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Introduction: Cervicouterine cancer (CC) is a health problem worldwide and is the fourth most common cancer in women, with a greater proportion of individuals affected by advanced stages of the disease in developing countries. Objective: To determine the sensitivity and specificity of the TruScreen™ opto-electronic device vs. conventional cytology in CC screenings. Methodology: This is a prospective observational study that included individuals who presented for the first time at the Dysplasia Clinic of the Instituto Nacional de Cancerología from March 1 through April 30, 2016, and those referred due to abnormal conventional cytology. The patients were evaluated with the TruScreen™ device, conventional cytology, colposcopy and, if necessary, cervical biopsy. The results were analyzed by descriptive statistics as well as the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the TruScreen™, using conventional cytology as the standard. Results: Thirty-two patients were included who met the inclusion criteria. The average age of the patients was 40 years (range, 23-61 years). For the diagnosis of high-grade intraepithelial lesions, the TruScreen™ device showed a 43% sensitivity, a 92% specificity, a PPV of 60%, and a NPV of 85%, whereas evaluation via cervical biopsy exhibited a 33% sensitivity, an 86% specificity, a 33% PPV, and an 86% NPV. The Kappa agreement index of the TruScreen™ with the colposcopies was 0.70. Conclusions: TruScreen™ demonstrated low sensitivity and high specificity compared with conventional cytology, which had a high NPV. [ABSTRACT FROM AUTHOR]

Objective: To compare overall survival (OS) and disease-free period (DFP) in patients with uterine sarcomas (US) in early stages with and without adjuvant treatment. Materials and Methods: One hundred sixteen clinical files with a diagnosis of US were reviewed. These were distributed into two groups: those who received adjuvant treatment with chemotherapy (CT) and/or radiotherapy (RT), and those who did not. Chi-square test was utilized for qualitative and the Mann-Whitney U test for quantitative variables. OS and the DFP were calculated with the Kaplan-Meier method and compared with the log-rank test. Results: Forty-seven patients were identified with clinical Stages I and II, of whom 25 patients (53.1%) received adjuvant treatment and 22 (46.8%) did not. Of the first group, 18 (72%) were treated with RT and 12 (48%) received CT. Five-year OS in patients who received adjuvant treatment was 68.05% (CI: 41.27-84.58) in comparison with those who did not, which was 78.41% (CI: 51.99-91.36, p = 0.41). Five-year DFP in the group that received adjuvant treatment was 46.88% (95% CI, 25.21-65.94), and in the group that did not it was 52.89% (95% CI, 30.00-71.39, p = 0.56). Conclusion: In early stage US, the benefit in OS and DFP using adjuvant management is limited, therefore, it has to be offered cautiously or not offered to this particular group of patients. Larger number of patients needs to be evaluated and collaborative phase III trial conducted in order to establish the role of adjuvant CT or RT for these neoplasms. [ABSTRACT FROM AUTHOR]

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Abstract Vulvar fibroadenomas are sporadic lesions informed in the literature and a controversy about origin has been discussed widely. We report a case of a 19 years old woman with a large slow growing mass in the right labia majora with the final diagnosis of fibroadenoma with mammary tissue surrounding it and positive hormone receptors. In this case, we support the origin in ectopic mammary tissue.

Abstract Background The development of breast cancer is multifactorial. Hormonal, environmental factors and genetic predisposition, among others, could interact in the presentation of breast carcinoma. Human leukocyte antigen (HLA) alleles play an important role in immunity (cellular immunity) and may be important genetic traits. HLAAllele-specific interaction has not been well established. Recently, several studies had been conducted in order to do so, but the results are controversial and in some instances contradictory. Methods We designed a case-control study to quantify the association of HLA class I and II genes and breast cancer. HLA typing was performed by high resolution sequence-specific oligotyping after DNA amplification (PCR-SSOP) of 100 breast cancer Mexican mestizo patients and 99 matched healthy controls. Results HLA-A frequencies that we were able to observe that there was no difference between both groups from the statistical viewpoint. HLA-B*1501 was found three times more common in the case group (OR, 3.714; p = 0.031). HLA-Cw is not a marker neither for risk, nor protection for the disease, because we did not find significant statistical differences between the two groups. DRB1*1301, which is expressed in seven cases and in only one control, observing an risk increase of up to seven times and DRB1*1602, which behaves similarly in being present solely in the cases (OR, 16.701; 95% CI, 0.947 – 294.670). DQ*0301-allele expression, which is much more common in the control group and could be protective for the presentation of the disease (OR, 0.078; 95% CI, 0.027–0.223, p = 0.00001). Conclusion Our results reveal the role of the MHC genes in the pathophysiology of breast cancer, suggesting that in the development of breast cancer exists a disorder of immune regulation. The triggering factor seems to be restricted to certain ethnic groups and certain geographical regions since the relevant MHC alleles are highly diverse. This is the first study in Mexican population where high resolutions HLA typing has been performed in order to try to establish an association with malignancy.

