Potential biomarkers of ductal carcinoma in situ progression.

BACKGROUND: Ductal carcinoma in situ is a non-obligate precursor of invasive breast carcinoma and presents a potential risk of over or undertreatment. Finding molecular biomarkers of disease progression could allow for more adequate patient treatment. We aimed to identify potential biomarkers that can predict invasiveness risk. METHODS: In this epithelial cell-based study archival formalin-fixed paraffin-embedded blocks from six patients diagnosed with invasive lesions (pure invasive ductal carcinoma), six with in-situ lesions (pure ductal carcinoma in situ), six with synchronous lesions (invasive ductal carcinoma with an in-situ component) and three non-neoplastic breast epithelium tissues were analyzed by gene expression profiling of 770 genes, using the nCounter® PanCancer Pathways panel of NanoString Technologies. RESULTS: The results showed that in comparison with non-neoplastic tissue the pure ductal carcinoma in situ was one with the most altered gene expression profile. Comparing pure ductal carcinoma in situ and in-situ component six differentially expressed genes were found, three of them (FGF2, GAS1, and SFRP1), play a role in cell invasiveness. Importantly, these genes were also differentially expressed between invasive and noninvasive groups and were negatively regulated in later stages of carcinogenesis. CONCLUSIONS: We propose these three genes (FGF2, GAS1, and SFRP1) as potential biomarkers of ductal carcinoma in situ progression, suggesting that their downregulation may be involved in the transition of stationary to migrating invasive epithelial cells.

Hypermethylation status of DAPK, MGMT and RUNX3 in HPV negative oral and oropharyngeal squamous cell carcinoma.

Squamous cell carcinoma of the oral cavity and oropharynx is the sixth most common type of cancer in the world. During tumorigenesis, gene promoter hypermethylation is considered an important mechanism of transcription silencing of tumor suppressor genes, such as DAPK, MGMT and RUNX3. These genes participate in signaling pathways related to apoptosis, DNA repair and proliferation whose loss of expression is possibly associated with cancer development and progression. In order to investigate associations between hypermethylation and clinicopathological and prognostic parameters, promoter methylation was evaluated in 72 HPV negative oral and oropharyngeal tumors using methylation-specific PCR. Hypermethylation frequencies found for DAPK, MGMT and RUNX3 were 38.88%, 19.44% and 1.38% respectively. Patients with MGMT hypermethylation had a better 2-year overall survival compared to patients without methylation. Being MGMT a repair gene for alkylating agents, it could be a biomarker of treatment response for patients who are candidates for cisplatin chemotherapy, predicting drug resistance. In view of the considerable levels of hypermethylation in cancer cells and, for MGMT, its prognostic relevance, DAPK and MGMT show potential as epigenetic markers, in a way that additional studies may test its viability and efficacy in clinical management.

Analysis of genome instability in breast cancer.

Breast cancer is a heterogeneous disease, previously associated with genomic instability. Our aim was to analyze microsatellite markers in order to determine patterns and levels of instability, as well as possible correlations with histopathological parameters. Polymerase chain reaction was used to characterize microsatellite instability (MSI) and loss of heterozygosity (LOH) in 107 breast carcinomas at twelve microsatellite loci. Some of the markers were selected because of their relation to steroid hormone metabolism, which seems to be related to sporadic breast cancer risk. D5S346 and D17S250 markers showed a statistically significant frequency of MSI. LOH in D3S1611, D17S250, AR and ER-ß were associated with some parameters of worse prognosis. Marker group analysis showed that CYP19, AR and ER-ß were related to histological grade III, ER-negative and PR-negative cases. Our results suggest that marker group analysis may be preferred to the single marker strategy, being predictive of worst prognosis when single markers are unable to provide such information. A further evaluation of steroid metabolism genes and their association with low penetrance genes in breast cancer may be useful.

Translational Bioinformatics Applied to the Study of Complex Diseases.

