Jorge Alberto Guadarrama-Orozco

Gastric cancer in Latin America

Abstract Every year, cancer affects more than one million Latin Americans. The increasing incidence of cancer could be secondary to an aging population, westernization of life style, and urbanization. LA has among the highest incidence rates of gastric cancer, compared to other countries. In this review, different studies on gastric cancer and its relation with risks factors, such as infections, diet and life styles typical of LA, besides the different molecular alterations of that specific population (mainly at a genetic polymorphism level) are analyzed. An exhaustive research was made in PubMed, MEDLINE and Embase of the most relevant studies conducted in the last 27 years (1990–2017) in LA.

Frequency of BRAF V600E Mutation in the Mexican Population of Patients With Metastatic Melanoma

Purpose The BRAF V600E mutation has been described in melanomas occurring in the Caucasian, European, and Asian populations. However, in the Mexican population, the status and clinical significance of BRAF mutation has not been researched on a large scale. Methods Consecutive BRAF-tested Mexican patients with metastatic melanoma (n = 127) were analyzed for mutations in exon 15 of the BRAF gene in genomic DNA by real-time polymerase chain reaction technology for amplification and detection. The results were correlated with the clinical-pathologic features and the prognosis of the patients. Results The frequency of somatic mutation V600E within the BRAF gene was 54.6% (43 of 127 patients). Nodular melanoma was the most prevalent subtype in our population, with BRAF mutations in 37.2% (16 of 55 patients). In contrast, superficial spread had a frequency of 18.6% BRAF mutation (eight of 24). Other clinicopathologic features were assessed to correlate with the mutation status. Conclusion This study searched for the most prevalent BRAF V600E mutation type in melanoma in a heterogeneous population from Mexico. Nodular melanoma was found to be the most prevalent in metastatic presentation and the presence of BRAF V600E mutation, perhaps related to the mixed ancestry; in the north, ancestry is predominantly European and in the south, it is predominantly Asian. The outcomes of the mutation correlations were similar to those found in other populations.

Search of the p.M918T Mutation in the RET Oncogene in Mexican Adult Patients with Medullary Thyroid Carcinoma

Inherited mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, predispose individuals to the multiple endocrine neoplasia type 2 (MEN 2) cancer syndromes. The major component tumor of these syndromes is medullary thyroid carcinoma (MTC). To date, somatic mutations in RET have been identified in tumors from individuals with MEN 2 finding. RET M918T mutation is present in 95% of the MEN2B cases, and approximately 50% of sporadic MTCs harbor this mutation. We performed a mutational analysis in 17 cases of Medullary thyroid carcinoma, the somatic missense mutation at codon 918 of RET was found in 2 of the 17 MTCs, and one case presented MEN2 phenotype including MTC. The percentage of RET M918T mutation is similar in Mexican MTC patients to other series, although other mutations could be implicated in our population.

Abstract 2870: Serine/arginine rich proteins show different distribution patterns in stratum of oral epidermoid carcinoma

Serine/arginine proteins increased their activity during the alternative splicing in cell nucleus. The nuclear speckles, also known as interchromatin granule clusters, are enriched with SR splicing factors and are implicated in gene expression. Nuclear speckle formation is developmentally regulated; in certain cases phosphorylated SR proteins are absent from the nucleus and are instead localized at granular structures in the cytoplasm. SR proteins are related with splicing during different types of cancers and metastasis. We search for phosphorylated SR proteins and the nuclear pattern and speckle formation in human oral carcinomas. Methods: To address nuclear pattern and speckle formation, we performed a series of immunostaining experiments, with SC35 antibody for phosphorylated srsf2 on sections derived from oral epidermoid tumor from 33 patients. The images were obtained with a microscope (Leica TCS SPE/CTR 4000). For imaging cytometry analyses, a Leica LAS AF Lite software (Leica Microsystems) was used to capture images automatically; images and recognition of nuclear speckles were quantitatively analyzed using analysis software (ImageJ). ANOVA analysis was performed for the cellular and staining correlation. Results: There are significant differences in morphology and distribution of intranuclear mottled pattern of SR proteins in each tissue layer between oral epithelial without neoplasia and oral squamous cell carcinoma (P We found that is in the granulosum stratum of oral squamous carcinomas where the SR proteins shows more transcriptional activity. This finding could be related with the increased metabolism of this layer. Citation Format: Cynthia J. Ceja-Lopez, Reyna Lara-Martinez, Lourdes Segura-Valdes, Luz Ruiz Godoy Rivera, Javier A. Ambrosio Hernandez, Jorge Alberto Guadarrama-Orozco, Erika Ruiz-Garcia, Luis Felipe Jimenez Garcia, Abelardo Meneses-Garcia. Serine/arginine rich proteins show different distribution patterns in stratum of oral epidermoid carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2870.