Abstract Background Synchronous gynecological tumors are rare; it is even rarer to find the rarest of gynecological tumors that of the fallopian tube, together with a histological sub-type as rare as verrucous cervix. Case presentation We report a synchronic fallopian tube adenocarcinoma and a verrucous cervical cancer. A 85-year-old woman with postmenopausal genital hemorrhage, endometrial biopsy was reported as squamous metaplasia, an exploratory laparotomy was performed finding a tubal tumor diagnosed as adenocarcinoma, a staging procedure was performed. Final staging revealed IB1 cervical carcinoma and IA G3 fallopian tube carcinoma. Adjuvant treatment with chemotherapy was not accepted by the patient. The patient has remained in follow-up, and at 9 months, there has been no documented evidence of recurrent disease. Conclusion Reasons for our presentation of this work are: first, due to the rarity of these, and second, because of the usefulness of possessing a case report for establishing a norm for later behavior with respect to treatment of these patients.

Objective: Clinical cancer genetics services are expanding globally, but national policy and health care systems influence availability and implementation. Understanding the environmental factors within a country is required to appropriately implement, adapt, and evaluate cancer genetics service delivery models. An environmental scan (ES) is an approach used in business, public health, health care and other sectors to collect information about an environment or system for strategic decision making and program planning. An ES has been previously used to assess cancer genetics clinic-level factors to inform quality improvement efforts in the United States. We assessed the feasibility of using an ES to collect information about factors that may influence cancer genetics service delivery in the outer-most socio-ecological model environmental levels (policy, national agencies, healthcare systems, cultural considerations) in three Latin American countries., Methods: Oncology and Genetics care team members at three participating sites used publicly available sources and personal experiences to complete a data collection form (DCF) that included questions about subtopics: laws and policies, relevant agencies and regulations, health care systems and insurance, and cultural considerations. Time to complete the DCF and DCF completeness were used to measure ES feasibility., Results: Participating sites completed the DCF in 3 months, and most questions (average, 87.0%) were answered. Questions in the cultural considerations subtopic had the fewest answers (average, 77.8%)., Conclusions: Overall, the ES was feasible and identified a lack of published literature related to cultural considerations impacting health care and genetics services uptake in Latin America. Environmental factors impact cancer genetics services, and identification of these factors will facilitate future collaborative research and genetics service delivery dissemination efforts., Competing Interests: Declarations. Compliance with ethical standards: IRB review was waived because this study is neither a research nor quality improvement study and did not require patients’ participation, animal subjects, or protected health information. Competing interests: The following authors declare no competing interests: E.M.B, R.N.W., K.J., M.T.W., S.N., K.H.L, L.N., A.P.S.D.S., G.S.O., C.E.M.C.A., N.P.-R., P.M., A.L., L.N.G.-A., D.C.-L. J.A.R.-H. reports consulting fees from Guidepoint Consulting and Schlesinger Group., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The mechanisms underlying the sustained activation of the PI3K/AKT and Wnt/β-catenin pathways mediated by HOTAIR in cervical cancer (CC) have not been extensively described. To address this knowledge gap in the literature, we explored the interactions between these pathways by driving HOTAIR expression levels in HeLa cells. Our findings reveal that HOTAIR is a key regulator in sustaining the activation of both signaling pathways. Specifically, altering HOTAIR expression-either by knockdown or overexpression-significantly influenced the transcriptional activity of the PI3K/AKT and Wnt/β-catenin pathways. Additionally, we discovered that HIF1α directly induces HOTAIR transcription, which in turn leads to the epigenetic silencing of the PTEN promoter via DNMT1. This process leads to the sustained activation of both pathways, highlighting a novel regulatory axis involving HOTAIR and HIF1α in cervical cancer. Our results suggest a new model in which HOTAIR sustains reciprocal activation of the PI3K/AKT and Wnt/β-catenin pathways through the HOTAIR/HIF1α axis, thereby contributing to the oncogenic phenotype of cervical cancer.