Translational Bioinformatics (TBI) is defined as the union of translational medicine and bioinformatics. It emerges as a major advance in science and technology by covering everything, from the most basic database discoveries, to the development of algorithms for molecular and cellular analysis, as well as their clinical applications. This technology makes it possible to access the knowledge of scientific evidence and apply it to clinical practice. This manuscript aims to highlight the role of TBI in the study of complex diseases, as well as its application to the understanding and treatment of cancer. An integrative literature review was carried out, obtaining articles through several websites, among them: PUBMED, Science Direct, NCBI-PMC, Scientific Electronic Library Online (SciELO), and Google Academic, published in English, Spanish, and Portuguese, indexed in the referred databases and answering the following guiding question: "How does TBI provide a scientific understanding of complex diseases?" An additional effort is aimed at the dissemination, inclusion, and perpetuation of TBI knowledge from the academic environment to society, helping the study, understanding, and elucidating of complex disease mechanics and their treatment.

Computational Biology Helps Understand How Polyploid Giant Cancer Cells Drive Tumor Success.

Precision and organization govern the cell cycle, ensuring normal proliferation. However, some cells may undergo abnormal cell divisions (neosis) or variations of mitotic cycles (endopolyploidy). Consequently, the formation of polyploid giant cancer cells (PGCCs), critical for tumor survival, resistance, and immortalization, can occur. Newly formed cells end up accessing numerous multicellular and unicellular programs that enable metastasis, drug resistance, tumor recurrence, and self-renewal or diverse clone formation. An integrative literature review was carried out, searching articles in several sites, including: PUBMED, NCBI-PMC, and Google Academic, published in English, indexed in referenced databases and without a publication time filter, but prioritizing articles from the last 3 years, to answer the following questions: (i) "What is the current knowledge about polyploidy in tumors?"; (ii) "What are the applications of computational studies for the understanding of cancer polyploidy?"; and (iii) "How do PGCCs contribute to tumorigenesis?"

Prognostic Factors and Markers in Non-Small Cell Lung Cancer: Recent Progress and Future Challenges.

Lung cancer is a highly aggressive neoplasm and, despite the development of recent therapies, tumor progression and recurrence following the initial response remains unsolved. Several questions remain unanswered about non-small cell lung cancer (NSCLC): (1) Which patients will actually benefit from therapy? (2) What are the predictive factors of response to MAbs and TKIs? (3) What are the best combination strategies with conventional treatments or new antineoplastic drugs? To answer these questions, an integrative literature review was carried out, searching articles in PUBMED, NCBI-PMC, Google Academic, and others. Here, we will examine the molecular genetics of lung cancer, emphasizing NSCLC, and delineate the primary categories of inhibitors based on their molecular targets, alongside the main treatment alternatives depending on the type of acquired resistance. We highlighted new therapies based on epigenetic information and a single-cell approach as a potential source of new biomarkers. The current and future of NSCLC management hinges upon genotyping correct prognostic markers, as well as on the evolution of precision medicine, which guarantees a tailored drug combination with precise targeting.

Investigation of maternal polymorphisms in genes related to glucose homeostasis and the influence on birth weight: a cohort study.

OBJECTIVES: To contribute to a better understanding of the maternal genetic mechanisms that influence obstetric outcomes and that are involved in maternal and child health, this study aimed to evaluate the association between maternal genetic variants and the offspring birth weight by analyzing single-nucleotide polymorphisms (SNPs) in genes related to glucose homeostasis. METHODS: Three polymorphisms were analyzed (GCK rs1799884, TCF7L2 rs7903146 and LEPR rs1137101) in 250 pregnant women who participated in a Brazilian prospective cohort study. Genotyping was performed by Real-Time Polymerase Chain Reaction (qPCR) using pre-designed TaqMan® SNP genotyping assays. Vitamin D dosage was performed by chemiluminescence. Variance, Pearson's chi-square test and multiple linear regression were used for the statistical analysis. RESULTS: It was possible to verify a significant association between birth weight and maternal GCK rs1799884 when obstetric outcomes, clinical and anthropometric characteristics were taken into consideration. The children of homozygous women for the minor allele GCK rs1799884 presented lower birth weight (ß = -335.25, 95% CI = -669.39; -1.17, p = 0.04). Furthermore, a direct link between a leptin receptor variant and gestational duration was found (p = 0.037). CONCLUSION: The variant GCK rs1799884 (mm) was associated with a reduction in newborn weight in the miscegenated Brazilian population.

