Publications by authors named "Rui Manuel Reis"

166 Publications

Somatic targeted mutation profiling of colorectal cancer precursor lesions.

BMC Med Genomics 2022 Jun 28;15(1):143. Epub 2022 Jun 28.

Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Vilela, 1331, Barretos, SP, 14784-400, Brazil.

Background: Most colorectal cancers (CRC) arise from precursor lesions. This study aimed to characterize the mutation profile of colorectal cancer precursor lesions in a Brazilian population.

Methods: In total, 90 formalin-fixed paraffin-embedded colorectal precursor lesions, including 67 adenomas, 7 sessile serrated lesions, and 16 hyperplastic polyps, were analyzed by next-generation sequencing using a panel of 50 oncogenes and tumor suppressor genes. The genetic ancestry of the patients was estimated.

Results: Somatic driver mutations were identified in 66.7% of cases, including alterations in APC (32.2%), TP53 (20.0%), KRAS (18.9%), BRAF (13.3%) and EGFR (7.8%). Adenomas displayed a higher number of mutations, mainly in APC, compared to serrated polyps (73.1% vs. 47.8%, p = 0.026). Advanced adenomas had a significantly higher frequency of mutation in KRAS and a high overall mutation rate than early adenomas (92.9% vs. 59%, p = 0.006). A high degree of ancestry admixture was observed in the population studied, with a predominance of European components (mean of 73%) followed by African (mean of 11.3%). No association between genetic ancestry and type of lesions was found. The mutation profile of Brazilian colorectal precursor lesions exhibits alteration in APC, KRAS, TP53, and BRAF at different frequencies according to lesion type.

Conclusions: These results bestow the knowledge of CRC's biologic history and support the potential of these biomarkers for precursor lesions detection in CRC screening of the Brazilian population.
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http://dx.doi.org/10.1186/s12920-022-01294-wDOI Listing
June 2022

NTRK2 gene fusions are uncommon in pilocytic astrocytoma.

Mol Biol Rep 2022 Jun 17. Epub 2022 Jun 17.

Molecular Oncology Research Center, Barretos Cancer Hospital, 1331 Antenor Duarte Vilela St, 14784-400, Barretos, SP, Brazil.

Background: Pilocytic astrocytoma is the most frequent pediatric glioma. Despite its overall good prognosis, complete surgical resection is sometimes unfeasible, especially for patients with deep-seated tumors. For these patients, the identification of targetable genetic alterations such as NTRK fusions, raised as a new hope for therapy. The presence of gene fusions involving NTRK2 has been rarely reported in pilocytic astrocytoma. The aim of the present study was to investigate the frequency of NTRK2 alterations in a series of Brazilian pilocytic astrocytomas.

Methods: Sixty-nine pilocytic astrocytomas, previously characterized for BRAF and FGFR1 alterations were evaluated. The analysis of NTRK2 alterations was performed using a dual color break apart fluorescence in situ hybridization (FISH) assay.

Results: NTRK2 fusions were successfully evaluated by FISH in 62 of the 69 cases. Neither evidence of NTRK2 gene rearrangements nor NTRK2 copy number alterations were found.

Conclusions: NTRK2 alterations are uncommon genetic events in pilocytic astrocytomas, regardless of patients' clinicopathological and molecular features.
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http://dx.doi.org/10.1007/s11033-022-07567-yDOI Listing
June 2022

African genetic ancestry is associated with lower frequency of PNPLA3 G allele in non-alcoholic fatty liver in an admixed population.

Ann Hepatol 2022 Jun 13:100728. Epub 2022 Jun 13.

University of Sao Paulo, School of Medicine, Sao Paulo-SP, Brazil; Laboratory of Clinical and Experimental Gastroenterology (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil.

Introduction And Objectives: PNPLA3(rs738409) and TM6SF2(rs58542926) variants, interindividual and ethnic differences may be risk factors for non-alcoholic fatty liver disease (NAFLD). The PNPLA3 G allele is associated with worse NAFLD evolution in Hispanics and Caucasians. TM6SF2 is associated with hypertriglyceridemia, NAFLD, and cardiovascular disease. We aimed to evaluate the association between genetic ancestry by Ancestry Informative Markers (AIM), PNPLA3 and TM6SF2 polymorphisms in patients with biopsy-proven NAFLD in an admixed population.

Methods: We included adults with biopsy-proven NAFLD and excluded patients with the presence of other chronic liver disease, alcohol intake >100g/week, HIV, drug-induced fatty liver disease, or liver transplantation. We classified NAFLD using the Non-Alcoholic Steatohepatitis Clinical Research Network (NASH-CRN) histological scoring system. The PNPLA3 (rs738409 c.444C>G) and TM6SF2 (rs58542926 c.449C>T) genotyping were performed by RT-PCR. Genetic ancestry was determined using 46 insertion-deletion AIM; α<0.05 was considered significant.

Results: 248 patients with NAFLD were enrolled [34 with simple steatosis (NAFL); 214 with NASH]. Overall, we detected a greater European ancestry contribution (0.645), followed by African (0.173), Amerindian (0.095), and East Asian (0.087) ancestry contribution, without differences between NAFL and NASH patients. However, we found a higher African genetic ancestry contribution among patients with NAFL who had the C/C PNPLA3 genotype than those with the G allele (0.216 ± 0.205 versus 0.105 ± 0.101, respectively; p=0.047). Ancestry contributions did not differ among TM6SF2 genotypes.

Conclusion: Among NAFL patients, greater African genetic ancestry was associated to a lower frequency of the PNPLA3 G allele, demonstrating a possible NASH ancestry-related protective factor.
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http://dx.doi.org/10.1016/j.aohep.2022.100728DOI Listing
June 2022

Does a Multiple Myeloma Polygenic Risk Score Predict Overall Survival of Myeloma Patients?

