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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 SEPT9, ALX4, NDRG4, BMP3, APC, p16 and MLH1 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 SEPT9, ALX4, NDRG4, and BMP3, 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 (p

Background: Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. The development of colorectal cancer is composed of multiple stages, starting with benign polyps in the large intestine and rectum, and gradually progress to carcinomas, providing a window of opportunity for early detection. Early diagnosis increases the survival rate of patients, thus making screening tests for precursor lesions (PL) and early-stage CRC essential for reducing the mortality rate. In this context, the early detection of tumors based on liquid biopsy could provide benefits for improving the survival rate of CRC patients and has emerged as a promising avenue for cancer screening. The aim of the study was to evaluate the presence of variants in plasma cell-free tumor DNA from patients with PL and CCR to identify diagnostic and early screening biomarkers. Material and Methods: The cell-free DNA (cfDNA) samples were obtained from plasma of patients that underwent diagnostic colonoscopy. Eight patients did not have any significant lesions (normal colonoscopy or hyperplastic polyp) and were classified as normal (N), 28 as CRC and 23 as PL - 13 as early adenomas (EA), 9 advanced adenomas (AA), and 1 sessile serrated lesion (SSL). In addition, the genomic DNA samples from 2 FFPE tumor matched pair samples were analyzed. Analysis of variants in 14 CRC associated genes was performed using Oncomine Colon cfDNA Assay and Ion Torrent PGM/S5 sequencer. Results and discussion: All variants were classified as missense or truncating and considered as pathogenic. Forty-seven variants were detected in nine genes (TP53, PIK3CA,FBXW7, APC, BRAF, GNAS, KRAS, MAP2K1, and SMAD4). TP53 gene showed the highest number of variants, comprising 53.19% of all detected variants, followed by KRAS (10.63%) and APC (8.51%). It was possible to detect the presence of at least one variant in ctDNA for 5 PL (5/23 - 21.73%) patients, including variants in 3 patients with early adenoma (3/13 - 23.07%) and 2 with advanced adenomas (2/9 - 22.22%) and fourteen CRC (14/28 - 50%). No variants were detected in patients with normal findings during colonoscopy. Concordance between detected variants in tumor tissue and plasma ctDNA (from matched samples) was observed only for two variants for CRC patients (GNAS and KRAS). Conclusion: The detection of variants in liquid biopsy demonstrates the potential for non-invasive early screening and diagnostic of CRC. Citation Format: Mariana Bisarro Dos Reis, Wellington dos Santos, Ana Carolina de Carvalho, Adhara Brandão, Adhara Brandão, Marcus Matsushita, Rui Manuel Reis, Denise Peixoto Guimarães. Use of liquid biopsy for detection of pathogenic variants in cell-free tumor DNA from patients with precursor lesions and colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3380.

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.

The current study aimed to identify new breast and/or ovarian cancer predisposition genes. For that, whole‐exome sequencing (WES) was performed in the germline DNA of 52 non‐BRCA1/BRCA2/TP53 mutation carrier women at high‐risk for hereditary breast and ovarian cancer (HBOC). All variants were classified using information from population and disease specific databases, in silico prediction tools and the American College of Medical Genetics and Genomics (ACMG) criteria. Loss of heterozygosity (LOH) of tumor samples and segregation analyses were performed whenever possible. The variants identified were investigated in a second, independent cohort of 17 BC cases. Pathogenic/Likely Pathogenic variants were identified in known cancer genes such as CHEK2, MUTYH, PMS2, and RAD51C. Rare and potentially pathogenic variants were identified in DNA repair genes (FAN1, POLQ, and RAD54L) and other cancer‐related genes such as DROSHA and SLC34A2. Interestingly, the variant c.149T>G in the FAN1 gene was identified in two unrelated families, and exhibited LOH in the tumor tissue of one of them. In conclusion, this is the largest Brazilian WES study involving families at high‐risk for HBOC which has brought novel insights into the role of potentially new genetic risk factors for hereditary breast and ovarian cancer., The current study aimed to identify new breast and/or ovarian cancer predisposition genes. Rare and potentially pathogenic variants were identified in DNA repair genes (FAN1, POLQ, and RAD54L) and other cancer‐related genes such as DROSHA and SLC34A2. This is the largest Brazilian WES study involving families at high‐risk for hereditary breast and ovarian cancer which has brought novel insights into the role of potentially new genetic risk factors for hereditary breast and ovarian cancer.

