Publications by authors named "Cristovam Scapulatempo-Neto"

118 Publications

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

Pathobiology 2021 Oct 12:1-9. 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
October 2021

Profile of esophageal squamous cell carcinoma mutations in Brazilian patients.

Sci Rep 2021 Oct 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

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

Cancer Epidemiol Biomarkers Prev 2021 Sep 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

Penile Cancer-Derived Cells Molecularly Characterized as Models to Guide Targeted Therapies.

Cells 2021 04 6;10(4). Epub 2021 Apr 6.

Department of Clinical Genetics, University Hospital of Southern Denmark-Vejle, Institute of Regional Health Research, University of Southern Denmark, 7100 Vejle, Denmark.

Penile cancer (PeCa) is a common disease in poor and developing countries, showing high morbidity rates. Despite the recent progress in understanding the molecular events involved in PeCa, the lack of well-characterized in vitro models precludes new advances in anticancer drug development. Here we describe the establishment of five human primary penile cancer-derived cell cultures, including two epithelial and three cancer-associated fibroblast (CAF) cells. Using high-throughput genomic approaches, we found that the epithelial PeCa derived- cells recapitulate the molecular alterations of their primary tumors and present the same deregulated signaling pathways. The differentially expressed genes and proteins identified are components of key oncogenic pathways, including EGFR and PI3K/AKT/mTOR. We showed that epithelial PeCa derived cells presented a good response to cisplatin, a common therapeutic approach used in PeCa patients. The growth of a PeCa-derived cell overexpressing EGFR was inhibited by EGFR inhibitors (cetuximab, gefitinib, and erlotinib). We also identified CAF signature markers in three PeCa-derived cells with fibroblast-like morphology, indicating that those cells are suitable models for PeCa microenvironment studies. We thus demonstrate the utility of PeCa cell models to dissect mechanisms that promote penile carcinogenesis, which are useful models to evaluate therapeutic approaches for the disease.
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http://dx.doi.org/10.3390/cells10040814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067406PMC
April 2021

Somatic Copy Number Alterations and Associated Genes in Clear-Cell Renal-Cell Carcinoma in Brazilian Patients.

Int J Mol Sci 2021 Feb 25;22(5). Epub 2021 Feb 25.

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

Somatic copy number aberrations (CNAs) have been associated with clear-cell renal carcinoma (ccRCC) pathogenesis and are a potential source of new diagnostic, prognostic and therapeutic biomarkers. Recurrent CNAs include loss of chromosome arms 3p, 14q, 9p, and gains of 5q and 8q. Some of these regional CNAs are suspected of altering gene expression and could influence clinical outcomes. Despite many studies of CNAs in RCC, there are currently no descriptions of genomic copy number alterations in a Brazilian ccRCC cohort. This study was designed to evaluate the chromosomal profile of CNAs in Brazilian ccRCC tumors and explore clinical associations. A total of 92 ccRCC Brazilian patients that underwent nephrectomy at Barretos Cancer Hospital were analyzed for CNAs by array comparative genomic hybridization. Most patients in the cohort had early-stage localized disease. The most significant alterations were loss of 3p (87.3%), 14q (35.8%), 6q (29.3%), 9p (28.6%) and 10q (25.0%), and gains of 5q (59.7%), 7p (29.3%) and 16q (20.6%). Bioinformatics analysis revealed 19 genes mapping to CNA significant regions, including , , , , and . Moreover, gain of 5q34-q35.3 ( and ) and loss of 6q23.2-q23.3 () and 9p21.3 () had gene expression levels that correlated with TCGA data and was also associated with advanced disease features, such as larger tumors, Fuhrman 3, metastasis at diagnosis and death. The loss of region 14q22.1 which encompasses the gene was associated with poor overall survival. Overall, this study provides the first CNA landscape of Brazilian patients and pinpoints genomic regions and specific genes worthy of more detailed investigations. Our results highlight important genes that are associated with copy number changes involving large chromosomal regions that are potentially related to ccRCC tumorigenesis and disease biology for future clinical investigations.
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http://dx.doi.org/10.3390/ijms22052265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956176PMC
February 2021

Clinicopathological and molecular characterization of Brazilian families at risk for Lynch syndrome.

Cancer Genet 2021 06 14;254-255:82-91. Epub 2021 Feb 14.

Molecular Diagnosis Laboratory, Barretos Cancer Hospital, Barretos, São Paulo, Brazil; Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil; Pele Pequeno Principe Research Institute, Curitiba, Brazil; Faculdades Pequeno Principe, Curitiba, Brazil. Electronic address:

Lynch syndrome (LS), is the most common hereditary colorectal cancer syndrome. However, it is poorly characterized in Brazil. Therefore, we aimed to determine the spectrum of pathogenic variants in Mismatch Repair (MMR) genes and investigate the MLH1 promotor methylation role as a second hit in LS tumors. Tumor screening through microsatellite instability and immunohistochemistry for MMR proteins was performed in 323 cases who met clinical criteria. BRAF-V600E and MLH1 promoter methylation were analyzed for all MLH1-deficient tumors. Patients with MMR deficient tumor proceeded to germline genetic testing. MMR deficient tumors were detected in 41% of patients recruited. About half of patients carried a pathogenic germline variant. Two recurrent variants in MLH1 and three novel pathogenic variants were identified. Furthermore, pathogenic germline variants with concomitant somatic MLH1 hypermethylation were found in 6% of cases. Predictive genetic testing was offered to 387 relatives. Overall, 127 tumors were diagnosed in 100 LS patients, from 62 unrelated families. Our molecular data provide new information about the spectrum of MMR mutations, which contributes to a better characterization of LS in Brazil. Furthermore, we call attention to the possibility of failure in the diagnosis of germline MLH1 mutation carriers when somatic MLH1 hypermethylation is used to rule out LS.
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http://dx.doi.org/10.1016/j.cancergen.2021.02.003DOI Listing
June 2021

Pyknon-Containing Transcripts Are Downregulated in Colorectal Cancer Tumors, and Loss of Is Associated With Worse Patient Outcome.