Cancer Epidemiol Biomarkers Prev 2022 Jun 14. Epub 2022 Jun 14.

Department of Haematology, Rigshospitalet, Copenhagen University, Copenhagen, Denmark, Denmark.

Background: Genome-wide association studies (GWAS) of multiple myeloma (MM) in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g. colorectum and melanoma), risk loci have also been associated with patient survival.

Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with MM overall survival (OS) in multiple populations of EA (IMMEnSE consortium, InterLymph consortium, CoMMpass and the German GWAS) for a total of 3748 MM cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed.

Results: SNP associations were meta-analyzed. From the meta-analysis, two MM risk SNPs were associated with OS (p<0.05), specifically POT1-AS1-rs2170352 (HR=1.37, 95% C.I.=1.09-1.73, p=0.007) and TNFRSF13B-rs4273077 (HR=1.19, 95% C.I.=1.01-1.41, p=0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant.

Conclusions: Overall, our results did not support an association between the majority of MM risk SNPs and OS.

Impact: This is the first study to investigate the association between MM PRS and OS in MM.
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http://dx.doi.org/10.1158/1055-9965.EPI-22-0043DOI Listing
June 2022

EGFL7 expression profile in IDH-wildtype glioblastomas is associated with poor patient outcome.

J Pathol Transl Med 2022 Jun 15. Epub 2022 Jun 15.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.

Background: Despite the advances in glioblastoma (GBM) treatment, the average life span of patients is 14 months. Therefore, it is urgent to identity biomarkers of prognosis, treatment response, or development of novel treatment strategies. We previously described the association of high epidermal growth factor-like domain multiple 7 (EGFL7) expression and unfavorable outcome of pilocytic astrocytoma patients. The present study aims to analyze the prognostic potential of EGFL7 in GBM isocitrate dehydrogenase (IDH)-wildtype, using immunohistochemistry and in silico approaches.

Materials And Methods: Spearman's correlation analysis of The Cancer Genome Atlas RNA sequencing data was performed. The genes strongly correlated to EGFL7 expression were submitted to enrichment gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Additionally, EGFL7 expression was associated with patient overall survival. The expression of EGFL7 was analyzed through immunohistochemistry in 74 GBM IDH-wildtype patients' samples, and was associated with clinicopathological data and overall survival.

Results: In silico analysis found 78 genes strongly correlated to EGFL7 expression. These genes were enriched in 40 biological processes and eight KEGG pathways, including angiogenesis/vasculogenesis, cell adhesion, and phosphoinositide 3-kinase-Akt, Notch, and Rap1 signaling pathways. The immunostaining showed high EGFL7 expression in 39 cases (52.7%). High immunolabelling was significantly associated with low Karnofsky Performance Status and poor overall survival. Cox analysis showed that GBMs IDH-wildtype with high EGFL7 expression presented a higher risk of death compared to low expression (hazard ratio, 1.645; 95% confidence interval, 1.021 to 2.650; p = .041).

Conclusion: This study gives insights regarding the genes that are correlated with EGFL7, as well as biological processes and signaling pathways, which should be further investigated in order to elucidate their role in glioblastoma biology.
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http://dx.doi.org/10.4132/jptm.2022.04.22DOI Listing
June 2022

Genomic instability evaluation by BMCyt and telomere length in Brazilian family farmers exposed to pesticides.

Mutat Res Genet Toxicol Environ Mutagen 2022 Jun 9;878:503479. Epub 2022 Mar 9.

Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil; University of Cuiabá, Mato Grosso, Brazil. Electronic address:

Brazil is one of the largest consumers of pesticides in the world. This high consumption has resulted in higher potential health risk to agricultural farm workers due to occupational exposure. Hence, the aim of this study is to evaluate genomic instability, using Buccal Micronucleus Cytome (BMCyt) and telomere length (TL) measurement as biomarkers of occupational exposure to pesticides in rural workers living in the State of São Paulo, Brazil. Genomic instability was evaluated in 81 pesticide-exposed farm workers (69 males and 12 females) with a mean age of 49.16 ± 10.06 years and a mean time job of 30.00 ± 14.00 years,81 non-exposed individuals (62 males and 15 females) with a mean age of 47.87 ± 10.66 years. BMCyt results showed significantly higher levels of cell damage (micronuclei and binucleated cells) and cell death (karyorrhectic and condensed chromatin cells) in subjects exposed to pesticide when compared to those non-exposed (p < 0.05). Although our results did not show significant differences in TL among exposed and non-exposed groups, effects in TL due to pesticide exposure was found in a multivariable linear regression model when we stratified the groups by age (≤ 49 years and ≥ 50 years old; β = 11.21, p = 0.006). In addition, TL reduction on was identified in relation to an increase in cigarette pack consumption (β = -0.633, p = 0.045). Furthermore, exposure to specific pesticides presented different effects in TL. Cypermethrin exposure resulted in a reduction in TL (β = -18.039, p = 0.018), while abamectin exposure led to an increase in TL (β = 23.990, p = 0.007). Thus, our findings substantiate genomic instability due to pesticides exposure.
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http://dx.doi.org/10.1016/j.mrgentox.2022.503479DOI Listing
June 2022

The Antitumoral/Antimetastatic Action of the Flavonoid Brachydin A in Metastatic Prostate Tumor Spheroids In Vitro Is Mediated by (Parthanatos) PARP-Related Cell Death.

Pharmaceutics 2022 Apr 29;14(5). Epub 2022 Apr 29.

Department of Clinical Analysis, Toxicology, and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-903, Brazil.