Medulloblastoma (MB) is the most common malignant brain tumor in children. It is currently classified in four main molecular subgroups with different clinical outcomes: sonic hedgehog, wingless, group 3, and group 4 (MBSHH, MBWNT, MBGRP3, or MBGRP4). Presently, a 22-gene expression panel has been efficiently applied for molecular subgrouping using nCounter technology. In this study, formalin-fixed, paraffin-embedded samples from 164 Brazilian medulloblastomas were evaluated, applying the 22-gene panel, and subclassified into the low and high expression of nine key medulloblastoma-related genes. In addition, TP53 mutation status was assessed using TruSight Tumor 15 Panel, and its correlation with expression and prognostic impact was evaluated. Samples from 149 of 164 patients (90%) were classified into MBSHH (47.7%), MBWNT (16.1%), MBGRP3 (15.4%), and MBGRP4 (20.8%). GNAS presented the highest expression levels, with higher expression in MBSHH. TP53, MYCN, SOX2, and MET were also up-regulated in MBSHH, whereas PTEN was up-regulated in MBGRP4. GNAS, TP53, and PTEN low expression was associated with the unfavorable patient outcome only for MBSHH (P = 0.04, P = 0.01, and P = 0.02, respectively). TP53 mutations were detected in 28.57% of MBSHH cases and exhibited association with lower expression and worse clinical outcome, although not statistically significant. The 22-gene panel for molecular classification of medulloblastoma associated with the expression of GNAS, TP53, and PTEN improves the patient prognostication in MBSHH subgroup and can be easily incorporated in the 22-gene panel without any additional costs.

The molecular basis of colorectal cancer (CRC) can guide patient prognosis and therapy. In Brazil, knowledge on the CRC mutation landscape is limited. Here, we investigated the mutation profile of 150 cancer-related genes by next-generation sequencing and associated with microsatellite instability (MSI) and genetic ancestry in a series of 91 Brazilian CRC patients. Driver mutations were found in the APC (71.4%), TP53 (56.0%), KRAS (52.7%), PIK3CA (15.4%) and FBXW7 (10.9%) genes. Overall, genes in the MAPK/ERK, PIK3/AKT, NOTCH and receptor tyrosine kinase signaling pathways were mutated in 68.0%, 23.1%, 16.5%, and 15.3% of patients, respectively. MSI was found in 13.3% of tumors, most of which were proximal (52.4%, P, We are thankful to Barretos Cancer Hospital. This work was supported by the Brazilian Federal Agency for the Support and Evaluation of Graduate Education (CAPES, Brazil), the National Council for Scientifc and Technological Development (CNPq, Brazil), and the Public Ministry of Labor Campinas (Research, Prevention and Education of Occupational Cancer, 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.

Glioblastoma (GBM) is the deadliest primary brain tumor. The standard treatment consists of surgery, radiotherapy, and temozolomide (TMZ). TMZ response is heterogeneous, and MGMT promoter (MGMTp) methylation has been the major predictive biomarker. We aimed to describe the clinical and molecular data of GBMs treated with TMZ, compare MGMT methylation with MGMT expression, and further associate with patient’s outcome. We evaluate 112 FFPE adult GBM cases. IDH1 and ATRX expression was analyzed by immunohistochemistry, hotspot TERT promoter (TERTp) mutations were evaluated by Sanger or pyrosequencing, and MGMTp methylation was assessed by pyrosequencing and MGMT mRNA expression using the nCounter® Vantage 3D™ DNA damage and repair panel. Of the 112 GBMs, 96 were IDH1WT, and 16 were IDH1MUT. Positive ATRX expression was found in 91.6% (88/96) of IDHWT and 43.7% (7/16) of IDHMUT. TERTp mutations were detected in 70.4% (50/71) of IDHWT. MGMTp methylation was found in 55.5% (35/63) of IDHWT and 84.6% (11/13) of IDHMUT, and as expected, MGMTp methylation was significantly associated with a better response to TMZ. MGMT expression was inversely correlated with MGMTp methylation levels (− 0.506, p

