Variants Identified in the HOXC13 and HOXD13 Genes Suggest Association with Cervical Cancer in a Cohort of Mexican Women.

HOX genes have been associated with carcinogenesis. However, the molecular mechanism by which tumors are generated remains unclear. The HOXC13 and HOXD13 genes are of interest for their involvement in the development of genitourinary structures. The aim of this first study in the Mexican population was to search for and analyze variants in the coding region of the HOXC13 and HOXD13 genes in women with cervical cancer. Samples from Mexican women with cervical cancer and healthy women were sequenced (50/50). Allelic and genotypic frequencies were compared between groups. The functional impact of the proteins was determined with two bioinformatics servers (SIFT and PolyPhen-2), and the oncogenic potential of the identified nonsynonymous variants was determined using the CGI server. We identified five unreported gene variants: c.895C>A p.(Leu299Ile) and c.777C>T p.(Arg259Arg) in the HOXC13 gene and c.128T>A p.(Phe43Tyr), c.204G>A p.(Ala68Ala), and c.267G>A p.(Ser89Ser) in the HOXD13 gene. In this study, we suggest that the non-synonymous variants c.895C>A p.(Leu299Ile) and c.128T>A p.(Phe43Tyr) could represent a risk factor for the development of the disease, although additional studies in larger patient populations and in different ethnic groups are needed in order to support the results observed.

Acetate Promotes a Differential Energy Metabolic Response in Human HCT 116 and COLO 205 Colon Cancer Cells Impacting Cancer Cell Growth and Invasiveness.

Under dysbiosis, a gut metabolic disorder, short-chain carboxylic acids (SCCAs) are secreted to the lumen, affecting colorectal cancer (CRC) development. Butyrate and propionate act as CRC growth inhibitors, but they might also serve as carbon source. In turn, the roles of acetate as metabolic fuel and protein acetylation promoter have not been clearly elucidated. To assess whether acetate favors CRC growth through active mitochondrial catabolism, a systematic study evaluating acetate thiokinase (AcK), energy metabolism, cell proliferation, and invasiveness was performed in two CRC cell lines incubated with physiological SCCAs concentrations. In COLO 205, acetate (+glucose) increased the cell density (50%), mitochondrial protein content (3-10 times), 2-OGDH acetylation, and oxidative phosphorylation (OxPhos) flux (36%), whereas glycolysis remained unchanged vs. glucose-cultured cells; the acetate-induced OxPhos activation correlated with a high AcK activity, content, and acetylation (1.5-6-fold). In contrast, acetate showed no effect on HCT116 cell growth, OxPhos, AcK activity, protein content, and acetylation. However, a substantial increment in the HIF-1α content, HIF-1α-glycolytic protein targets (1-2.3 times), and glycolytic flux (64%) was observed. Butyrate and propionate decreased the growth of both CRC cells by impairing OxPhos flux through mitophagy and mitochondrial fragmentation activation. It is described, for the first time, the role of acetate as metabolic fuel for ATP supply in CRC COLO 205 cells to sustain proliferation, aside from its well-known role as protein epigenetic regulator. The level of AcK determined in COLO 205 cells was similar to that found in human CRC biopsies, showing its potential role as metabolic marker.

S-allylcysteine induces cytotoxic effects in two human lung cancer cell lines via induction of oxidative damage, downregulation of Nrf2 and NF-κB, and apoptosis.

In this study, we investigated the putative cytotoxic effect elicited by the garlic-derived compound S-allylcysteine (SAC) in two human cancer cell lines (HCC827 and NCI-H1975) in order to develop an experimental approach to the therapeutic potential of this molecule for lung cancer. Cells were incubated for 24, 48 and 72 h in the presence of SAC (10 or 20 mM), which resulted in a concentration- and time-dependent decrease in cell viability and culture confluence in both cell lines. These effects were contrasted with - and validated through - those observed in an immortalized but nontumorigenic epithelial cell line from human bronchial epithelium (BEAS-2B, negative control) and an adenocarcinoma human alveolar basal epithelial cell line (A549, positive control). SAC (20 mM at 72 h) also increased the oxidative damage to lipids, augmented apoptosis, and decreased the expression of the nuclear factor erythroid 2-related factor 2 (Nrf2) and the nuclear factor kappa B (NF-κB) proteins in HCC827 and NCI-H1975 cells. Our results establish the efficacy of SAC in reducing malignant growth and proliferation of lung tumor cells. This effect is mediated by the induction of oxidative damage associated with the downregulation of Nrf2 and NF-κB and their corresponding signaling pathways.