Metastatic prostate cancer (mPCa) is resistant to several chemotherapeutic agents. Brachydin A (BrA), a glycosylated flavonoid extracted from , displays a remarkable antitumoral effect against in vitro mPCa cells cultured as bidimensional (2D) monolayers. Considering that three-dimensional (3D) cell cultures provide a more accurate response to chemotherapeutic agents, this study investigated the antiproliferative/antimetastatic effects of BrA and the molecular mechanisms underlying its action in mPCa spheroids (DU145) in vitro. BrA at 60-100 μM was cytotoxic, altered spheroid morphology/volume, and suppressed cell migration and tumor invasiveness. High-content analysis revealed that BrA (60-100 µM) reduced mitochondrial membrane potential and increased apoptosis and necrosis markers, indicating that it triggered cell death mechanisms. Molecular analysis showed that (i) 24-h treatment with BrA (80-100 µM) increased the protein levels of DNA disruption markers (cleaved-PARP and p-γ-H2AX) as well as decreased the protein levels of anti/pro-apoptotic (BCL-2, BAD, and RIP3K) and cell survival markers (p-AKT1 and p-44/42 MAPK); (ii) 72-h treatment with BrA increased the protein levels of effector caspases (CASP3, CASP7, and CASP8) and inflammation markers (NF-kB and TNF-α). Altogether, our results suggest that PARP-mediated cell death (parthanatos) is a potential mechanism of action. In conclusion, BrA confirms its potential as a candidate drug for preclinical studies against mPCa.
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http://dx.doi.org/10.3390/pharmaceutics14050963DOI Listing
April 2022

Association of microsatellite instability (MSI) status with the 5-year outcome and genetic ancestry in a large Brazilian cohort of colorectal cancer.

Eur J Hum Genet 2022 Apr 26. Epub 2022 Apr 26.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.

Colorectal cancer (CRC) has a high incidence and mortality worldwide. Microsatellite instability (MSI) is crucial in CRC, with distinct molecular and clinicopathological features in patients. Nowadays, it is a predictive marker for immunotherapy. We proposed to evaluate the 5-year outcome of MSI status in 1002 Brazilian CRC, and associate it with genetic ancestry, molecular and clinicopathological features. MSI evaluation was performed using molecular markers. MSI+ tumors were analyzed for alterations in 23 MSI-targeted genes. Genetic ancestry was evaluated using an Ancestry-Informative markers panel. MSI status was analyzed in relation to CRC specific survival and other clinical and genetic variables. MSI+ status was observed in 10.5% of cases. MSI+ status was significantly associated with the anatomic site right colon, mucinous histological type, clinical stage II, histological grade III/undifferentiated, no recurrence of disease, and live cases without cancer. No association of MSI status with genetic ancestry components was observed. MSI-targeted genes analyses showed the most frequently altered genes: ATM, EGFR, MRE11, ROCK1, and TGFBRII. There was a statistically significant difference in cancer-specific survival between cases according to MSI status. This study constitutes the most comprehensive analyses of the MSI impact on the Brazilian CRC. MSI+ frequency in Brazilian CRC agreed with the literature and was associated with several clinicopathological features related with less aggressive tumors, independently of their genetic ancestry.
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http://dx.doi.org/10.1038/s41431-022-01104-yDOI Listing
April 2022

Absolute telomere length in peripheral blood lymphocytes of workers exposed to construction environment.

Int J Environ Health Res 2022 Apr 24:1-9. Epub 2022 Apr 24.

Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil.

Construction environment is composed of various substances classified as carcinogens. Thus, workers exposed in this environment can be susceptible to genomic instability that can be evaluated by absolute telomere length (TL). In this work, we evaluated TL in construction workers compared to a non-exposed group performed by qPCR assay. The TL was evaluated in 59 men exposed to the construction environment (10 years of exposure) and 49 men non-exposed. Our data showed that individuals exposed to the construction environment exhibited a significantly lower TL in relation to non-exposed group ( = 0.009). Also, on the multiple linear regression model, we observed that TL was significantly influenced by the construction environment exposure ( ≤ 0.001). Additionally, the arsenic exposure is associated to a shortening telomere ( ≤ 0.001), and the lead exposure caused an increase in TL ( ≤ 0.001). Thus, our findings suggest a modulation in TL by construction environment exposure, mainly by arsenic and lead exposure.
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http://dx.doi.org/10.1080/09603123.2022.2066069DOI Listing
April 2022

MicroRNA Interrelated Epithelial Mesenchymal Transition (EMT) in Glioblastoma.

Genes (Basel) 2022 01 27;13(2). Epub 2022 Jan 27.

SAMRC Precision Oncology Research Unit (PORU), Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa.

MicroRNAs (miRNA) are small non-coding RNAs that are 20-23 nucleotides in length, functioning as regulators of oncogenes or tumor suppressor genes. They are molecular modulators that regulate gene expression by suppressing gene translation through gene silencing/degradation, or by promoting translation of messenger RNA (mRNA) into proteins. Circulating miRNAs have attracted attention as possible prognostic markers of cancer, which could aid in the early detection of the disease. Epithelial to mesenchymal transition (EMT) has been implicated in tumorigenic processes, primarily by promoting tumor invasiveness and metastatic activity; this is a process that could be manipulated to halt or prevent brain metastasis. Studies show that miRNAs influence the function of EMT in glioblastomas. Thus, miRNA-related EMT can be exploited as a potential therapeutic target in glioblastomas. This review points out the interrelation between miRNA and EMT signatures, and how they can be used as reliable molecular signatures for diagnostic purposes or targeted therapy in glioblastomas.
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http://dx.doi.org/10.3390/genes13020244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8872331PMC
January 2022

New insights on familial colorectal cancer type X syndrome.

Sci Rep 2022 02 18;12(1):2846. Epub 2022 Feb 18.

Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela Street, 1331, Barretos, São Paulo, CEP 14784-400, Brazil.