Anaplasia may be identified in a subset of tumors with a presumed pilocytic astrocytoma (PA) component or piloid features, which may be associated with aggressive behavior, but the biologic basis of this change remains unclear. Fifty-seven resections from 36 patients (23 M, 13 F, mean age 32 years, range 3–75) were included. A clinical diagnosis of NF1 was present in 8 (22%). Alternative lengthening of telomeres (ALT) was assessed by telomere-specific FISH and/or CISH. A combination of immunohistochemistry, DNA sequencing and FISH were used to study BRAF, ATRX, CDKN2A/p16, mutant IDH1 p.R132H and H3-K27M proteins. ALT was present in 25 (69%) cases and ATRX loss in 20 (57%), mostly in the expected association of ALT+/ATRX- (20/24, 83%) or ALT-/ATRX+ (11/11, 100%). BRAF duplication was present in 8 (of 26) (31%). H3-K27M was present in 5 of 32 (16%) cases, all with concurrent ATRX loss and ALT. ALT was also present in 9 (of 11) cases in the benign PA precursor, 7 of which also had ATRX loss in both the precursor and the anaplastic tumor. In a single pediatric case, ALT and ATRX loss developed in the anaplastic component only, and in another adult case, ALT was present in the PA-A component only, but ATRX was not tested. Features associated with worse prognosis included subtotal resection, adult vs. pediatric, presence of a PA precursor preceding a diagnosis of anaplasia, necrosis, presence of ALT and ATRX expression loss. ALT and ATRX loss, as well as alterations involving the MAPK pathway, are frequent in PA with anaplasia at the time of development of anaplasia or in their precursors. Additionally, a small subset of PA with anaplasia have H3-K27M mutations. These findings further support the concept that PA with anaplasia is a neoplasm with heterogeneous genetic features and alterations typical of both PA and diffuse gliomas.

Medulloblastoma is the most frequent malignant brain tumor in children, representing 20% of all childhood brain tumors. Currently, medulloblastomas are molecularly classified in 4 subgroups that are associated with distinctive clinicopathological features. KBTBD4 mutations were recently described in a subset of MBGRP3 and MBGRP4 medulloblastomas subgroups. However, no other studies reported KBTBD4 mutations in medulloblastomas. Thus, our aim was to investigate KBTBD4 mutations in a Brazilian series of medulloblastoma. We evaluated 128 medulloblastoma patients molecularly classified from 4 Brazilian reference centers. DNA from formalin-fixed, paraffin-embedded samples was screened for KBTBD4 hotspot mutations by Sanger sequencing. Most of the patients were male, average age was 16.5 years old and average overall survival was 55.9 months. The predominant histological subtype was the classic subtype, followed by nodular/desmoplastic, and the predominant medulloblastoma molecular subtype was the MBSHH subgroup (46%), followed by MBGRP3 and MBGRP4 (19%/each), and MBWNT (16%). Among the 128 samples, 111 were successfully sequenced. No KBTBD4 mutations were identified in 111 samples. Our findings suggest that KBTBD4 mutations are uncommon in Brazilian MBGRP3 and MBGRP4 medulloblastomas subgroups. Further studies in a larger series of MBGRP3 and MBGRP4 medulloblastomas are warranted to better assess role of KBTBD4 mutations., We thank Barretos Cancer Hospital and FINEP for partially funding the present study. Leticia Ferro Leal is supported by Public Ministry of Labor Campinas (Research, Prevention and Education of Occupational Cancer) in Campinas, Brazil. Rui Manuel Reis is sponsored by the National Council for Scientific and Technological Development (CNPq, Brazil).