Front Genet 2020 12;11:581454. Epub 2020 Nov 12.

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

Pyknons are specific human/primate-specific DNA motifs at least 16 nucleotides long that are repeated in blocks in intergenic and intronic regions of the genome and can be located in a new class of non-coding RNAs of variable length. Recent studies reported that pyknon deregulation could be involved in the carcinogenesis process, including colorectal cancer. We evaluated the expression profile of a set of 12 pyknons in a set of molecularly characterized colorectal cancer (CRC) patients. The pyknons (, , , , , , , , , , , and ) expression was determined by qRT-PCR. A pilot analysis of 20 cases was performed, and consistent results were obtained for , , , , and . Further, the expression of the selected pyknons was evaluated in 73 CRC cases. Moreover, in 52 patients, we compared the expression profile in both tumor and normal tissues. All five pyknons analyzed showed significantly lower expression levels in the tumor compared to normal tissue. It was observed an association between expression of with mutations ( = 0.029), to histologic grade ( = 0.035), and to clinical staging ( = 0.016). Moreover, levels of were significantly associated with the patient's poor overall survival ( = 0.04). We reported the significant downregulation of pyknons motifs in tumor tissue compared with the normal counterpart, and the association of lower expression with worse patient outcome. Further studies are needed to extend and validate these findings and determine the clinical-pathological impact.
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http://dx.doi.org/10.3389/fgene.2020.581454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693444PMC
November 2020

Evaluation of Elafin Immunohistochemical Expression as Marker of Cervical Cancer Severity.

Acta Cytol 2021 3;65(2):165-174. Epub 2020 Dec 3.

Centro de Investigação Translacional em Oncologia, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil,

Introduction: The main risk factor for the development of cervical cancer (CC) is persistent infection by human papillomavirus (HPV) oncogenic types. In order to persist, HPV exhibits a plethora of immune evasion mechanisms. PI3/Elafin (Peptidase Inhibitor 3) is an endogenous serine protease inhibitor involved in epithelial protection against pathogens. PI3/Elafin's role in CC is still poorly understood.

Materials And Methods: In the present study, we addressed PI3/Elafin protein detection in 123 CC samples by immunohistochemistry and mRNA expression in several datasets available at Gene Expression Omnibus and The Cancer Genome Atlas platforms.

Results: We observed that PI3/Elafin is consistently downregulated in CC samples when compared to normal tissue. Most of PI3/Elafin-positive samples exhibited this protein at the plasma membrane. Besides, high PI3/Elafin expression at the cellular membrane was more frequent in in situ stages I + II than in invasive cervical tumor stages III + IV. This indicates that PI3/Elafin expression is gradually lost during the CC progression. Of note, advanced stages of CC were more frequently associated with a more intense PI3/Elafin reaction in the nuclei and cytoplasm.

Conclusion: Our results suggest that PI3/Elafin levels and subcellular localization may be used as a biomarker for CC severity.
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http://dx.doi.org/10.1159/000512010DOI Listing
March 2021

Human Papillomavirus DNA Detection by Droplet Digital PCR in Formalin-Fixed Paraffin-Embedded Tumor Tissue from Oropharyngeal Squamous Cell Carcinoma Patients.

Mol Diagn Ther 2021 01 27;25(1):59-70. Epub 2020 Nov 27.

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

Introduction: High-risk human papillomavirus infection impacts staging and prognosis of oropharyngeal squamous cell carcinomas (OPSCCs). Determination of HPV status in tumor tissue by p16-immunohistochemistry (p16-IHC) can be challenging; therefore, complementary methodologies could be useful in a clinical setting.

Objective: To test for accuracy and clinical relevance of HPV-DNA detection in formalin-fixed and paraffin-embedded (FFPE) tumor samples by droplet digital PCR (ddPCR).

Materials And Methods: Fifty OPSCCs were tested for p16-IHC status followed by HPV-16/18 DNA detection/quantification in FFPE-recovered DNA using ddPCR. Accuracy for HPV status determination and association with patient information were also evaluated.

Results: 32.0% (16/50) of the cases were p16-IHC positive (p16 +), 42.0% (21/50) had detectable levels of HPV-16 DNA, and none were positive for HPV-18 DNA. A higher median viral load of HPV-16 DNA was observed in p16 + cases (p < 0.0001). Concordance between p16-IHC and HPV-16 DNA ranged from 78.0 to 86.0% and accuracy rates were between 78.0 and 86.0%. P16-IHC and HPV-16 DNA detection was associated with gender, smoking status, and tumor subsite, while only HPV-16 DNA was associated with cT stage. The combination of HPV positivity by p16-IHC and ddPCR showed higher overall survival rates in comparison with p16 + /HPV-DNA- and p16 - /HPV-DNA- results.

Conclusions: Type-specific HPV-DNA detection by ddPCR is highly specific but moderately sensitive for the determination of HPV status and showed clinical relevance, mainly when associated with p16-IHC status. Results highlight the importance of performing HPV-DNA testing in combination with p16-IHC for proper identification of HPV-associated OPSCC and to improve clinical management of OPSCC patients.
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http://dx.doi.org/10.1007/s40291-020-00502-6DOI Listing
January 2021

Comprehensive Analysis of DNA Methylation and Prediction of Response to NeoadjuvantTherapy in Locally Advanced Rectal Cancer.

Cancers (Basel) 2020 Oct 22;12(11). Epub 2020 Oct 22.

Department of Clinical Genetics, University Hospital of Southern Denmark, 7100 Vejle, Denmark.

