We demonstrate, for the first time, the activation of Wnt/PCP and Wnt/Ca noncanonical pathway genes, and their association with poor outcome in children and adults, suggesting their putative involvement in ACTs aggressiveness.
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http://dx.doi.org/10.1111/cen.12462DOI Listing
October 2014

Resistance to octreotide LAR in acromegalic patients with high SSTR2 expression: analysis of AIP expression.

Arq Bras Endocrinol Metabol 2012 Nov;56(8):501-6

Endocrinology Division, Clementino Fraga Filho University Hospital, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.

We present here the clinical and molecular data of two patients with acromegaly treated with octreotide LAR after non-curative surgery, and who presented different responses to therapy. Somatostatin receptor type 2 and 5 (SSTR2 and SSTR5), and aryl hydrocarbon receptor-interacting protein (AIP) expression levels were analyzed by qPCR. In both cases, high SSTR2 and low SSTR5 expression levels were detected; however, only one of the patients achieved disease control after octreotide LAR therapy. When we analyzed AIP expression levels of both cases, the patient whose disease was controlled after therapy exhibited AIP expression levels that were two times higher than the patient whose disease was still active. These two cases illustrate that, although the currently available somatostatin analogs bind preferentially to SSTR2, some patients are not responsive to therapy despite high expression of this receptor. This difference could be explained by differences in post-receptor signaling pathways, including the recently described involvement of AIP.
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http://dx.doi.org/10.1590/s0004-27302012000800007DOI Listing
November 2012

[Childhood adrenocortical tumors: from a clinical to a molecular approach].

Arq Bras Endocrinol Metabol 2011 Nov;55(8):599-606

Departamento de Pediatria, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Brasil.

Adrenocortical tumors (ACT) are more frequent during childhood, but they can appear at any age. ACTs can be classified in functioning, nonfunctioning (mainly observed in adults) and mixed. The diagnosis is based on clinical, biochemical findings and imaging. In children, in order to classify ACT as benign or malignant, tumor staging classification is recommended. Regarding molecular markers some studies should be taken into account: besides TP53 mutations, previous studies have also provided evidences of IGF2 involvement in 90% of the malignant ACT. Mutations altering exon 3 of CTNNB1 gene have been found in 6% of childhood ACTs. In addition, microRNAs can act as negative regulators of gene expression by targeting mRNA controlling cell growth, differentiation and apoptosis and have been implicated in adrenal tumorigenesis. High-throughput methods to analyze genome-wide expression have been developed over the last decade and identified a subset of tumors with good or poor prognosis. In the future, these studies can provide the basis of specific drug development, which can treat patients according to specific altered signaling pathway.
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http://dx.doi.org/10.1590/s0004-27302011000800014DOI Listing
November 2011