Background: Glioblastomas (GB) are the most common primary malignant brain tumors in adults. The standard therapy consists of surgery, radiotherapy and concomitant and adjuvant administration of temozolomide (TMZ). GB is a heterogeneous disease and despite extensive efforts for improving treatment strategies in the last decades, few advances have been reached in patients’ overall survival (OS), which remains nearly 15 months. Recently, many researches have been focusing on the tumor microenvironment which is particularly immunosuppressed in GB and more studies are necessary to investigate the immunological factors involved in tumor progression for the development of new therapeutic approaches. Objectives: The present study aimed to evaluate the expression profile of 730 genes associated with immune-oncology using NanoString in 37 primary GB samples from patients treated with TMZ and investigate the relationships with patient’s survival and response to TMZ. Methods: In this retrospective study, GB patients from Barretos Cancer Hospital (BCH), Brazil, were divided into short term survivals (STS), OS < 12 months (n=26) and Long term survivals (LTS), OS > 3 years (n=11). The OS was calculated from the date of diagnosis to death or last follow up. The RNA was extracted from FFPE samples (first surgery), using the RNAeasy mini kit (Qiagen) and quantified using Qubit HS assay (ThermoFisher). The evaluation of mRNA levels was performed using the Pan-Cancer Immunoprofiling panel, which contains 770 targets with 730 immuno-oncology related and 40 housekeeping genes. The nSolver software and the Advanced analysis package (NanoString Technologies) was used for data analysis. The TCGA data banks (cBioPortal – RNAseq TCGA 2013/2018 and Betastasis – microarrays, Affymetrix Human Exon 1.0 ST/ HT HG U133A) were assessed to confirm our findings. Results: The NanoString analyses revealed that 24 immuno-oncology related genes were significantly upregulated in GB STS (p Conclusion: In the present study we found that immune-oncology related genes as NFSF14, LY96, SLC11A1, and CTSL, are overexpressed in GB. These genes are possible biomarkers of TMZ response in GB. Future functional studies should be conducted to evaluate the potential of these targets for immunotherapy. Citation Format: Daniel Moreno, Luciane Sussuchi, Letícia Leal, Bruna Sorroche, Iara Santana, Marcus Matsushita, Krishna Bhat, Sean Lawlew, Rui Reis. The overexpression of Immune oncology-related genes NFSF14, LY96, SLC11A1 and CTSL are associated with short survival in glioblastoma [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO005.

Human hotspot TERT promoter (TERTp) mutations have been reported in a wide range of tumours. Several studies have shown that TERTp mutations are associated with clinicopathological features; in some instances, TERTp mutations were considered as biomarkers of poor prognosis. The rs2853669 SNP, located in the TERT promoter region, was reported to modulate the increased TERT expression levels induced by the recurrent somatic mutations. In this study we aimed to determine the frequency and prognostic value of TERTp mutations and TERT rs2853669 SNP in 504 gliomas from Portuguese and Brazilian patients. TERTp mutations were detected in 47.8% of gliomas (216/452). Glioblastomas (GBM) exhibited the highest frequency of TERTp mutations (66.9%); in this glioma subtype, we found a significant association between TERTp mutations and poor prognosis, regardless of the population. Moreover, in a multivariate analysis, TERTp mutations were the only independent prognostic factor. Our data also showed that the poor prognosis conferred by TERTp mutations was restricted to GBM patients carrying the rs2853669 A allele and not in those carrying the G allele. In conclusion, the presence of TERTp mutations was associated with worse prognosis in GBM patients, although such association depended on the status of the rs2853669 SNP. The status of the rs2853669 SNP should be taken in consideration when assessing the prognostic value of TERTp mutations in GBM patients. TERTp mutations and the rs2853669 SNP can be used in the future as biomarkers of glioma prognosis.

BACKGROUND Diencephalic syndrome (DS) is a rare condition associated with neoplastic lesions of the sellar-suprasellar region, whose pathophysiological mechanisms are still unclear. DS occurs in CONCLUSION DS should be considered as a differential diagnosis in any child with failure to thrive, and imaging studies should be performed even if there are no additional neurological symptoms.