The treatment for locally advanced rectal carcinomas (LARC) is based on neoadjuvant chemoradiotherapy (nCRT) and surgery, which results in pathological complete response (pCR) in up to 30% of patients. Since epigenetic changes may influence response to therapy, we aimed to identify DNA methylation markers predictive of pCR in LARC patients treated with nCRT. We used high-throughput DNA methylation analysis of 32 treatment-naïve LARC biopsies and five normal rectal tissues to explore the predictive value of differentially methylated (DM) CpGs. External validation was carried out with The Cancer Genome Atlas-Rectal Adenocarcinoma (TCGA-READ 99 cases). A classifier based on three-CpGs DM (linked to , , and genes) was able to discriminate pCR from incomplete responders with high sensitivity and specificity. The methylation levels of the selected CpGs confirmed the predictive value of our classifier in 77 LARCs evaluated by bisulfite pyrosequencing. Evaluation of external datasets (TCGA-READ, GSE81006, GSE75546, and GSE39958) reproduced our results. As the three CpGs were mapped near to regulatory elements, we performed an integrative analysis in regions associated with predicted cis-regulatory elements. A positive and inverse correlation between DNA methylation and gene expression was found in two CpGs. We propose a novel predictive tool based on three CpGs potentially useful for pretreatment screening of LARC patients and guide the selection of treatment modality.
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http://dx.doi.org/10.3390/cancers12113079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690383PMC
October 2020

Inflammatory Breast Cancer: Clinical Implications of Genomic Alterations and Mutational Profiling.

Cancers (Basel) 2020 Sep 30;12(10). Epub 2020 Sep 30.

Department of Clinical Genetics, University Hospital of Southern Denmark, 7100 Vejle, Denmark.

Inflammatory breast cancer (IBC) is a rare and aggressive type of breast cancer whose molecular basis is poorly understood. We performed a comprehensive molecular analysis of 24 IBC biopsies naïve of treatment, using a high-resolution microarray platform and targeted next-generation sequencing (105 cancer-related genes). The genes more frequently affected by gains were (75%) and (71%), while frequent losses encompassed (71%) and (58%). Increased MYC and MDM4 protein expression levels were detected in 18 cases. These genes have been related to IBC aggressiveness, and MDM4 is a potential therapeutic target in IBC. Functional enrichment analysis revealed genes associated with inflammatory regulation and immune response. High homologous recombination (HR) deficiency scores were detected in triple-negative and metastatic IBC cases. A high telomeric allelic imbalance score was found in patients having worse overall survival (OS). The mutational profiling was compared with non-IBC (TCGA, = 250) and IBC ( = 118) from four datasets, validating our findings. Higher frequency of and variants were detected compared to non-IBC, while showed similar frequency. Variants in mismatch repair and HR genes were associated with worse OS. Our study provided a framework for improved diagnosis and therapeutic alternatives for this aggressive tumor type.
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http://dx.doi.org/10.3390/cancers12102816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650681PMC
September 2020

The Performance of Colorectal Cancer Screening in Brazil: The First Two Years of the Implementation Program in Barretos Cancer Hospital.

Cancer Prev Res (Phila) 2021 02 30;14(2):241-252. Epub 2020 Sep 30.

Department of Prevention, Barretos Cancer Hospital, Barretos, Brazil.

Colorectal cancer is the second most common cancer in Brazil. Yet, a nationally organized colorectal screening program is not implemented. Barretos Cancer Hospital (BCH) is one of the largest Brazilian institution that cares for underserved patients. BCH developed a fecal immunochemical test (FIT)-based organized colorectal cancer screening program to improve colorectal cancer outcomes.This study aims to present the quality/performance measures of the first 2 years of the FIT-based colorectal cancer screening program and its impact on the colorectal cancer disease stage. Between 2015 and 2017, a total of 6,737 individuals attending the Outpatient Department of Prevention or the Mobile Unit of BCH, which visits 18 cities of Barretos county, ages 50 to 65 years, were personally invited by a health agent/nurse practitioner. Exclusion criteria were personal history of colorectal cancer, adenomatous polyps, inflammatory bowel disease, and colonoscopy, or flexible sigmoidoscopy performed in the past 5 years. European Union (EU) guidelines for colorectal cancer screening programs were evaluated. Overall, 92.8% returned the FIT, with an inadequate examination rate of 1.5%. Among the 6,253 adequately tested, 12.5% had a positive result. The colonoscopy compliance and completion rates were 84.6 and 98.2%, respectively. The PPVs were 60.0%, 16.5%, and 5.6% for adenoma, advanced adenoma, and cancer, respectively. Stage distribution of screen-detected cancers shows earlier stages than clinically diagnosed colorectal cancer cancers reported at BCH and Brazilian cancer registries. Our colorectal cancer screening program achieved desirable quality metrics, aligned with the EU guidelines. The observed shift toward earlier colorectal cancer stages suggests an exciting opportunity to improve colorectal cancer-related cancers in Brazil.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0179DOI Listing
February 2021

Deregulated microRNAs Are Associated with Patient Survival and Predicted to Target Genes That Modulate Lung Cancer Signaling Pathways.

Cancers (Basel) 2020 Sep 22;12(9). Epub 2020 Sep 22.

Department of Surgery and Orthopedics, Faculty of Medicine, São Paulo State University, UNESP, Botucatu 18618-687, SP, Brazil.

(1) Background: Although the advances in diagnostic and treatment strategies, lung cancer remains the leading cause of cancer-related deaths, worldwide, with survival rates as low as 16% in developed countries. Low survival rates are mainly due to late diagnosis and the lack of effective treatment. Therefore, the identification of novel, clinically useful biomarkers is still needed for patients with advanced disease stage and poor survival. Micro(mi)RNAs are non-coding RNAs and potent regulators of gene expression with a possible role as diagnostic, prognostic and predictive biomarkers in cancer. (2) Methods: We applied global miRNA expression profiling analysis using TaqMan arrays in paired tumor and normal lung tissues ( = 38) from treatment-naïve patients with lung adenocarcinoma (AD; = 23) and lung squamous cell carcinoma (SCC; = 15). miRNA target genes were validated using The Cancer Genome Atlas (TCGA) lung AD ( = 561) and lung SCC ( = 523) RNA-Seq datasets. (3) Results: We identified 33 significantly deregulated miRNAs (fold change, FC ≥ 2.0 and < 0.05) in tumors relative to normal lung tissues, regardless of tumor histology. Enrichment analysis confirmed that genes targeted by the 33 miRNAs are aberrantly expressed in lung AD and SCC, and modulate known pathways in lung cancer. Additionally, high expression of miR-25-3p was significantly associated ( < 0.05) with poor patient survival, when considering both tumor histologies. (4) Conclusions: miR-25-3p may be a potential prognostic biomarker in non-small cell lung cancer. Genes targeted by miRNAs regulate and signaling, among other known pathways relevant to lung tumorigenesis.
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http://dx.doi.org/10.3390/cancers12092711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563870PMC
September 2020

Analysis of RPL37A, MTSS1, and HTRA1 expression as potential markers for pathologic complete response and survival.