Familial colorectal cancer type X (FCCTX) is a heterogeneous colorectal cancer predisposition syndrome that, although displays a cancer pattern similar to Lynch syndrome, is mismatch repair proficient and does not exhibit microsatellite instability. Besides, its genetic etiology remains to be elucidated. In this study we performed germline exome sequencing of 39 cancer-affected patients from 34 families at risk for FCCTX. Variant classification followed the American College of Medical Genetics and Genomics (ACMG) guidelines. Pathogenic/likely pathogenic variants were identified in 17.65% of the families. Rare and potentially pathogenic alterations were identified in known hereditary cancer genes (CHEK2), in putative FCCTX candidate genes (OGG1 and FAN1) and in other cancer-related genes such as ATR, ASXL1, PARK2, SLX4 and TREX1. This study provides novel important clues that can contribute to the understanding of FCCTX genetic basis.
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http://dx.doi.org/10.1038/s41598-022-06782-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8857274PMC
February 2022

Single nCounter assay for prediction of MYCN amplification and molecular classification of medulloblastomas: a multicentric study.

J Neurooncol 2022 Mar 15;157(1):27-35. Epub 2022 Feb 15.

Molecular Oncology Research Center Dr. Paulo Prata, Barretos Cancer Hospital, Barretos, Brazil.

Purpose: Medulloblastoma is the most frequent pediatric malignant brain tumor, and is divided into four main subgroups: WNT, SHH, group 3, and group 4. MYCN amplification is an important medulloblastoma prognostic biomarker. We aimed to molecular classify and predict MYCN amplification in a single assay.

Methods: It was included 209 medulloblastomas from 205 patients (Brazil, Argentina, and Portugal), divided into training (n = 50) and validation (n = 159) sets. A nCounter assay was carried out using a custom panel for molecular classification, with additional genes, including MYCN. nSolver 4.0 software and the R environment were used for profiling and MYCN mRNA analysis. MYCN amplification by FISH was performed in 64 cases.

Results: The 205 medulloblastomas were classified in SHH (44.9%), WNT (15.6%), group 3 (18.1%) and group 4 (21.4%). In the training set, MYCN amplification was detected in three SHH medulloblastomas by FISH, which showed significantly higher MYCN mRNA counts than non-FISH amplified cases, and a cutoff for MYCN amplification was established ([Formula: see text] + 4σ = 11,124.3). Applying this threshold value in the validation set, we identified MYCN mRNA counts above the cutoff in three cases, which were FISH validated.

Conclusion: We successfully stratified medulloblastoma molecular subgroups and predicted MYCN amplification using a single nCounter assay without the requirement of additional biological tissue, costs, or bench time.
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http://dx.doi.org/10.1007/s11060-022-03965-1DOI Listing
March 2022

Challenges of Implementing Lung Cancer Screening in a Developing Country: Results of the Second Brazilian Early Lung Cancer Screening Trial (BRELT2).

JCO Glob Oncol 2022 01;8:e2100257

Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.

Purpose: This paper aims to present the results of a series of several Brazilian institutions that have been carrying out lung cancer screening (LCS).

Materials And Methods: This is a retrospective, cohort study, with follow-up of individuals of both sexes, with a heavy smoking history, who participated in LCS programs between December 2013 and January 2021 in six Brazilian institutions located in the states of São Paulo, Rio Grande do Sul, and Bahia.

Results: Three thousand four hundred seventy individuals were included, of which 59.8% were male (n = 2,074) and 50.6% were current smokers (n = 1,758), with 60.7 years (standard deviation 8.8 years). Lung-RADS 4 was observed in 233 (6.7%) patients. Biopsy was indicated by minimally invasive methods in 122 patients (3.5%). Two patients who demonstrated false-negative biopsies and lung cancer were diagnosed in follow-up. Diagnosis of lung cancer was observed in 74 patients (prevalence rate of 2.1%), with 52 (70.3%) in stage I or II. Granulomatous disease was found in 20 patients. There were no statistical differences in the incidence of lung cancer, biopsies, granulomatous disease, and Lung-RADS 4 nodules between public and private patients.

Conclusion: There are still many challenges and obstacles in the implementation of LCS in developing countries; however, our multi-institutional data were possible to obtain satisfactory results in these scenarios and to achieve similar results to the main international studies. Granulomatous diseases did not increase the number of lung biopsies. The authors hope that it could stimulate the creation of organized screening programs in regions still endemic for tuberculosis and other granulomatous diseases.
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http://dx.doi.org/10.1200/GO.21.00257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8789215PMC
January 2022

Accuracy and Clinical Relevance of Intra-Tumoral Detection in Formalin-Fixed Paraffin-Embedded (FFPE) Tissue by Droplet Digital PCR (ddPCR) in Colorectal Cancer.

Diagnostics (Basel) 2022 Jan 5;12(1). Epub 2022 Jan 5.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784400, Brazil.

The use of droplet digital PCR (ddPCR) to identify and quantify low-abundance targets is a significant advantage for accurately detecting potentially oncogenic bacteria. () is implicated in colorectal cancer (CRC) tumorigenesis and is becoming an important prognostic biomarker. We evaluated the detection accuracy and clinical relevance of Fn DNA by ddPCR in a molecularly characterized, formalin-fixed, paraffin-embedded (FFPE) CRC cohort previously analyzed by qPCR for levels. Following a ddPCR assay optimization and an analytical evaluation, DNA were measured in 139 CRC FFPE cases. The measures of accuracy for status compared to the prior results generated by qPCR and the association with clinicopathological and molecular patients' features were also evaluated. The ddPCR-based assay was sensitive and specific to positive controls. DNA were detected in 20.1% of cases and further classified as -high and -low/negative, according to the median amount of DNA that were detected in all cases and associated with the patient's worst prognosis. There was a low agreement between the status determined by ddPCR and qPCR (Cohen's Kappa = 0.210). Our findings show that ddPCR can detect and quantify in FFPE tumor tissues and highlights its clinical relevance in detection in a routine CRC setting.
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http://dx.doi.org/10.3390/diagnostics12010114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8775036PMC
January 2022

A Unique Case Report of Infant-Type Hemispheric Glioma (Gliosarcoma Subtype) with TPR-NTRK1 Fusion Treated with Larotrectinib.