Heart myxoma develops oncogenic and metastatic phenotype.

PURPOSE: Heart myxomas have been frequently considered as benign lesions associated with Carney's complex. However, after surgical removal, myxomas re-emerge causing dysfunctional heart. METHODS: To identify whether cardiac myxomas may develop a metastatic phenotype as occurs in malignant cancers, a profile of several proteins involved in malignancy such as oncogenes (c-MYC, K-RAS and H-RAS), cancer-associated metabolic transcriptional factors (HIF-1α, p53 and PPAR-γ) and epithelial-mesenchymal transition proteins (fibronectin, vimentin, ß-catenin, SNAIL and MMP-9) were evaluated in seven samples from a cohort of patients with atrial and ventricular myxomas. The analysis was also performed in: (1) cardiac tissue surrounding the area where myxoma was removed; (2) non-cancer heart tissue (NCHT); and (3) malignant triple negative breast cancer biopsies for comparative purposes. RESULTS: Statistical analysis applying univariate (Kruskal-Wallis and Dunn's tests) and multivariate analyses (PCA, principal component analysis) revealed that heart myxomas (7-15 times) and myxoma surrounding tissue (22-99 times) vs. NCHT showed high content of c-MYC, p53, vimentin, and HIF-1α, indicating that both myxoma and its surrounding area express oncogenes and malignancy-related proteins as occurs in triple negative breast cancer. CONCLUSIONS: Based on ROC (receiver operating characteristics) statistical analysis, c-MYC, HIF-1α, p53, and vimentin may be considered potential biomarkers for malignancy detection in myxoma.

A pharmacoeconomic analysis of the collection and preservation of samples in the biobank of the "Instituto Nacional de Cancerología" in Mexico City.

In this work we estimated the budgetary impact of the samples produced by the biobank of the "Instituto Nacional de Cancerología" (BT-INCan) to set a recuperation fee from the perspective of the Health Ministry of Mexico. The study is an observational retrospective review of the direct medical costs (DMCs) of the processes involved in cryopreservation of the samples collected, on a per sample basis, including materials, laboratory tests, personnel, and administrative costs. Materials and labor costs were determined by information collected from the BT-INCan. DMCs were provided depending on the type of sample: plasma, tissue and biopsy; they were calculated according to the process required to preserve them. Sensitivity analysis was performed using bootstrap. Recuperation costs ranged from 130 to 155 USD. Costs were considered on a 5-year time frame for the maintenance per sample, which is the average time that a sample is kept in the BT-INCan. The cost analysis is perceived as an approximation to the most adequate recuperation fee per sample needed to guarantee the correct development of the BT-INCan. This work provides a basis and valuable information about costs, to enable several health institutions to strategically plan and manage a biobank or even motivate to establish their own biobank.

Identification of a metabolic and canonical biomarker signature in Mexican HR+/HER2-, triple positive and triple-negative breast cancer patients.

Infiltrating ductal breast cancer (IDC) is the principal tumor associated-malignancy in Mexican women. In IDC, the development of intermittent hypoxia leads to an adaptive response coordinated by the transcriptional factor HIF-1α. In the present pilot, retrospective/cross-sectional study, the HIF-1α expression was analyzed in 102 tru-cut biopsies from female patients (51 ± 12 years) without previous clinical treatment and compared to 31 normal breast biopsies. The 102 IDC samples corresponded to 56% of HER2-/HR+; 8% of HER2+/HR-; 22% of triple positive (HER2+/HR+); and 14% of triple negative (TN, HER2-/HR-) subtypes. To assess HIF-1α functionality, proteomic and kinetic analysis of glycolytic as well as mitochondrial enzymes, were determined. Validation of HIF-1α as cancer biomarker was assessed by determining the contents of the commonly used biomarkers c-MYC, Ki67, and H- and K-RAS, as well as metastatic and autophagy proteins. Proteomic analysis revealed that HIF-1α, c-MYC, HER2 and COXIV contents were significantly increased in all IDC subtypes vs. normal tissue. The contents and activities of glycolytic proteins were similar between normal and IDC samples, except for HER2-/HR+ where a substantial increase of HKII was observed. Significant increase in 2OGDH and E-cadherin was detected for TN samples vs. other IDC subtypes and for normal samples. These results clearly indicated that HIF-1α + COXIV + c-MYC (+ HER2 for HER2+ subtype) may be useful to depict a breast cancer metabolic marker pattern for diagnosis, whereas the contents of HIF-1α + c-MYC + 2OGDH + E-cadherin may be an alternative useful and reliable signature for TN subtype cancer prognosis.