Breast Cancer 2021 Mar 20;28(2):307-320. Epub 2020 Sep 20.

Programa de Pós-Graduação em Oncologia, Hospital de Câncer de Barretos, Rua Antenor Duarte Villela, 1331, Bairro Dr Paulo Prata, Barretos, São Paulo, 14.784-400, Brasil.

Background: Non-metastatic locally advanced breast carcinoma (LABC) treatment involves neoadjuvant chemotherapy (NCT). We evaluated the association of clinical-pathological data and immunoexpression of hormone receptors, HER2 and Ki67, and new biomarkers, RPL37A, MTSS1 and HTRA1, with pathological complete response (PCR) or tumour resistance (stable disease or disease progression), disease-free survival (DFS) and cancer-specific survival (CSS).

Methods: This is a retrospective study of 333 patients with LABC who underwent NCT. Expression of MTSS1, RPL37A and HTRA1/PRSS11 was evaluated by immunohistochemistry in TMA slides. Cutoff values were established for low and high tumour expression. ROC plotter evaluated response to NCT. Chi-square test for factors related to PCR, and Kaplan-Meier test and Cox model for factors related to DFS and CSS were prformed.

Results: The mean follow-up was 70.0 months and PCR rate was 15.6%. At 120 months, DFS rate was 32.5% and CSS rate was 67.1%. In multivariate analysis, there was an association between: (1) necrosis presence, intense inflammatory infiltrate, ER absence, HER2 molecular subtype and high RPL3A expression with increased odds of PCR; (2) lymph node involvement (LNI), high Ki67, low RPL37A and high HTRA1 expression with increased risk for NCT non-response; (3) LNI, high proliferation, necrosis absence, low RPL37A and high HTRA1 expression with increased recurrence risk; (4) advanced LNI, ER negative tumours, high HTRA1, low RPL37A expression and desmoplasia presence with higher risk of cancer death.

Conclusion: RPL37A is a potential biomarker for response to NCT and for prognosis. Additional studies evaluating HTRA1 and MTSS1 prognostic value are needed.
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http://dx.doi.org/10.1007/s12282-020-01159-zDOI Listing
March 2021

Promoter Mutation C228T Increases Risk for Tumor Recurrence and Death in Head and Neck Cancer Patients.

Front Oncol 2020 28;10:1275. Epub 2020 Jul 28.

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

Head and neck squamous cell carcinoma (HNSCC) is usually associated to tobacco and alcohol consumption. Increased telomerase activity has been consistently detected in 80-90% of malignant tumors, including HNSCC. Mutations within the promoter region of telomerase reverse transcriptase () that confer enhanced promoter activity have been reported in two major hotspots, designated C228T and C250T. To evaluate promoter mutations C228T and C250T in HNSCC patients from Brazil and correlate with patients' outcome. Formalin-fixed paraffin-embedded tissues were obtained from 88 HNSCC patients and analyzed for promoter mutations C228T and C250T by pyrosequencing. The overall prevalence of hotspot mutations in HNSCC samples was of 27.3%, with 6.8% at locus C228T and 20.5% at C250T. The majority (92%) of mutated cases were located in oral cavity, mainly at the tongue. We observed that 94.4% of the patients harboring promoter mutation C250T were alcohol consumers ( = 0.032) and 66.7% of the patients harboring promoter mutation C228T were not alcohol consumers ( = 0.035). The presence of C228T mutation impacted patient outcome, with a significant decrease in disease-free survival (20.0 vs. 63.0%, =0.017) and in overall survival (16.7 vs. 45.1%, = 0.017). This is the first report of a promoter mutations in HNSCC patients from South America. The high prevalence of mutation, as well as its association with poor disease-free survival and overall survival, particular at C228T locus might serve as a prognostic biomarker in HNSCC to help clinicians in the management of treatment.
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http://dx.doi.org/10.3389/fonc.2020.01275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399085PMC
July 2020

Feasibility of methylated ctDNA detection in plasma samples of oropharyngeal squamous cell carcinoma patients.

Head Neck 2020 11 20;42(11):3307-3315. Epub 2020 Jul 20.

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

Background: Oropharyngeal squamous cell carcinomas (OpSCCs) are commonly associated with high rates of treatment failure.

Objectives: To evaluate methylation-based markers in plasma from OpSCC patients as emerging tools for accurate/noninvasive follow-up.

Methods: Pretreatment formalin-fixed paraffin-embedded (FFPE) biopsies (n = 52) and paired plasma (n = 15) were tested for the methylation of CCNA1, DAPK, CDH8, and TIMP3 by droplet digital PCR (ddPCR).

Results: Seventy-one percent (37/52) of the biopsies showed methylation of at least one of the evaluated genes and tumor CCNA1 methylation was associated with recurrence-free survival. Methylated circulating tumor DNA (meth-ctDNA) was detected in 11/15 (73.3%) plasma samples; conversely, plasma samples from healthy controls were all negative for DNA methylation (area under the curve = 0.867; 95% confidence interval = 0.720-1.000). Additionally, preliminary results on the detection of meth-ctDNA in plasma collected during follow-up closely matched patient outcome.

Conclusions: The results suggest the feasibility of detecting meth-ctDNA in plasma using ddPCR and a possible application on routine setting after further validation.
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http://dx.doi.org/10.1002/hed.26385DOI Listing
November 2020

Impact of genetic variants in clinical outcome of a cohort of patients with oropharyngeal squamous cell carcinoma.

Sci Rep 2020 06 19;10(1):9970. Epub 2020 Jun 19.