Pathobiology 2022 14;89(3):178-185. Epub 2022 Jan 14.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.

Herein, we present a rare case of a nine-month-old boy diagnosed with infant-type hemispheric glioma (gliosarcoma subtype) at the left frontal lobe. Following subtotal resection, the patient started chemotherapy with the BABY POG protocol. We describe the clinical diagnosis, histological characteristics, radiological features, molecular aspects, and management of this tumor. A comprehensive molecular analysis on the tumor tissue showed a TPR-NTRK1 gene fusion. The patient was treated with a TRK inhibitor, larotrectinib, and exhibited a stable disease with residual lesion following 8 months of target therapy. The present study is the first report of an infantile gliosarcoma harboring NTRK1 rearrangement treated with larotrectinib.
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http://dx.doi.org/10.1159/000521253DOI Listing
May 2022

Accounting for EGFR Mutations in Epidemiologic Analyses of Non-Small Cell Lung Cancers: Examples Based on the International Lung Cancer Consortium Data.

Cancer Epidemiol Biomarkers Prev 2022 Mar;31(3):679-687

Catalan Institute of Oncology (ICO), Barcelona, Spain.

Background: Somatic EGFR mutations define a subset of non-small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches.

Methods: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status.

Results: Of 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4,231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance index of 0.75 (95% CI, 0.74-0.77) in the training and 0.77 (95% CI, 0.74-0.79) in the testing dataset. At an optimal cut-point of probability-score = 0.335, sensitivity = 69% and specificity = 72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of patients with NSCLC, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients.

Conclusions: We introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC.

Impact: The proposed method is generalizable in the common occurrence in which EGFR-status data are missing.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9063819PMC
March 2022

Information theory approaches to improve glioma diagnostic workflows in surgical neuropathology.

Brain Pathol 2022 Jan 10:e13050. Epub 2022 Jan 10.

Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

Aims: Resource-strained healthcare ecosystems often struggle with the adoption of the World Health Organization (WHO) recommendations for the classification of central nervous system (CNS) tumors. The generation of robust clinical diagnostic aids and the advancement of simple solutions to inform investment strategies in surgical neuropathology would improve patient care in these settings.

Methods: We used simple information theory calculations on a brain cancer simulation model and real-world data sets to compare contributions of clinical, histologic, immunohistochemical, and molecular information. An image noise assay was generated to compare the efficiencies of different image segmentation methods in H&E and Olig2 stained images obtained from digital slides. An auto-adjustable image analysis workflow was generated and compared with neuropathologists for p53 positivity quantification. Finally, the density of extracted features of the nuclei, p53 positivity quantification, and combined ATRX/age feature was used to generate a predictive model for 1p/19q codeletion in IDH-mutant tumors.

Results: Information theory calculations can be performed on open access platforms and provide significant insight into linear and nonlinear associations between diagnostic biomarkers. Age, p53, and ATRX status have significant information for the diagnosis of IDH-mutant tumors. The predictive models may facilitate the reduction of false-positive 1p/19q codeletion by fluorescence in situ hybridization (FISH) testing.

Conclusions: We posit that this approach provides an improvement on the cIMPACT-NOW workflow recommendations for IDH-mutant tumors and a framework for future resource and testing allocation.
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http://dx.doi.org/10.1111/bpa.13050DOI Listing
January 2022

Comprehensive Molecular Landscape of Cetuximab Resistance in Head and Neck Cancer Cell Lines.

Cells 2022 01 4;11(1). Epub 2022 Jan 4.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil.

Cetuximab is the sole anti-EGFR monoclonal antibody that is FDA approved to treat head and neck squamous cell carcinoma (HNSCC). However, no predictive biomarkers of cetuximab response are known for HNSCC. Herein, we address the molecular mechanisms underlying cetuximab resistance in an in vitro model. We established a cetuximab resistant model (FaDu), using increased cetuximab concentrations for more than eight months. The resistance and parental cells were evaluated for cell viability and functional assays. Protein expression was analyzed by Western blot and human cell surface panel by lyoplate. The mutational profile and copy number alterations (CNA) were analyzed using whole-exome sequencing (WES) and the NanoString platform. FaDu resistant clones exhibited at least two-fold higher IC compared to the parental cell line. WES showed relevant mutations in several cancer-related genes, and the comparative mRNA expression analysis showed 36 differentially expressed genes associated with EGFR tyrosine kinase inhibitors resistance, RAS, MAPK, and mTOR signaling. Importantly, we observed that overexpression of KRAS, RhoA, and CD44 was associated with cetuximab resistance. Protein analysis revealed EGFR phosphorylation inhibition and mTOR increase in resistant cells. Moreover, the resistant cell line demonstrated an aggressive phenotype with a significant increase in adhesion, the number of colonies, and migration rates. Overall, we identified several molecular alterations in the cetuximab resistant cell line that may constitute novel biomarkers of cetuximab response such as mTOR and RhoA overexpression. These findings indicate new strategies to overcome anti-EGFR resistance in HNSCC.
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http://dx.doi.org/10.3390/cells11010154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750399PMC
January 2022

A computational approach for the discovery of significant cancer genes by weighted mutation and asymmetric spreading strength in networks.

Sci Rep 2021 12 7;11(1):23551. Epub 2021 Dec 7.