BACKGROUND The challenge of surgery in neurooncology is to achieve the maximum extent of resection while preserving eloquent functions. Intra-operative cortical mapping during resection of a brain tumor allows direct stimulation in eloquent areas with a reduction in postoperative deficits. This procedure has been performed in adults and children down to the age of 11 years. There are only two cases reported on the literature of an 8-year-old and 9-year-old child submitted to an awake craniotomy for brain tumor resection. Pediatric patients are prone to more risks than adults because they become easily agitated after pain sensation. Extensive preparation for the procedure is essential for pediatric patients in order to avoid a lack of cooperation. CASE PRESENTATION: Two patients, with 9-year-old presented with seizures due to a tumor in the left temporoparietal region. In order to identify language and motor–controlling areas during resection, we proposed an awake craniotomy. Because of their ages, they were prepared by a multidisciplinary team. The children’s cooperation during the mapping procedure and tumor resection were exceptional. Postoperative cranial MRI confirmed partial resection of the lesion, whose remnant was located in the left motor area. No seizures occurred during the postoperative period, and both were discharged without a neurological disability on the fifth day after the surgery. Histology revealed a dysembryoplastic neuroepithelial tumor (WHO grade I). CONCLUSION Brain mapping during resection of a tumor in an awake pediatric patient is feasible and can be safely performed even in patients under 11-year-old.

BACKGROUND Atypical teratoid/rhabdoid tumor (ATRT) is a malignant neoplasm of the central nervous system and corresponds to 1.5% of all intracranial tumors. Mainly affects children under three years of age and shows aggressive behavior (most pediatric patients succumb to their disease within a year after the initial diagnosis, despite the treatment performed). Its place of occurrence in children is preferably in the posterior fossa, and it is rare to appear in other regions. There are only seven patients with ATRT reported on literature; all of them are adults. We present the case of a pediatric patient with a tumor in the pineal region diagnosed as ATRT. CASE REPORT: Three-year-old female patient admitted with occipital headache, vomiting, and seizure. Magnetic resonance imaging (MRI) showed obstructive hydrocephalus secondary to a solid-cystic lesion located at the pineal region that was 3.0 x 3.0 x 3.5 cm in size. Spine MRI did not reveal leptomeningeal spreading. We performed an occipital transtentorial approach to achieve the best safe resection possible, and a ventriculoperitoneal shunt. Histological examination revealed ATRT. The patient received adjuvant treatment with radiotherapy and chemotherapy according to the “Head Start” protocol. One year after the surgery, MRI did not identify any remaining lesion. CONCLUSION ATRT is an aggressive and rare neoplasm whose clinical picture depends on the location of the tumor; however, it must be considered in the differential diagnosis of tumors of the pineal region in the pediatric population.

The aim of the present study was to compare fecal immunochemical tests (FITs) for colorectal cancer (CRC) screening with the traditional guaiac-based FOB tests (gFOBT). Background/Aim: The aim of the present study was to compare fecal immunochemical tests (FITs) for colorectal cancer (CRC) screening with the traditional guaiac-based FOB tests (gFOBT). Materials and Methods: A cohort of 368 colonoscopy-referral patients were evaluated by i) the new-generation FIT: ColonView quick test (CV; Biohit Oyj, Finland) and ii) a conventional gFOBT HemoccultSENSA (HS; Beckman Coulter, USA). Three fecal samples were requested for both assays, and all subjects underwent diagnostic colonoscopy with biopsy confirmation. Sensitivity (SE), specificity (SP), positive predictive value (PPV), negative predictive value (NPV) and area under curve (AUC) were calculated for both tests using three endpoints: adenoma (A), advanced adenoma (AA) and adenocarcinoma (AC). Results: Colonoscopy and biopsies disclosed normal mucosa in 90/378 (24.5%) subjects, early A in 108/368 (29.3%) cases, AA in 48/368 (13.0%) and AC in 37/368 (10.1%), and non-neoplastic conditions in the remaining 85 (30.3%). For the AC endpoint, the CV (Hb/Hp) test had 94.6% SE and 65.1% SP (AUC=0.799), while the HS test had SE of 75.7% and SP of 84.3% (AUC=0.800). For the A endpoint, the difference between CV and HS was even more pronounced; SE of 44.2% and 19.2%, respectively (p, The Authors thank Ms. Gabriela de Oliveira for the identification and tracking all the patients included in the study. The Authors would also like to give special thanks to Ms. Thais Thalarico for assisting in data analysis, as well as to Ms. Maraisa Costa and Ms. Adriana Carloni for running the analysis of the gFOBT and FIT tests. This study was supported by Biohit Oyj.