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

Tobacco- or human papillomavirus- driven oropharyngeal squamous cell carcinomas (OpSCC) represent distinct clinical, biological and epidemiological entities. The aim of this study was to identify genetic variants based on somatic alterations in OpSCC samples from an admixed population, and to test for association with clinical features. The entire coding region of 15 OpSCC driver genes was sequenced by next-generation sequencing in 51 OpSCC FFPE samples. Thirty-five percent of the patients (18/51) were HPV-positive and current or past tobacco consumption was reported in 86.3% (44/51). The mutation profile identified an average of 2.67 variants per sample. Sixty-three percent of patients (32/51; 62.7%) were mutated for at least one of the genes tested and TP53 was the most frequently mutated gene. The presence of mutation in NOTCH1 and PTEN, significantly decreased patient's recurrence-free survival, but only NOTCH1 mutation remained significant after stepwise selection, with a risk of recurrence of 4.5 (HR 95% CI = 1.11-14.57; Cox Regression p = 0.034). These results show that Brazilian OpSCC patients exhibit a similar clinical and genetic profile in comparison to other populations. Molecular characterization is a promising tool for the definition of clinical subgroups, aiding in a more precise tailoring of treatment and prognostication.
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http://dx.doi.org/10.1038/s41598-020-66741-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305218PMC
June 2020

Role of Genetic Ancestry in 1,002 Brazilian Colorectal Cancer Patients From Barretos Cancer Hospital.

Front Oncol 2020 4;10:145. Epub 2020 Mar 4.

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

Colorectal cancer (CRC) is the third most frequent and the second deadliest cancer worldwide. The ethnic structure of the population has been gaining prominence as a cancer player. The purpose of this study was to determine the genetic ancestry of Brazilian CRC patients. Moreover, we intended to interrogate its impact on patients' clinicopathological features. Retrospective observational cohort study with 1,002 patients with CRC admitted from 2000 to 2014 at Barretos Cancer Hospital. Following tumor DNA isolation, genetic ancestry was assessed using a specific panel of 46 ancestry informative markers. Survival rates were obtained by the Kaplan-Meier method, and the log-rank test was used to compare the survival curves. Multivariable Cox proportional regression models were used to estimate hazard ratios (HRs). We observed considerable admixture in the genetic composition, with the following average proportions: European 74.2%, African 12.7%, Asian 6.5%, and Amerindian 6.6%. The multivariate analysis for cancer-specific survival showed that clinical stage, lymphovascular invasion, and the presence of recurrence were associated with an increased relative risk of death from cancer ( < 0.05). High African proportion was associated with younger age at diagnosis, while high Amerindian proportion was associated with the mucinous histological subtype. This represents the larger assessment of genetic ancestry in a population of Brazilian patients with CRC. Brazilian CRC patients exhibited similar clinicopathological features as described in Western countries. Genetic ancestry components corroborated the significant admixture, and importantly, patients with high African proportion develop cancer at a younger age.
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http://dx.doi.org/10.3389/fonc.2020.00145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065467PMC
March 2020

Odontogenic Carcinoma With Dentinoid in Long-Term Follow-up With 2 Recurrences.

Int J Surg Pathol 2020 Apr 5;28(2):181-187. Epub 2019 Sep 5.

Metropolitan Autonomous University, Mexico City, Mexico.

Dentinoid has been mentioned as a frequent component in several types of benign odontogenic tumors; however, there are some other very rare dentinoid-producing odontogenic tumors that have been described, which are not recognized in the current . In this context, we report an unusual malignant odontogenic tumor containing dentinoid located in the left maxilla of a 41-year-old man. The lesion was initially diagnosed and treated as a cemento-ossifying fibroma. After 7 years, a tumor was noted at the same location and was diagnosed as pleomorphic adenoma. The patient developed a new lesion 2 years later. Histological features included an epithelial proliferation of basaloid and clear cells, some with peripheral palisading, which were scattered both in a fibrous stroma and within an amorphous eosinophilic dentinoid product. Because of doubts about the first 2 diagnoses and the current situation, all histopathological slides were reviewed in our service as a consultation case, and the findings were consistent with the diagnosis of an odontogenic carcinoma with dentinoid. Immunohistochemical analysis was performed and an ultrastructural study by scanning electronic microscopy and energy-dispersive X-ray microanalysis was made to characterize dentinoid material. After 1 year of follow-up, the patient is alive and free of the disease. This case highlights the wide variability regarding cytological evidence of malignancy, and adds a new case of odontogenic carcinoma with dentinoid, which represents a distinct entity with locally aggressive behavior and should be considered be included in a future .
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http://dx.doi.org/10.1177/1066896919871662DOI Listing
April 2020

CAIX is a predictor of pathological complete response and is associated with higher survival in locally advanced breast cancer submitted to neoadjuvant chemotherapy.

BMC Cancer 2019 Dec 3;19(1):1173. Epub 2019 Dec 3.

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

Background: Locally advanced breast cancer often undergoes neoadjuvant chemotherapy (NAC), which allows in vivo evaluation of the therapeutic response. The determination of the pathological complete response (pCR) is one way to evaluate the response to neoadjuvant chemotherapy. However, the rate of pCR differs significantly between molecular subtypes and the cause is not yet determined. Recently, the metabolic reprogramming of cancer cells and its implications for tumor growth and dissemination has gained increasing prominence and could contribute to a better understanding of NAC. Thus, this study proposed to evaluate the expression of metabolism-related proteins and its association with pCR and survival rates.

Methods: The expression of monocarboxylate transporters 1 and 4 (MCT1 and MCT4, respectively), cluster of differentiation 147 (CD147), glucose transporter-1 (GLUT1) and carbonic anhydrase IX (CAIX) was analyzed in 196 locally advanced breast cancer samples prior to NAC. The results were associated with clinical-pathological characteristics, occurrence of pCR, disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS).

Results: The occurrence of pCR was higher in the group of patients whith tumors expressing GLUT1 and CAIX than in the group without expression (27.8% versus 13.1%, p = 0.030 and 46.2% versus 13.5%, p = 0.007, respectively). Together with regional lymph nodes staging and mitotic staging, CAIX expression was considered an independent predictor of pCR. In addition, CAIX expression was associated with DFS and DSS (p = 0.005 and p = 0.012, respectively).