[Main malignant neoplasms in Mexico and their geographic distribution, 1993-2002]. / Principales neoplasias malignas en México y su distribución geográfica (1993-2002).

UNLABELLED: INTRODUCCION: Cancer is one of the main causes of death worldwide. In Mexico it represents the third cause of death. OBJECTIVE. To know the frequency and distribution of the malignancies diagnosed in Mexico during 10 years. MATERIAL AND METHODS: From the data-base of the histopathological register of malignant neoplasms in Mexico, was obtained a descriptive analysis from the period 1993-2002. The variables included were: city and federative entity of residence, age, sex, anatomical region and histopathologic diagnosis. From the 12 more common malignant neoplasms a descriptive demographic analysis was performed adjusted by four regions: Center, North, South and Federal District. RESULTS: A total of 767,464 cases with cancer were reported. In order of frequency were: cervix-uterine cancer, breast cancer, prostate cancer, lymphomas, colorectal cancer, gastric cancer, sarcomas, ovary cancer, lung cancer, leukemias, urinary bladder cancer and uterine body. Seventy-two percent were diagnosed in women and 28% in men, the reason for a ratio W:M of 2.5:1. The states more developed and industrialized, near to United States had the majority of cases from breast, prostate, ovary and lung cancer. CONCLUSION: There is a distinctive distribution type of malignant tumors in Mexico, according to the region of residence. It absolutely is necessary to developed population based cancer registries. These are the best instruments to better understand the magnitude of cancer, and evaluate incidence, survival and mortality.

Costs of breast cancer treatment prior to the introduction of immune-based therapy in Mexico.

BACKGROUND: the aim was to perform a cost analysis on direct data of integral medical care provided to BC patients prior to introduction of immunotherapy. METHODS: a total of 633 patients were studied. Direct costs calculations were performed on individual patient data in a subset of 309 randomly selected patients, extrapolating calculations to the universe of 633 patients. Information was obtained for each management process (diagnosis and staging, cancer management, symptoms control, palliative care and follow-up). Costs are expressed in 2008 US dollars (USD) and adjusted to a 3 % discount rate. RESULTS: the clinical stage distribution in the 633 patients was 41, 191, 240 and 58 patients for clinical stages I to IV, respectively; with 103 patients referred from other institutions without staging. The annual costs of care per patient was, in clinical stage I: 6,219,94 USD; stage II: 7,498.04 USD; stage III: 9,610.31 USD; stage IV: 9,917.82 USD; and in patients without staging: 7,504.41 USD. The exact total integral cost according to the universe of BC patients (n = 633) by 2004 was 5,341,805.37 USD. CONCLUSIONS: before the introduction of immune-based therapy costs of care for Mexican women with BC increased with advanced stages do to a significant proportion of patients were diagnosed late.

Expression of the metalloproteases MMP-1, MMP-2, MMP-3, MMP-9, MMP-11, TIMP-1 and TIMP-2 in angiocentric midfacial lymphomas.

BACKGROUND: Extranodal T/NK cell lymphomas possess distinctive clinico-pathological characteristics: they are angiocentric, exhibit extensive necrosis. Prognosis is poor in the short term. The objective is to explore the expression of different MMPs in the cells and stroma which are around of the blood vessels damaged and their correlation with clinico-pathological parameters. PATIENTS AND METHODS: Twenty cases of this type of lymphomas were studied and collected patient clinical data. The expressions of MMP-1, 2, 3, 9, 11, 13 and TIMP-1, 2 were studied by immunohistochemistry. Ultrastructural studies were performed in two cases. Statistical analysis was done with Fisher's exact test, Chi(2) test. RESULTS: Of the 20 patients, 13 were men with median age of 43 years. In 13 patients the primary tumor was localized in the nasal cavity. Treatment was combined chemotherapy and radiotherapy in 60%. The 55% advanced clinical stages, 70% died from the disease. There were neoplastic cell and peritumoral fibroblasts positivity to MMP-1 and MMP-11 in most of the cases. The MMPs-2, 3 and 9 were expressed in neoplastic cell between 30 to 65%of the cases. TIMP-1 was presented mainly in the epithelium and TIMP-2 was poor expressed of the all cases. CONCLUSION: There were no statistical significance between the different enzymes used and the clinical parameters, besides status and survival of the patients. It is necessary to study more enzymes and focus them to quantify and determine their activity, in order to have a better correlation with histological features in this type of neoplasm.