University of Sao Paulo, Sao Carlos, SP, Brazil.

Identifying significantly mutated genes in cancer is essential for understanding the mechanisms of tumor initiation and progression. This task is a key challenge since large-scale genomic studies have reported an endless number of genes mutated at a shallow frequency. Towards uncovering infrequently mutated genes, gene interaction networks combined with mutation data have been explored. This work proposes Discovering Significant Cancer Genes (DiSCaGe), a computational method for discovering significant genes for cancer. DiSCaGe computes a mutation score for the genes based on the type of mutations they have. The influence received for their neighbors in the network is also considered and obtained through an asymmetric spreading strength applied to a consensus gene network. DiSCaGe produces a ranking of prioritized possible cancer genes. An experimental evaluation with six types of cancer revealed the potential of DiSCaGe for discovering known and possible novel significant cancer genes.
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http://dx.doi.org/10.1038/s41598-021-02671-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8651746PMC
December 2021

A polygenic risk score for multiple myeloma risk prediction.

Eur J Hum Genet 2022 04 30;30(4):474-479. Epub 2021 Nov 30.

Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.

There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53-4.69, p = 3.55 × 10 for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34-4.33, p = 1.62 × 10 for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population.
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http://dx.doi.org/10.1038/s41431-021-00986-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8991223PMC
April 2022

Frequency of Human Papillomavirus Detection in Chagasic Megaesophagus Associated or Not with Esophageal Squamous Cell Carcinoma.

Pathobiology 2022 12;89(1):29-37. Epub 2021 Oct 12.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.

Background: Chagasic megaesophagus (CM) as well as the presence of human papillomavirus (HPV) has been reported as etiological factors for esophageal squamous cell carcinoma (ESCC).

Objective: We assessed the prevalence of HPV DNA in a series of ESCCs associated or not with CM. Data obtained were further correlated to the pathological and clinical data of affected individuals.

Methods: A retrospective study was performed on 92 formalin-fixed and paraffin-embedded tissues collected from patients referred to 3 different hospitals in São Paulo, Brazil: Barretos Cancer Hospital, Barretos, São Paulo; Federal University of Triângulo Mineiro, Uberaba, Minas Gerais; and São Paulo State University, Botucatu, São Paulo. Cases were divided into 3 groups: (i) 24 patients with CM associated with ESCC (CM/ESCC); (ii) 37 patients with ESCC without CM (ESCC); and (iii) 31 patients with CM without ESCC (CM). Detection of HPV DNA was assessed in all samples by a genotyping assay combining multiplex polymerase chain reaction and bead-based Luminex technology.

Results: We identified a high prevalence of high-risk HPV in patients in the CM group (12/31, 38.8%) and CM/ESCC (8/24, 33.3%), compared to individuals in the ESCC group (6/37, 16.3%). The individuals in the groups with cancer (ESCC and CM/ESCC) had a higher frequency of HPV-16 (4/9, 44.5% and 2/8, 25.0%). The other types of high-risk HPVs detected were HPV-31, 45, 51, 53, 56, 66, and 73. We also observed in some samples HPV coinfection by more than one viral type. Despite the high incidence of HPV, it did not show any association with the patient's clinical-pathological and molecular (TP53 mutation status) characteristics.

Conclusion: This is the first report of the presence of HPV DNA in CM associated with ESCC. HPV infection was more presence in megaesophagus lesions. Further studies are needed to confirm and better understand the role of persistent HPV infection in patients with CM.
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http://dx.doi.org/10.1159/000518697DOI Listing
January 2022

Microsatellite Instability Is Rare in the Admixed Brazilian Population of Non-Small Cell Lung Cancer: A Cohort of 526 Cases.

Pathobiology 2022 15;89(2):101-106. Epub 2021 Nov 15.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.

Background: Microsatellite instability (MSI) in non-small cell lung cancer (NSCLC) is uncommon; however, most studies refer to European and Asian populations. There are currently no data on MSI frequency in highly admixed populations, such as the one represented by Brazilian NSCLC patients.

Aim: This study aimed to evaluate the frequency of MSI in Brazilian NSCLC patients.

Methods: We evaluated 526 patients diagnosed with NSCLC at the Barretos Cancer Hospital (Brazil). The molecular MSI evaluation was performed using a hexa-plex marker panel by polymerase chain reaction followed by fragment analysis. The mutation profile of MSI-positive cases was performed using next-generation sequencing.

Results: Only 1 patient was MSI positive (0.19%). This patient was a female, white, and active smoker, and she was diagnosed with clinical stage IV lung adenocarcinoma at 75 years old. The molecular profile exhibited 4 Tumor Protein p53 (TP53) mutations and the absence of actionable mutations in the Epidermal Growth Factor Receptor (EGFR), Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), or V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) genes.

Conclusions: The frequency of MSI in Brazilian NSCLC patients is equally rare, a finding that is consistent with the current literature based on other populations such as Europeans, North Americans, and Asians.
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http://dx.doi.org/10.1159/000520023DOI Listing
March 2022

Profile of esophageal squamous cell carcinoma mutations in Brazilian patients.

Sci Rep 2021 10 18;11(1):20596. Epub 2021 Oct 18.

Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos, São Paulo, 14784 400, Brazil.