Conclusions: CAIX expression was a predictor of pCR and was associated with higher DFS and DSS in locally advanced breast cancer patients subjected to NAC.
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http://dx.doi.org/10.1186/s12885-019-6353-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889185PMC
December 2019

Mutational Profile of Driver Genes in Brazilian Melanomas.

J Glob Oncol 2019 11;5:1-14

Barretos Cancer Hospital, Barretos, São Paulo, Brazil.

Purpose: Mutation testing of the key genes involved in melanoma oncogenesis is now mandatory for the application of targeted therapeutics. However, knowledge of the mutational profile of melanoma remains largely unknown in Brazil.

Patients And Methods: In this study, we assessed the mutation status of melanoma driver genes , , , , and in a cohort of 459 patients attended at Barretos Cancer Hospital between 2001 and 2012. We used polymerase chain reaction followed by Sanger sequencing to analyze the hot spot mutations of exon 15 (V600E), (codons 12/13 and 61), (promoter region), (exons 9, 11, 13, and 17), and (exons 12, 14, and 18) in tumors. The mutational profile was investigated for associations with demographic, histopathologic, and clinical features of the disease.

Results: The nodular subtype was most frequent (38.9%) followed by the superficial spreading subtype (34.4%). The most frequent tumor location was in the limbs (50.0%). The mutation rates were 34.3% for and 34.1% for followed by (7.9%), (6.2%), and (2.9%). The ( = .014) and ( = .006) mutations were associated with younger patients and with different anatomic locations, particularly in the trunk, for the superficial spreading and nodular subtypes, respectively ( = .0001 for both). mutations were associated with black skin color ( = .023) and promoter mutations with an absence of ulceration ( = .037) and lower levels of lactate dehydrogenase. There was no association between patient survival rates and mutational status.

Conclusion: The similar mutational profile we observe in melanomas in Brazil compared with other populations will help to guide precision medicine in this country.
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http://dx.doi.org/10.1200/JGO.19.00169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882511PMC
November 2019

Human papillomavirus is not associated to non-small cell lung cancer: data from a prospective cross-sectional study.

Infect Agent Cancer 2019 2;14:18. Epub 2019 Aug 2.

1Teaching and Research Institute, Molecular Oncology Research Center, Barretos Cancer Hospital - Pio XII Foundation, Barretos, Brazil.

Background: The pathogenesis of lung cancer is triggered by a combination of genetic and environmental factors, being the tobacco smoke the most important risk factor. Nevertheless, the incidence of lung cancer in non-smokers is gradually increasing, which demands the search for different other etiological factors such as occupational exposure, previous lung disease, diet among others. In the early 80's a theory linked specific types of human papillomavirus (HPV) to lung cancer due to morphological similarities of a subset of bronchial squamous cell carcinomas with other HPV-induced cancers. Since then, several studies revealed variable rates of HPV DNA detection. The current study aimed to provide accurate information on the prevalence of HPV DNA in lung cancer.

Methods: Biopsies were collected from 77 newly diagnosed non-small cell lung cancer (NSCLC) patients treated at the Thoracic Oncology Department at Barretos Cancer Hospital. The samples were formalin fixed and paraffin embedded (FFPE), histologic analysis was performed by an experienced pathologist. DNA was extracted from FFPE material using a commercial extraction kit and HPV DNA detection was evaluated by multiplex PCR and HPV16 specific real-time PCR.

Results: HPV was not identified in any of the samples analysed (69).

Conclusions: Our data demonstrated a lack of HPV DNA in a series of NSCL cancers.
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http://dx.doi.org/10.1186/s13027-019-0235-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679449PMC
August 2019

The Warburg Effect Is Associated With Tumor Aggressiveness in Testicular Germ Cell Tumors.

Front Endocrinol (Lausanne) 2019 28;10:417. Epub 2019 Jun 28.

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

Testicular Germ Cell Tumors (TGCTs) are a rare group of neoplasms and the most common solid malignancy arising in young male adults. Despite the good response of these tumors to platinum-based chemotherapy, some patients are refractory to treatment and present poor clinical outcomes. During carcinogenesis and tumor development, cancer cells reprogram energy metabolism toward a hyper-glycolytic phenotype, an emerging hallmark of cancer. This phenomenon, known as the Warburg effect or aerobic glycolysis, involves overexpression of metabolism-related proteins, like glucose and monocarboxylate transporters, pH regulators and intracellular glycolytic enzymes. The metabolic profile of TGCTs is very little explored and, recently, this metabolic rewiring of cancer cells has been associated with aggressive clinicopathological characteristics of these tumors. The overexpression of monocarboxylate transporter 4 (MCT4) in TGCTs has been pointed out as a poor prognostic factor, as well as a promising therapeutic target. As a result, the main aim of the present study was to evaluate the prognostic value of key metabolism-related proteins in TGCTs. The immunohistochemical expressions of CD44 (as a monocarboxylate transporter chaperone), glucose transporter 1 (GLUT1), carbonic anhydrase IX (CAIX), hexokinase II (HKII) and lactate dehydrogenase V (LDHV) were evaluated in a series of 148 adult male patients with TGCTs and associated with clinicopathological parameters. In addition, paired normal tissues were also evaluated. The sample included 75 seminoma and 73 non-seminoma tumors. GLUT1 and CD44 expression was significantly increased in malignant samples when compared to paired normal samples. Conversely, HKII and LDHV expressions were significantly decreased in malignant samples. Concerning the clinicopathological values, CAIX expression was significantly associated with disease recurrence, while HKII expression was significantly associated with aggressive characteristics of TGCTs, including higher staging and non-seminoma histology. In conclusion, this study brings new insights on the metabolic characteristics of TGCTs, showing alterations in the expression of proteins related with the Warburg effect, as well as associations of the hyper-glycolytic and acid-resistant phenotype with aggressive clinicopathological parameters.
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http://dx.doi.org/10.3389/fendo.2019.00417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610306PMC
June 2019

Differential Profile of BRCA1 vs. BRCA2 Mutated Families: A Characterization of the Main Differences and Similarities in Patients.