Hybrid tumours of the salivary glands. A report of two cases involving the palate and a review of the literature.

Hybrid tumours are very rare salivary gland lesions composed of two or more different tumoural entities in a single neoplasm that arise within a definite topographical region. In most cases adenoid cystic carcinoma has been the predominant component in these lesions. In this study we describe two patients with hybrid tumours located in the palate, one in a 49-year-old woman and one in a 71-year-old man. The first case involved adenoid cystic carcinoma and mucoepidermoid carcinoma, and the patient in the second case exhibited adenoid cystic carcinoma and epithelial-myoepithelial carcinoma. Both patients were treated with surgery and radiotherapy, and there has been no evidence of recurrence after 13 and 36 months of follow-up, respectively. The recognition of the histologic component with the higher grade of malignancy in every case of hybrid tumour of the salivary glands is a necessary step to determine the biological behaviour and, consequently, to determine the proper therapeutic approach.

El manejo de los paragangliomas en el Instituto Nacional de Cancerología / Management of the parangangliomas in the Instituto Nacional de Cancerologia

Los paragangliomas son tumores cuyas células se derivan del sistema extraadrenal cromafín. Se le conoce por una variedad de nombres que incluyen glomus, quemodectomas y glomerulocitomas. Ocurren con mayor frecuencia en el cuerpo carotídeo, en la mujer y en personas que viven en ciudades ubicadas en altitud elevada. Se realizó un estudio retrospectivo para evaluar las formas de diagnóstico y manejo de esta tumoración en el Instituto Nacional de Cancerología de la Ciudad de México. Se reportan 31 casos que ocurrieron exclusivamente en mujeres. La localización más frecuente fue en el cuerpo carotídeo (90.3 por ciento). El estudio de imagen más utilizado fue la tomografía computada (61.3 por ciento) seguido de la angiografía (51.6 por ciento). El tratamiento de elección fue la resección quirúrgica (81.8 por ciento), seguido de la radioterapia (6.1 por ciento); cuatro casos rechazaron tratamiento (12.1 por ciento). Con estas modalidades de tratamiento no se registraron defunciones ni secuelas y todos los pacientes se encuentran vivos en la actualidad.

Mixoma odontogénico: presentacion de dos casos / Odontogenic mixoma: presentation of two cases

Dos casos de mixoma en maxilar son descritos. Estos fueron encontrados durante la presencia de edema en maxilar izquierdo, en el primer caso y, por examen dental por persistencia del incisivo lateral superior, en el segundo caso. Los tumores fueron examinados por microscopia de luz, histoquímica, inmunohistoquímica y radiológicamente. Células estrelladas con procesos ramificantes inmersas en abundantes cantidades de mucopolisacáridos ácidos se encontraron. En el segundo caso, un odontoma compuesto con islas de epitelio odontogénico fue identificado. Debido a su morfología, debe diferenciarse de la hiperplasia folicular y de algunos sarcomas con material mixoide. Los dos tumores fueron positivos a filamentos de vimentina y negativos a PS-100. El tratamiento, en ambos casos consistió en resección quirúrgica y después de 14 y ocho meses de seguimiento, respectivamente, no hay evidencia de recurrencias.Palabras clave: Mixoma. Mixoma odontogénico. Neoplasias mixoides

Cordomas de cabeza y cuello: presentación de 10 casos / Head and neck chordomas: presentation of 10 cases

Se describen 10 casos de cordomas localizados en la región de cabeza y cuello, recopilados en el período de 1987 a 1997, cuyo tiempo de evolución fue de 41 meses (9-96 meses) y tamaño que fue valorable en cinco pacientes, variando entre 1.5 y 10cm. (6.3 cm. Promedio). La localización más frecuente fue la región del clivus (30 por ciento), seguida de la región cervical y la nasofaringe. Nueve de los casos fueron cordomas convencionales y uno cordoma condroide. Hubo estudios de inmunohistoquímica en cinco casos, que presentaron reactividad a queratina, proteína S-100 y EMA. El tratamiento fue quirúrgico con radioterapia postoperatoria. El 60 por ciento presentaron recurrencias o persistencia tumoral. El seguimiento promedio fue de 15.6 meses