Esophageal cancer is an aggressive tumor that has a high rate of incidence and mortality worldwide. It is the 10th most frequent type in Brazil, being squamous cell carcinoma (ESCC) the predominant subtype. There is currently an incessant search to identify the frequently altered genes associated with esophageal squamous cell carcinoma biology that could be druggable. This study aimed to analyze the somatic mutation profile of a large panel of cancer-related genes in Brazilian ESCC. In a series of 46 ESCC diagnoses at Barretos Cancer Hospital, DNA isolated from paired fresh-frozen and blood tissue, a panel of 150 cancer-related genes was analyzed by next-generation sequencing. The genes with the highest frequency of mutations were TP53 (39/46, 84.8%), followed by NOTCH1 (7/46, 15.2%), NFE2L2 (5/46, 10.8%), RB1 (3/46, 6.5%), PTEN (3/46, 6.5%), CDKN2A (3/46, 6.5%), PTCH1 (2/46, 4.3%) and PIK3CA (2/46, 4.3%). There was no significant association between molecular and patients' clinicopathological features. Applying an evolutionary action score of p53 (EAp53), we observed that 14 (35.9%) TP53 mutations were classified as high-risk, yet no association with overall survival was observed. Concluding, this the largest mutation profile of Brazilian ESCC patients, which helps in the elucidation of the major cancer-related genes in this population.
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http://dx.doi.org/10.1038/s41598-021-00208-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523676PMC
October 2021

A 4-Gene Signature Associated With Recurrence in Low- and Intermediate-Risk Endometrial Cancer.

Front Oncol 2021 17;11:729219. Epub 2021 Aug 17.

Department of Gynecologic Oncology, Barretos Cancer Hospital, Barretos, Brazil.

Background: The molecular profile of endometrial cancer has become an important tool in determining patient prognosis and their optimal adjuvant treatment. In addition to The Cancer Genome Atlas (TCGA), simpler tools have been developed, such as the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE). We attempted to determine a genetic signature to build a recurrence risk score in patients diagnosed with low- and intermediate-risk endometrial cancer.

Methods: A case-control study was conducted. The eligible patients were women diagnosed with recurrence low- and intermediate-risk endometrial cancer between January 2009 and December 2014 at a single institution; the recurrence patients were matched to two nonrecurrence patients with the same diagnosis by age and surgical staging. Following RNA isolation of 51 cases, 17 recurrence and 34 nonrecurrence patients, the expression profile was determined using the , which contains 770 genes.

Results: The expression profile was successfully characterized in 49/51 (96.1%) cases. We identified 12 genes differentially expressed between the recurrence and nonrecurrence groups. The ROC curve for each gene was generated, and all had AUCs higher than 0.7. After backward stepwise logistic regression, four genes were highlighted: . The recurrence risk score was calculated, leading to a ROC curve of the 4-gene model with an AUC of 0.93, sensitivity of 100%, and specificity of 72.7%.

Conclusion: We identified a four-gene signature that may be associated with recurrence in patients with low- and intermediate-risk endometrial cancer. This finding suggests a new prognostic factor in this poorly explored group of patients with endometrial cancer.
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http://dx.doi.org/10.3389/fonc.2021.729219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416164PMC
August 2021

Decoding the Roles of Astrocytes and Hedgehog Signaling in Medulloblastoma.

Curr Oncol 2021 08 11;28(4):3058-3070. Epub 2021 Aug 11.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil.

The molecular evolution of medulloblastoma is more complex than previously imagined, as emerging evidence suggests that multiple interactions between the tumor cells and components of the tumor microenvironment (TME) are important for tumor promotion and progression. The identification of several molecular networks within the TME, which interact with tumoral cells, has provided new clues to understand the tumorigenic roles of many TME components as well as potential therapeutic targets. In this review, we discuss the most recent studies regarding the roles of astrocytes in supporting sonic hedgehog (SHH) subgroup medulloblastoma (MB) and provide an overview of MB progression through SHH expression and signal transduction mechanisms into the complex tumor microenvironment. In addition, we highlight the associations between tumor and stromal cells as possible prognostic markers that could be targeted with new therapeutic strategies.
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http://dx.doi.org/10.3390/curroncol28040267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395412PMC
August 2021

Reproduction of the Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) Gastric Cancer Molecular Classifications and Their Association with Clinicopathological Characteristics and Overall Survival in Moroccan Patients.

Dis Markers 2021 28;2021:9980410. Epub 2021 Jul 28.

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.

Introduction: The Cancer Genome Atlas (TCGA) project and Asian Cancer Research Group (ACRG) recently categorized gastric cancer into molecular subtypes. Nevertheless, these classification systems require high cost and sophisticated molecular technologies, preventing their widespread use in the clinic. This study is aimed to generating molecular subtypes of gastric cancer using techniques available in routine diagnostic practice in a series of Moroccan gastric cancer patients. In addition, we assessed the associations between molecular subtypes, clinicopathological features, and prognosis.

Methods: Ninety-seven gastric cancer cases were classified according to TCGA, ACRG, and integrated classifications using a panel of four molecular markers (EBV, MSI, E-cadherin, and p53). HER2 status and PD-L1 expression were also evaluated. These markers were analyzed using immunohistochemistry (E-cadherin, p53, HER2, and PD-L1), in situ hybridization (EBV and HER2 equivocal cases), and multiplex PCR (MSI).

Results: Our results showed that the subtypes presented distinct clinicopathological features and prognosis. EBV-positive gastric cancers were found exclusively in male patients. The GS (TCGA classification), MSS/EMT (ACRG classification), and E-cadherin aberrant subtype (integrated classification) presented the Lauren diffuse histology enrichment and tended to be diagnosed at a younger age. The MSI subtype was associated with a better overall survival across all classifications (TCGA, ACRG, and integrated classification). The worst prognosis was observed in the EBV subtype (TCGA and integrated classification) and MSS/EMT subtype (ACRG classification). . We reported a reproducible and affordable gastric cancer subtyping algorithms that can reproduce the recently recognized TCGA, ACRG, and integrated gastric cancer classifications, using techniques available in routine diagnosis. These simplified classifications can be employed not only for molecular classification but also in predicting the prognosis of gastric cancer patients.
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http://dx.doi.org/10.1155/2021/9980410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342151PMC
January 2022

Methylation profile of colon cancer genes in colorectal precursor lesions and tumor tissue: perspectives for screening.