Asian Pac J Cancer Prev 2019 06 1;20(6):1655-1660. Epub 2019 Jun 1.

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

The identification of families at-risk for hereditary breast cancer (BC) is important because affected individuals present a much higher cancer risk than the general population. The aim of this study was to identify the most important factors associated with the presence of a pathogenic BRCA1/BRCA2 mutation. Family history (FH), histopathological and immunohistochemical characteristics were compared among BC women with pathogenic BRCA1/BRCA2 variants; VUSs in BRCA1/BRCA2; BRCA1/BRCA2 WT and sporadic BC. The most significative differences observed concerned the molecular subtype of the tumors, age at cancer diagnosis and FH of cancer. The presence of bilateral breast cancer (BBC), number of BC cases and the presence of ovarian cancer (OC) increased (respectively) 5.797, 5.033 and 4.412 times the risk of being a BRCA1/BRCA2 mutation carrier. Besides, women with BRCA1 or BRCA2 mutations presented different tumor and FH profiles. The main characteristics associated with a BRCA1 mutation were triple negativity (OR: 17.31), BBC history (OR: 4.96) and occurrence of OC (OR: 4.32). There were no major discerning components associated with BRCA2 mutations. Thus, we conclude that tumor pathology and FH of cancer might be considered together at the time of genetic testing mainly in countries where access to genetic testing is still restricted.
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http://dx.doi.org/10.31557/APJCP.2019.20.6.1655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021617PMC
June 2019

Locally advanced rectal cancer transcriptomic-based secretome analysis reveals novel biomarkers useful to identify patients according to neoadjuvant chemoradiotherapy response.

Sci Rep 2019 06 18;9(1):8702. Epub 2019 Jun 18.

Department of Clinical Genetics, University Hospital of Southern Denmark, Vejle, 7100, Denmark.

Most patients with locally advanced rectal cancer (LARC) present incomplete pathological response (pIR) to neoadjuvant chemoradiotherapy (nCRT). Despite the efforts to predict treatment response using tumor-molecular features, as differentially expressed genes, no molecule has proved to be a strong biomarker. The tumor secretome analysis is a promising strategy for biomarkers identification, which can be assessed using transcriptomic data. We performed transcriptomic-based secretome analysis to select potentially secreted proteins using an in silico approach. The tumor expression profile of 28 LARC biopsies collected before nCRT was compared with normal rectal tissues (NT). The expression profile showed no significant differences between complete (pCR) and incomplete responders to nCRT. Genes with increased expression (pCR = 106 and pIR = 357) were used for secretome analysis based on public databases (Vesiclepedia, Human Cancer Secretome, and Plasma Proteome). Seventeen potentially secreted candidates (pCR = 1, pIR = 13 and 3 in both groups) were further investigated in two independent datasets (TCGA and GSE68204) confirming their over-expression in LARC and association with nCRT response (GSE68204). The expression of circulating amphiregulin and cMET proteins was confirmed in serum from 14 LARC patients. Future studies in liquid biopsies could confirm the utility of these proteins for personalized treatment in LARC patients.
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http://dx.doi.org/10.1038/s41598-019-45151-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582145PMC
June 2019

Increased Levels of Genomic Instability and Mutations in Homologous Recombination Genes in Locally Advanced Rectal Carcinomas.

Front Oncol 2019 14;9:395. Epub 2019 May 14.

Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark.

Pre-operative 5-fluoracil-based chemoradiotherapy (nCRT) is the standard treatment for patients with locally advanced rectal cancer (LARC). Patients with pathological complete response (pCR-0% of tumor cells in the surgical specimen after nCRT) have better overall survival and lower risk of recurrence in comparison with incomplete responders (pIR). Predictive biomarkers to be used for new therapeutic strategies and capable of stratifying patients to avoid overtreatment are needed. We evaluated the genomic profiles of 33 pre-treatment LARC biopsies using SNP array and targeted-next generation sequencing (tNGS). Based on the large number of identified genomic alterations, we calculated the genomic instability index (GII) and three homologous recombination deficiency (HRD) scores, which have been reported as impaired DNA repair markers. We observed high GII in our LARC cases, which was confirmed in 165 rectal cancer cases from TCGA. Patients with pCR presented higher GII compared with pIR. Moreover, a negative correlation between GII and the fraction of tumor cells remaining after surgery was observed (ρ = -0.382, = 0.02). High HRD scores were detected in 61% of LARC, of which 70% were incomplete responders. Using tNGS (105 cancer-related genes, 13 involved in HR and 5 in mismatch repair pathways), we identified 23% of cases with mutations in HR genes, mostly in pIR cases (86% of mutated cases). In agreement, the analysis of the TCGA dataset ( = 145) revealed 21% of tumors with mutations in HR genes. The HRD scores were shown to be predictive of better response to PARP-inhibitors and platinum-based chemotherapy in breast and ovarian cancer. Our results suggest that the same strategy could be applied in a set of LARC patients with HRD. In conclusion, we identified high genomic instability in LARC, which was related to alterations in the HR pathway, especially in pIR. These findings suggest that patients with impaired HRD would clinically benefit from PARP-inhibitors and platinum-based therapy.
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http://dx.doi.org/10.3389/fonc.2019.00395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527873PMC
May 2019

Mutational profile of Brazilian lung adenocarcinoma unveils association of EGFR mutations with high Asian ancestry and independent prognostic role of KRAS mutations.

Sci Rep 2019 03 1;9(1):3209. Epub 2019 Mar 1.