Purpose: This study aimed to determine the prevalence of endocrine resistance in a cohort of Hispanic Mexican breast cancer (BC) patients receiving care at Instituto Nacional de Cancerología (INCan). Additionally, the clinical-pathological factors associated with endocrine resistance were identified, and their impact on patient survival was explored., Methods: A retrospective analysis of 200 BC patients who attended INCan between 2012 and 2016 with estrogen receptor (ER) and progesterone receptor (PR) positive tumors was made. Endocrine resistance was defined according to the International Consensus Guidelines for Advance Breast Cancer 2 definition. Their clinicopathological characteristics were analyzed to determine the association with endocrine resistance presence. We used sensitivity analyses and multivariate-adjusted logistic regressions, Kaplan-Meier curves, and multivariate-adjusted Cox regressions. P-value < 0.05 was considered as statistically significant., Results: Endocrine resistance was observed in 32.5% of patients included in this study. The distinction between hormone resistance and sensitivity was influenced by tumor size and node status. It had a mean diameter of 7.15 cm in endocrine resistance cases compared to 5.71 cm in non-endocrine, with N3 status present in 20% of endocrine resistance cases versus only 2.2% in non-endocrine (p-value < 0.001). The clinical stage exhibited a strong association with endocrine resistance (Risk Ratio [RR] 4.39, 95% confidence interval [95%CI] 1.50, 11.43). Furthermore, endocrine resistance significantly impacted mortality during the follow-up, with a Hazard Ratio [HR] of 23.7 (95%CI 5.20, 108.42) in multivariable-adjusted models. However, a complete pathological response reduced the endocrine resistance risk, as demonstrated by a Risk Ratio (RR) of 0.15 (95% CI 0.03, 0.75)., Conclusions: Advanced clinical stage at diagnosis predicted endocrine resistance in Hispanic Mexican BC patients. Complete pathologic response in locally advanced disease patients was also a key predictor of endocrine resistance. These results indicated that endocrine resistance was a critical factor in BC during follow-up., Competing Interests: Competing interests The authors declare that they have no competing interests.

Cervical cancer (CC) remains among the most frequent cancers worldwide despite advances in screening and the development of vaccines against human papillomavirus (HPV), involved in virtually all cases of CC. In mid-income countries, a substantial proportion of the cases are diagnosed in advanced stages, and around 40% of them are diagnosed in women under 49 years, just below the global median age. This suggests that members of this age group share common risk factors, such as chronic inflammation. In this work, we studied samples from 46 patients below 45 years old, searching for a miRNA profile regulating cancer pathways. We found 615 differentially expressed miRNAs between tumor samples and healthy tissues. Through bioinformatic analysis, we found that several of them targeted elements of the JAK/STAT pathway and other inflammation-related pathways. We validated the interactions of miR-30a and miR-34c with JAK1 and STAT3, respectively, through dual-luciferase and expression assays in cervical carcinoma-derived cell lines. Finally, through knockdown experiments, we observed that these miRNAs decreased viability and promoted proliferation in HeLa cells. This work contributes to understanding the mechanisms through which HPV regulates inflammation, in addition to its canonical oncogenic function, and brings attention to the JAK/STAT signaling pathway as a possible diagnostic marker for CC patients younger than 45 years. To our knowledge to date, there has been no previous description of a panel of miRNAs or even ncRNAs in young women with locally advanced cervical cancer.