Scand J Gastroenterol 2021 Aug 3;56(8):920-928. Epub 2021 Jul 3.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.

Aims: Epigenetic alterations of genes involved in colorectal carcinogenesis are likely to be informative biomarkers for early detection. We assessed the methylation profile of a panel of seven colon cancer-related genes comparing normal colon, colorectal cancer (CRC) precursor lesions and cancer tissues from a Brazilian cohort.

Methods: The cohort comprised 114 CRC patients, including 40 matched normal tissue, 47 patients with adenomas, 33 with serrated polyps and 8 with normal colonic biopsy. DNA methylation status of , , , , , and was determined by pyrosequencing and correlated with clinicopathological features. Sensitivity, specificity, positive predictive value and negative predictive value were calculated for all genes using cancer endpoint.

Results: The most frequently methylated genes in cancer and in precancer lesions were , , and , ranging from 55.3 to 95% of the samples. Overall, the frequency of methylation of these four genes in normal colonic tissue was significantly lower as compared to cancer or precursor lesions both in adenoma-carcinoma ( < .001 and  < .050) and serrated (sessile-serrated lesion) ( < .001 and  < .050) pathways. Additionally, sensitivity for the cancer endpoint ranged from 65.6 to 91.8%, and specificity from 17.9 to 62.9% for , , , and genes. Moreover, the comethylation of ≥4 genes was higher in sessile-serrated lesion (87.5%) and conventional adenomas (78.7%) than in hyperplastic polyps (43.7%) ( = .025) and was significantly associated with proximal cancers ( = .042).

Conclusions: Our study suggests the DNA methylation can constitute potential biomarkers in CRC screening of Brazilian population.
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http://dx.doi.org/10.1080/00365521.2021.1922744DOI Listing
August 2021

The biobank of barretos cancer hospital: 14 years of experience in cancer research.

Cell Tissue Bank 2022 Jun 3;23(2):271-284. Epub 2021 Jul 3.

Barretos Cancer Hospital Biobank, São Paulo, Brazil.

Despite the developments in cancer research over years, cancer is still one of the leading causes of death worldwide. In Brazil, the number of cancer cases for the several next years (2020-2022) is expected to increase up to 625,000. Thus, translational research has been vital to determine the potential risk, prognostic, and predictive biomarkers in cancer. Therefore, Barretos Cancer Hospital implemented a biobank (BB-BCH) in 2006, which is responsible for processing, storage, and provision of biological materials from cancer and non-cancer participants. Hence, this article aimed to describe BB-BCH's history, experiences, and outcomes and explore its impact on Brazilian translational oncology research scenario. BB-BCH has a multidisciplinary team who are responsible for guaranteeing the quality of all processes as recommended by international guidelines for biobanks. Furthermore, BB-BCH has ample equipment to ensure the quality of all material requested by researchers as genetic material (DNA and RNA) and/or entire biospecimens. From 2006 to 2019, BB-BCH contained 252,069 samples from 44,933 participants, the whole collection is represented by 15 different types of biospecimens collected from them. According to our data, the most collected and stored topography in men is head and neck (29%); in women is breast (28%); and in children is torso and limb (27%) samples. Finally, we supported national and international consortia and projects such as The Cancer Genome Atlas. BB-BCH is a vital knowledge source for scientific community, enabling the development of high-quality studies, with a wide variety of tumor categories and high national representativeness of Brazilian population.
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http://dx.doi.org/10.1007/s10561-021-09941-9DOI Listing
June 2022

HPV-Induced Oropharyngeal Squamous Cell Carcinomas in Brazil: Prevalence, Trend, Clinical, and Epidemiologic Characterization.

Cancer Epidemiol Biomarkers Prev 2021 09 21;30(9):1697-1707. Epub 2021 Jun 21.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.

Background: Tobacco or human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCC) represent different clinical and epidemiologic entities. This study investigated the prevalence of HPV-positive and HPV-negative OPSCC in a reference cancer hospital in Brazil and its association with clinical and demographic data, as well as its impact on overall survival.

Methods: HPV infection was determined by p16-IHC in pre-treatment formalin-fixed paraffin-embedded samples from all patients with OPSCC diagnosed at Barretos Cancer Hospital between 2008 and 2018. The prevalence of HPV-positive cases and its temporal trend was assessed, and the association of clinical and demographic data with HPV infection and the impact on patient overall survival was evaluated.

Results: A total of 797 patients with OPSCC were included in the study. The prevalence of HPV-associated tumors in the period was 20.6% [95% confidence interval, 17.5-24.0] with a significant trend for increase of HPV-positive cases over the years (annual percentage change = 12.87). In a multivariate analysis, the variables gender, level of education, smoking, tumor sublocation, region of Brazil, and tumor staging had a significant impact in HPV positivity, and a greater overall survival (OS) was observed in HPV-positive patients (5-year OS: 47.9% vs. 22.0%; = 0.0001).

Conclusions: This study represents the largest cohort of Brazilian patients with OPSCC characterized according to HPV status. We report significant differences in demographics and clinical presentation according to HPV status, and an increasing trend in prevalence for HPV-induced tumors.

Impact: These findings can potentially contribute to a better stratification and management of patients as well as assist in prevention strategies.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0016DOI Listing
September 2021

Genetically determined telomere length and multiple myeloma risk and outcome.

Blood Cancer J 2021 04 14;11(4):74. Epub 2021 Apr 14.

Department of Hematology, Aarhus University Hospital, Aarhus, Denmark.

Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 × 10 for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.
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http://dx.doi.org/10.1038/s41408-021-00462-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046773PMC
April 2021
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