Colorectal cancer (CRC) is the third most frequent cancer worldwide and the fourth leading cause of death due to cancer. The development of this disease usually occurs due to the progression of precursor lesions in the normal intestinal mucosa to tumor. Environment, age, lifestyle, and genetic background are considered risk factors for the development and progression of CRC. The molecular abnormalities involved in the progression of CRC have been well characterized, including mutations, microsatellite instability, and epigenetic changes. Although the molecular profile of colorectal cancer is well known in developed countries, in the Brazilian population information is still very limited. Therefore, in the present study we intended to characterize the mutation profile of a Brazilian population and associate this with their clinicopathologic features. A total of 61 colorectal cancer cases of different stages were included. DNA was extracted from frozen fresh tumors and sequenced using a panel of 298 genes by next-generation sequencing (NGS). The mean age of patients was 63 years old; 57.4% were male. Three patients had CRC in stage 0, 16 in stage I, 29 in stage II, 10 in stage III, and three in stage IV. Considering only nonsynonymous alterations, we found on average 7.24 mutations per patient. The majority were missense (61.8%), followed by nonsense (15.2%) and frameshift mutations (10.9%). The genes most frequently mutated were APC (78.7%), TP53 (72.1%), KRAS (60.7%), PIK3CA (14.8%), and FBXW7 (14.8%). Alterations in tumor suppressor genes such as APC and TP53 were found throughout the entire gene. On the other hand, oncogenes such as KRAS had alterations in hotspots of the gene. In conclusion, the frequency of alterations in genes sequenced in our population was similar to that found in the international literature for other populations. Citation Format: Wellington Santos, Adriane Feijó Evangelista, Ronilson Durães, Marcus Matsushita, Rui Manuel Reis, Denise Peixoto Guimarães. Somatic mutation profile of a panel of oncogenes and tumor suppressor genes in colorectal cancer in a Brazilian population [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A35.

Background: Colorectal cancer (CRC) is the third most common cancer in Brazil, where it appears as the fifth most deadly cancer. Brazilian National Cancer Institute estimates for the year of 2016 in Brazil 16,660 newly diagnosed cases of CRC in men and 17,620 in women. There is evidence that the incidence and mortality rates can be reduced through the detection of precursor lesions and early cancer in the context of CRC screening. Aberrant hypermethylation of cancer-related genes has emerged as a promising strategy for the molecular CRC screening. However, the methylation profile of colorectal cancer of the Brazilian population has limited information about its characterization and frequency. Objective: To investigate the frequency of DNA methylation in the promoter region of tumor suppressor genes SEPT9, NDRG4, and CDKN2A (p16) in sporadic CRCs of Brazilian patients. Methods: Retrospective molecular analysis included 57 adult patients with CRC in different clinical stages attended at the Barretos Cancer Hospital. Demographic, clinical, and tumor-related characteristics were obtained from medical records. DNA was extracted from fresh-frozen tumor tissues. Levels of DNA methylation were determined by quantitative pyrosequencing. Results: The mean ± SD age of the 57 patients' analysis was 64.40 ±14 years; 56.14% (32/57) were males. Almost all tumors (56/57; 98.24%) were located in the left side of the colon, from descending colon to rectum. Regarding stage, 3/57 (5.26%) were stage 0, 15/57 (26.31 %) stage I, 27/57 (47.36%) stage II, 10/57 (17.54%) stage III, and 2/57 (3.53%) stage IV tumors. Among 57 analyzed, 52/57 (91.22%) were methylated for SEPT9, 42/57 (73.68%) for NDRG4, and 15/57 (26.31%) for CDKN2A. In conclusion, in our Brazilian case series, the gene SEPT9 and NDGR4 showed high frequency of methylation CRC tissues, similar with results found in other populations. Citation Format: Thais Sobanski, Lidia Arantes, Wellington dos Santos, Ronilson Durães, Marcus Matsushita, Rui Manuel Reis, Denise Peixoto Guimaraes. Methylation profile of SEPT9, NDRG4, p16 genes in colorectal cancer [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A17.