This was a retrospective study that included 114 women younger than 40 years with induced primary ovarian insufficiency. Patients who presented vasomotor symptoms had a higher proportion (26 [63.41%] versus 58 [79.45%], OR 2.23, 95% CI 0.95-5.23, p = . 065) to initiate hormone replacement therapy. Vasomotor symptoms were present in patients with ovarian cancer (OR 0.27, 95% CI 0.09-0.8, p = . 18), haematologic cancer (OR 0.11, 95% CI 0.2-0.65, p = . 014), radiotherapy (OR 2.62, 95% CI 1.04-6.54, p = . 039) and chemotherapy with radiotherapy (OR 2.72, 95% CI 1.01-7.35, p = . 049). Having ovarian or haematological cancer, being managed with radiotherapy and/or chemotherapy, and having follicle-stimulating hormone parameters higher than 35 mUI/mL are factors that significantly increase the risk of presenting vasomotor symptoms.Impact Statement What is already known on this subject? In young women with cancer, induced primary ovarian insufficiency can result as an ovarian surgery or as an adverse effect of chemotherapy or radiotherapy. Regardless of aetiology, patients are going to manifest early climacteric symptoms with an increased risk for cardiovascular disease, metabolic syndrome and osteoporosis. What do the results of this study add? Patients who presented vasomotor symptoms had initially a higher proportion of hormone replacement therapy. Patients that were treated exclusively with radiotherapy or with chemotherapy and concomitant radiotherapy have a significantly increased risk to manifest vasomotor symptoms. What are the implications of these findings for clinical practice and/or future research? Having ovarian or haematological cancer, being managed with radiotherapy and/or chemotherapy and having follicle-stimulating hormone parameters higher than 35 mUI/mL are factors that significantly increase the risk of presenting vasomotor symptoms.

Colorectal cancer (CRC) represents the second deadliest malignancy worldwide. Around 75% of CRC patients exhibit high levels of chromosome instability that result in the accumulation of somatic copy number alterations. These alterations are associated with the amplification of oncogenes and deletion of tumor-ppressor genes and contribute to the tumoral phenotype in different malignancies. Even though this relationship is well known, much remains to be investigated regarding the effect of said alterations in long non-coding RNAs (lncRNAs) and, in turn, the impact these alterations have on the tumor phenotype. The present study aimed to evaluate the role of differentially expressed lncRNAs coded in regions with copy number alterations in colorectal cancer patient samples. We downloaded RNA-seq files of the Colorectal Adenocarcinoma Project from the The Cancer Genome Atlas (TCGA) repository (285 sequenced tumor tissues and 41 non-tumor tissues), evaluated differential expression, and mapped them over genome sequencing data with regions presenting copy number alterations. We obtained 78 differentially expressed (LFC > 1|< -1, padj < 0.05) lncRNAs, 410 miRNAs, and 5028 mRNAs and constructed a competing endogenous RNA (ceRNA) network, predicting significant lncRNA-miRNA-mRNA interactions. Said network consisted of 30 lncRNAs, 19 miRNAs, and 77 mRNAs. To understand the role that our ceRNA network played, we performed KEGG and GO analysis and found several oncogenic and anti-oncogenic processes enriched by the molecular players in our network. Finally, to evaluate the clinical relevance of the lncRNA expression, we performed survival analysis and found that C5orf64, HOTAIR, and RRN3P3 correlated with overall patient survival. Our results showed that lncRNAs coded in regions affected by SCNAs form a complex gene regulatory network in CCR.

Introduction: Metastatic breast cancer causes the most breast cancer-related deaths around the world, especially in countries where breast cancer is detected late into its development. Genetic testing for cancer susceptibility started with the BRCA 1 and 2 genes. Still, recent research has shown that variations in other members of the DNA damage response (DDR) are also associated with elevated cancer risk, opening new opportunities for enhanced genetic testing strategies., Methods: We sequenced BRCA1/2 and twelve other DDR genes from a Mexican-mestizo population of 40 metastatic breast cancer patients through semiconductor sequencing., Results: Overall, we found 22 variants -9 of them reported for the first time- and a strikingly high proportion of variations in ARID1A. The presence of at least one variant in the ARID1A, BRCA1, BRCA2, or FANCA genes was associated with worse progression-free survival and overall survival in our patient cohort., Discussion: Our results reflected the unique characteristics of the Mexican-mestizo population as the proportion of variants we found differed from that of other global populations. Based on these findings, we suggest routine screening for variants in ARID1A along with BRCA1/2 in breast cancer patients from the Mexican-mestizo population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Vázquez-Romo, Millan-Catalan, Ruíz-García, Martínez-Gutiérrez, Alvarado-Miranda, Campos-Parra, López-Camarillo, Jacobo-Herrera, López-Urrutia, Guardado-Estrada, Cantú de León and Pérez-Plasencia.)