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

Lung cancer is the deadliest cancer worldwide. The mutational frequency of EGFR and KRAS genes in lung adenocarcinoma varies worldwide per ethnicity and smoking. The impact of EGFR and KRAS mutations in Brazilian lung cancer remains poorly explored. Thus, we investigated the frequency of EGFR and KRAS mutations in a large Brazilian series of lung adenocarcinoma together with patients' genetic ancestry, clinicopathological and sociodemographic characteristics. The mutational frequency of EGFR was 22.7% and KRAS was 20.4%. The average ancestry proportions were 73.1% for EUR, 13.1% for AFR, 6.5% for AME and 7.3% for ASN. EGFR mutations were independently associated with never-smokers, high-Asian ancestry, and better performance status. KRAS mutations were independently associated with tobacco exposure and non-Asian ancestry. EGFR-exon 20 mutations were associated with worse outcome. The Cox regression model indicated a worse outcome for patients whose were older at diagnosis (>61 y), solid histological subtype, loss of weight (>10%), worse performance status (≥2), and presence of KRAS mutations and EGFR mutational status in TKi non-treated patients. In conclusion, we assessed the clinicopathological and ethnic impact of EGFR and KRAS mutations in the largest series reported of Brazilian lung adenocarcinomas. These findings can support future clinical strategies for Brazilian lung cancer patients.
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http://dx.doi.org/10.1038/s41598-019-39965-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397232PMC
March 2019

EGF+61 A>G polymorphism is not associated with lung cancer risk in the Brazilian population.

Mol Biol Rep 2019 Apr 19;46(2):2417-2425. Epub 2019 Feb 19.

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

Epidermal growth factor (EGF) and its receptor (EGFR) play an important role in lung carcinogenesis. A functional single nucleotide polymorphism (SNP) in EGF promoter region (EGF+61 A>G-rs4444903) has been associated with cancer susceptibility. Yet, in lung cancer, the EGF+61 A>G role is unclear. The aim of this study was to evaluate the risk of lung cancer associated with EGF+61 A>G SNP in the Brazilian population. For that, 669 lung cancer patients and 1104 controls were analyzed. EGF+61 A>G genotype was assessed by PCR-RFLP and TaqMan genotyping assay. Both patients and controls were in Hardy-Weinberg equilibrium. As expected, uni- and multivariate analyses showed that tobacco consumption and age were significant risk factors for lung cancer. The genotype frequencies in lung cancer patients were 27.3% of AA, 47.4% of AG and 25.3% of GG, and for controls were 25.3% of AA, 51.6% of AG and 23.1% of GG. The allele frequencies were 51.1% of A and 48.9% of G for both cases and controls. No significant differences for the three genotypes (AA, AG and GG-codominant model) were observed between cases and controls. We then grouped AG and GG (recessive model) genotypes, as well as AA and AG (dominant model), and again, no significant differences were also found. This is the largest study to explore EGF+61 A>G polymorphism association with lung cancer risk and suggests that this SNP is not a risk factor for lung cancer in the Brazilian population.
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http://dx.doi.org/10.1007/s11033-019-04702-0DOI Listing
April 2019

A mobile-phone based high-resolution microendoscope to image cervical precancer.

PLoS One 2019 6;14(2):e0211045. Epub 2019 Feb 6.

Department of Bioengineering, Rice University, Houston, Texas, United States of America.

Nearly 90% of cervical cancer cases and deaths occur in low- and middle-income countries that lack comprehensive national HPV immunization and cervical cancer screening programs. In these settings, it is difficult to implement screening programs due to a lack of infrastructure and shortage of trained personnel. Screening programs based on visual inspection with acetic acid (VIA) have been successfully implemented in some low-resource settings. However, VIA has poor specificity and up to 90% of patients receiving treatment based on a positive VIA exam are over-treated. A number of studies have suggested that high-resolution cervical imaging to visualize nuclear morphology in vivo can improve specificity by better distinguishing precancerous and benign lesions. To enable high-resolution imaging in low-resource settings, we developed a portable, low-cost, high-resolution microendoscope that uses a mobile phone to detect and display images of cervical epithelium in vivo with subcellular resolution. The device was fabricated for less than $2,000 using commercially available optical components including filters, an LED and triplet lenses assembled in a 3D-printed opto-mechanical mount. We show that the mobile high-resolution microendoscope achieves similar resolution and signal-to-background ratio as previously reported high-resolution microendoscope systems using traditional cameras and computers to detect and display images. Finally, we demonstrate the ability of the mobile high-resolution microendoscope to image normal and precancerous squamous epithelium of the cervix in vivo in a gynecological referral clinic in Barretos, Brazil.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211045PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364962PMC
November 2019

mutations are frequent in esophageal squamous cell carcinoma associated with chagasic megaesophagus and are associated with a worse patient outcome.

Infect Agent Cancer 2018 29;13:43. Epub 2018 Dec 29.

1Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, Barretos, SP CEP 14784 400 Brazil.

Background: Chronic diseases such as chagasic megaesophagus (secondary to Chagas' disease) have been suggested as etiological factors for esophageal squamous cell carcinoma; however, the molecular mechanisms involved are poorly understood.

Objective: We analyzed hotspot gene mutations in a series of esophageal squamous cell carcinomas associated or not with chagasic megaesophagus, as well as, in chagasic megaesophagus biopsies. We also checked for correlations between the presence of mutations with patients' clinical and pathological features.

Methods: The study included three different groups of patients: i) 23 patients with chagasic megaesophagus associated with esophageal squamous cell carcinoma (CM/ESCC); ii) 38 patients with esophageal squamous cell carcinoma not associated with chagasic megaesophagus (ESCC); and iii) 28 patients with chagasic megaesophagus without esophageal squamous cell carcinoma (CM). hotspot mutations in exons 9 and 20 were evaluated by PCR followed by direct sequencing technique.

Results: mutations were identified in 21.7% (5 out of 23) of CM/ESCC cases, in 10.5% (4 out of 38) of ESCC and in only 3.6% (1 case out of 28) of CM cases. In the CM/ESCC group, mutations were significantly associated with lower survival (mean 5 months), when compared to wild-type patients (mean 2.0 years). No other significant associations were observed between mutations and patients' clinical features or mutation profile.

Conclusion: This is the first report on the presence of mutations in esophageal cancer associated with chagasic megaesophagus. The detection of mutations in benign chagasic megaesophagus lesions suggests their putative role in esophageal squamous cell carcinoma development and opens new opportunities for targeted-therapies for these diseases.
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http://dx.doi.org/10.1186/s13027-018-0216-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311070PMC
December 2018
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