Neuroendocrine differentiation in prostatic carcinomas generally confers a more aggressive clinical behavior and less favorable prognosis than usual prostatic carcinomas. In this manuscript, we report a case of a 58-year-old man with prostatic carcinoma who died 1 year after initial diagnosis. Autopsy showed a disseminated prostatic carcinoma with neuroendocrine differentiation. There were metastasis to the spleen, an organ infrequently involved by disseminated epithelial neoplasms. Neuroendocrine differentiation was demonstrated by immunohistochemical studies in the biopsy and autopsy material.

Extracellular matrix (ECM) composition has an important role in determining airway structure. We postulated that ECM lung composition of chronic obstructive pulmonary disease (COPD) patients differs from that observed in smoking and nonsmoking subjects without airflow obstruction. We determined the fractional areas of elastic fibres, type-I, -III and -IV collagen, versican, decorin, biglycan, lumican, fibronectin and tenascin in different compartments of the large and small airways and lung parenchyma in 26 COPD patients, 26 smokers without COPD and 16 nonsmoking control subjects. The fractional area of elastic fibres was higher in non-obstructed smokers than in COPD and nonsmoking controls, in all lung compartments. Type-I collagen fractional area was lower in the large and small airways of COPD patients and in the small airways of non-obstructed smokers than in nonsmokers. Compared with nonsmokers, COPD patients had lower versican fractional area in the parenchyma, higher fibronectin fractional area in small airways and higher tenascin fractional area in large and small airways compartments. In COPD patients, significant correlations were found between elastic fibres and fibronectin and lung function parameters. Alterations of the major ECM components are widespread in all lung compartments of patients with COPD and may contribute to persistent airflow obstruction.

It has been suggested that airway remodelling is responsible for the persistent airway obstruction and decline in lung function observed in some asthmatic patients. The small airways are thought to contribute significantly to this functional impairment. Proteoglycans (PGs) are important components of the extracellular matrix (ECM) in the lungs. Besides controlling biophysical properties of the ECM, they play important roles in the regulation of some cytokines. Increased subepithelial PG deposition in the airways of mild asthmatics has been reported. However, there are no data on the PG content in small airways in asthma. This study has compared the content and distribution of PGs in large and small airways of patients who died of asthma with those in control lungs. Immunohistochemistry and image analysis were used to determine the content of lumican, decorin, biglycan, and versican in large (internal perimeter >6 mm) and small (internal perimeter < or =6 mm) airways of 18 patients who had died of asthma (A) and ten controls (C). The results were expressed as PG area (microm2)/epithelial basement membrane length (microm). The main differences between asthmatics and controls were observed in the small airways. There was a significant decrease in decorin and lumican contents in the external area of small airways in asthmatics (decorin: A = 1.05 +/- 0.27 microm, C = 3.97 +/- 1.17 microm, p = 0.042; lumican: A = 1.97 +/- 0.37 microm, C = 5.66 +/- 0.99 microm, p = 0.002). A significant increase in versican content in the internal area of small and large airways in asthmatics was also observed (small: A = 7.48 +/- 0.84 microm, C = 5.16 +/- 0.61 microm, p = 0.045; large: A = 18.38 +/- 1.94 microm, C = 11.90 +/- 2.86 microm, p = 0.028). The results show that PGs are differentially expressed in the airways of fatal asthma and may contribute to airway remodelling. These data reinforce the importance of the small airways in airway remodelling in asthma.