Background: Recent studies have shown that the classification of high-grade urothelial carcinoma non-muscle invasive (HGBCNMI) based on molecular subtypes might be a valuable strategy to identify patients with a worse clinical prognosis., Objective: Determine the effect of the luminal and basal molecular subtype determined by immunistochemical on prognosis in patients with HGBC in Mexican population., Methods: Phenotypes were evaluated by immunohistochemical staining of luminal (GATA3, FOXA1) and basal (CK5/6, CK14) markers in paraffin-embedded tissue samples from 45 patients with a diagnosis of HGBCNMI treated at Instituto Nacional de Cancerología-México (INCan) between 2009 and 2019. The association with prognosis was evaluated using Kaplan-Meier curves and multivariable-adjusted Cox models., Results: HGBCNMI patients showed mean age of 58.77 years (SD: ±12.08 years). We identified expression of the luminal molecular subtype in 35 cases (77.78 %), and 10 cases (22.22 %) with "combined" expression of the molecular subtype (basal and luminal expression). The combined phenotype was statistically more frequent in metastatic cases (p-value = 0.028). In Kaplan-Meier curves, combined expression of luminal and basal molecular markers was associated with disease progression (p-value = 0.002, log-rank test). Cox regression models confirmed this association, which was not influenced by age (p-value = 0.007) or gender (p-value = 0.007). No association of phenotypes with overall survival (p-value = 0.860) or relapse (p-value = 0.5) was observed., Conclusion: The combined expression of immunohistochemical markers of the luminal and basal subtype might be considered as predictor for disease progression in patients with HGBCNMI in Mexican population., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest in any form., (Copyright © 2022. Published by Elsevier Inc.)

Bladder cancer (BC) is the most common neoplasm of the urinary tract, which originates in the epithelium that covers the inner surface of the bladder. The molecular BC profile has led to the development of different classifications of non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). However, the genomic BC landscape profile of the Mexican population, including NMIBC and MIBC, is unknown. In this study, we aimed to identify somatic single nucleotide variants (SNVs) and copy number variations (CNVs) in Mexican patients with BC and their associations with clinical and pathological characteristics. We retrospectively evaluated 37 patients treated between 2012 and 2021 at the National Cancer Institute-Mexico (INCan). DNA samples were obtained from paraffin-embedded tumor tissues and exome sequenced. Strelka2 and Lancet packages were used to identify SNVs and insertions or deletions. FACETS was used to determine CNVs. We found a high frequency of mutations in TP53 and KMT2D , gains in 11q15.5 and 19p13.11-q12, and losses in 7q11.23. STAG2 mutations and 1q11.23 deletions were also associated with NMIBC and low histologic grade.