Abstract 3173: Next generation sequencing (NGS) of dihydropyrimidine dehydrogenase (DPYD) gene in Mexican patients with gastrointestinal (GI) carcinomas

Background: Fluoropyrimidines (5-fluorouracil (5-FU), capecitabine and tegafur) are the mainstay chemotherapeutic drugs for gastrointestinal cancer. Patients with deficiency of dihydropyrimidine dehydrogenase enzyme (DPD), which interfere with the pyrimidine metabolism, could be at risk toxicity (mild, severe or lethal) because >80% of the administered 5-FU is catabolized by DPD. Previously, our group studied DPYD single-nucleotide polymorphism (SNPs) by real-time PCR assay, in 72 Mexicans. We found that frequency of SNP 85T>C and 85T>T was similar as Oriental race (2-3%), but contrast with Caucasians (0.19%), meanwhile, for SNP 496A>G which Caucasian prevalence was reported 0.8%, in our Mexican sample was very high (14%). Even though, none of our patients with toxicity grade 3-4, were positive to the SNP associated to higher toxicity (IVS14 + 1G>A). Because of this heterogeneity, we decide to sequence the complete gen in our population. Methods: We included prospectively, 19 patients of the GI Oncology Department of the National Cancer Institute of Mexico, who were treated with fluoropyrimidines. We follow them during the whole treatment. DNA was extracted from whole blood using the DNeasy blood and tissue kit (Qiagen Ltd, Crawley, UK). We use the AmpliSeq™ Designer for the full coverage of all 23 exons of DPYD gene; 25 μg of DNA was used for library construction (Ion Ampliseq Library kit 2.0), we follow the manufacturer9s instructions for the target sequencing of DPYD gene with the Ion Torrent PGM platform. The data management was performed with the Ion Reporter Software of Thermo Fisher. Results: We found that 89.5% of the patients had SNPs (c.85C>T), 44.1% (c.1627A>G) and 5.2% (c.496A>G). Mean while SNPs: c.1896T>C, c.451A>G, c.771C>T, c.2384G>A, c.2605G>A, c.1462A>G, c.1422_1422delA were present in a lower frequencies. These results were associated to clinical toxicity (mucositis, neurotoxicity, hand foot syndrome, hematological toxicity and diarrhea grade >2) but there wasn9t any association (chi2 test). Not a single patient were positive for IVS14 + 1G>A. Conclusion: These are the first results using NGS for DPYD gene in Mexican people. We confirm that our population had a different molecular profile that Caucasians. We need to improve the sample size, to see if we could find an association between SNPs and clinical toxicity. Citation Format: Erika Ruiz-Garcia, Alicia Lopez-Yanez, Alette Ortega, Jorge Guadarrama-Orozco, Gisela Hernandez-Luis, Fabiola De la Rosa, Abelardo Meneses-Garcia, Horacio Astudillo-de la Vega. Next generation sequencing (NGS) of dihydropyrimidine dehydrogenase (DPYD) gene in Mexican patients with gastrointestinal (GI) carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3173.

Stem Cells in Pancreatic Cancer

Pancreatic adenocarcinoma (PDAC), the fourth cause of cancer-related death, is highly resistant to conventional chemo and radiation therapy. Despite the efforts in therapy research and those to improve the survival of patients with pancreatic cancer in the last 10 years, there has not been major advance. The increasing study and understanding of pancreatic cancer biology has led us to discover the pancreatic cancer stem cells (CSC), a cell subpopulation with self-renewal characteristics and multipotential phenotype. They are considered the drivers of tumorigenesis and metastasis, and also responsible to confer resistance to current therapy, and repopulate the tumor after chemotherapy withdrawal. These CSCs are changing the way to understand and treat PDAC. Significant efforts have been made in CSC to define the underling mechanisms of resistance, progression and metastasis; and identify potential therapeutic targets in these cells to improve response rates and survival in patients with PDAC. The question to answer is whether this effort is working or not?