Investigation of maternal polymorphisms in genes related to glucose homeostasis and the influence on birth weight: a cohort study

Abstract Objectives: To contribute to a better understanding of the maternal genetic mechanisms that influence obstetric outcomes and that are involved in maternal and child health, this study aimed to evaluate the association between maternal genetic variants and the offspring birth weight by analyzing single-nucleotide polymorphisms (SNPs) in genes related to glucose homeostasis. Methods: Three polymorphisms were analyzed (GCK rs1799884, TCF7L2 rs7903146 and LEPR rs1137101) in 250 pregnant women who participated in a Brazilian prospective cohort study. Genotyping was performed by Real-Time Polymerase Chain Reaction (qPCR) using pre-designed TaqMan® SNP genotyping assays. Vitamin D dosage was performed by chemiluminescence. Variance, Pearson's chi-square test and multiple linear regression were used for the statistical analysis. Results: It was possible to verify a significant association between birth weight and maternal GCK rs1799884 when obstetric outcomes, clinical and anthropometric characteristics were taken into consideration. The children of homozygous women for the minor allele GCK rs1799884 presented lower birth weight (β = -335.25, 95% CI = -669.39; -1.17, p = 0.04). Furthermore, a direct link between a leptin receptor variant and gestational duration was found (p = 0.037). Conclusion: The variant GCK rs1799884 (mm) was associated with a reduction in newborn weight in the miscegenated Brazilian population.

Histological profile and age at diagnosis of breast and ovarian tumors: A register-based study in Espirito Santo, Brazil.

Breast and ovarian cancers are important public health problems in Brazil. However, in various locations in the Brazilian territory these types of cancer remain poorly characterized. Therefore, this study aimed to compare data collected from the Pathology Services of two Oncology Reference Hospitals in Espirito Santo state (Brazil) with the data in previous Brazilian studies. Histological type frequency and age at diagnosis of breast and ovarian tumors between 2001-2004 and 2009-2010 were analyzed. Tumor size, histological grade, lymph node status, hormone receptor status [estrogen (ER) and progesterone receptors (PR)] as well as HER2 and Ki-67 marker status were obtained for the cases of infiltrating ductal carcinomas of the breast during the period 2009-2010. Categorical variables were described by their absolute and/or relative frequencies, while quantitative variables were expressed as the mean ± standard deviation and median, using 95% confidence intervals. Chi-square tests were performed to examine whether or not the studied variables differed by age at the time of diagnosis. Malignant breast tumors (1,758) and 119 malignant ovarian tumors were examined. Mean ages for malignant breast and ovarian tumors were 53.59 and 52.98 years, respectively. An increased tumor frequency in the age group of ≤35 years was observed for other malignant tumors of the breast during the period of 2009-2010, compared to 2001-2004. When considering only infiltrating ductal carcinomas with immunohistochemistry records available, there were 82.1% (133 cases) of ER+/PR+ tumors, 1.9% (3 cases) of ER-/PR-/HER2 3+ and 16.04% (26 cases) of ER-/PR-/HER2- tumors. The findings of this study demonstrated detailed information concerning breast and ovarian tumor behavior in the Espirito Santo state (Brazil), allowing for a precise comparison with other populations (Brazilian or international), which may be helpful in the planning of prevention and treatment strategies.

Polymorphism analysis of MTHFR, factor II, and factor V genes in the Pomeranian population of Espirito Santo, Brazil.

Pomeranian populations worldwide immigrated originally from the north of Europe, and because of their preferential marriage, religion, and cultural habits, they show little or no reproductive mixing with local populations. Methylenetetrahydrofolate reductase gene (MTHFR) C677T, Factor V Leiden, and Factor II G20210A polymorphisms are linked to augmented clotting and their frequencies may vary according to population ethnicity. We aimed to assess the frequencies of these thrombophilic alleles in the Pomeranian population residing in Espirito Santo and compare with the general population of the Espirito Santo state, Brazil. A total of 200 individuals were analyzed. The intrapopulation fixation index of the MTHFR C677T polymorphism was 0.03736. The observed heterozygosity was 0.44 and 0.4 for the general and Pomeranian populations, respectively. According to the chi-square test, both populations are in Hardy-Weinberg equilibrium. Four polymorphic alleles were detected for Factor II (2.02%) and 8 for Factor V (4.81%). Our results show that there is gene flow between the general and the Pomeranian population of Espirito Santo, which should no longer be considered an isolated population.