Alterations in DNA methylation are critical for the carcinogenesis of ovarian tumors, especially ovarian carcinoma (OC). DNMT3B, a de novo DNA methyltransferase (DNMT), encodes for fifteen spliced protein products or isoforms. DNMT3B isoforms lack exons for the catalytic domain, with functional consequences on catalytic activity. Abnormal expression of DNMT3B isoforms is frequently observed in several types of cancer, such as breast, lung, kidney, gastric, liver, skin, leukemia, and sarcoma. However, the expression patterns and consequences of DNMT3B isoforms in OC are unknown. In this study, we analyzed each DNMT and DNMT3B isoforms expression by qPCR in 63 OC samples and their association with disease-free survival (DFS), overall survival (OS), and tumor progression. We included OC patients with the main histological subtypes of EOC and patients in all the disease stages and found that DNMTs were overexpressed in advanced stages (p-value < 0.05) and high-grade OC (p-value < 0.05). Remarkably, we found DNMT3B1 overexpression in advanced stages (p-value = 0.0251) and high-grade serous ovarian carcinoma (HGSOC) (p-value = 0.0313), and DNMT3B3 was overexpressed in advanced stages (p-value = 0.0098) and high-grade (p-value = 0.0004) serous ovarian carcinoma (SOC). Finally, we observed that overexpression of DNMT3B isoforms was associated with poor prognosis in OC and SOC. DNMT3B3 was also associated with FDS (p-value = 0.017) and OS (p-value = 0.038) in SOC patients. In addition, the ovarian carcinoma cell lines OVCAR3 and SKOV3 also overexpress DNMT3B3. Interestingly, exogenous overexpression of DNMT3B3 in OVCAR3 causes demethylation of satellite 2 sequences in the pericentromeric region. In summary, our results suggest that DNMT3B3 expression is altered in OC.

The Hispanic population, compared with other ethnic groups, presents a more aggressive gastric cancer phenotype with higher frequency of diffuse-type gastric adenocarcinoma (GA); this could be related to the mutational landscape of GA in these patients. Using whole-exome sequencing, we sought to present the mutational landscape of GA from 50 Mexican patients who were treated at The Instituto Nacional de Cancerología from 2019 to 2020. We performed a comprehensive statistical analysis to explore the relationship of the genomic variants and clinical data such as tumor histology and presence of signet-ring cell, H. pylori , and EBV. We describe a potentially different mutational landscape between diffuse and intestinal GA in Mexican patients. Patients with intestinal-type GA tended to present a higher frequency of NOTCH1 mutations, copy number gains in cytobands 13.14, 10q23.33, and 12q25.1, and copy number losses in cytobands 7p12, 14q24.2, and 11q13.1; whereas patients with diffuse-type GA tended to present a high frequency of CDH1 mutations and CNV gains in cytobands 20q13.33 and 22q11.21. This is the first description of a mutational landscape of GA in Mexican patients to better understand tumorigenesis in Hispanic patients and lay the groundwork for discovering potential biomarkers and therapeutic targets.

Hypoxia in cancer is a thoroughly studied phenomenon, and the logical cause of the reduction in oxygen tension is tumor growth itself. While sustained hypoxia leads to death by necrosis in cells, there is an exquisitely regulated mechanism that rescues hypoxic cells from their fatal fate. The accumulation in the cytoplasm of the transcription factor HIF-1α, which, under normoxic conditions, is marked for degradation by a group of oxygen-sensing proteins known as prolyl hydroxylases (PHDs) in association with the von Hippel-Lindau anti-oncogene (VHL) is critical for the cell, as it regulates different mechanisms through the genes it induces. A group of microRNAs whose expression is regulated by HIF, collectively called hypoxaMIRs, have been recognized. In this review, we deal with the hypoxaMIRs that have been shown to be expressed in colorectal cancer. Subsequently, using data mining, we analyze a panel of hypoxaMIRs expressed in both normal and tumor tissues obtained from TCGA. Finally, we assess the impact of these hypoxaMIRs on cancer hallmarks through their target genes.

Background: Even with different histologic origins, squamous cell carcinoma (SCC) and adenocarcinoma (AC) are considered a single entity, and the first-line treatment is the same. Locally advanced disease at the diagnosis of cervical cancer is the most important prognostic factor, the recurrence rate is high, making it necessary to evaluate prognostic factors other than clinical or radiological staging; histology could be one of them but continues to be controversial. The aim of this study was to evaluate tumor histology as a prognostic factor in terms of treatment outcomes, disease-free survival (DFS) and overall survival (OS) in a retrospective cohort of patients with Locally Advanced Cervical Carcinoma (LACC)., Methods: The records of 1291patients with LACC were reviewed, all of them were treated with 45-50 Gy of external beam radiotherapy with concurrent chemotherapy and brachytherapy. A descriptive and comparative analysis was conducted. Treatment response was analyzed by the chi-square test; DFS and OS were calculated for each histology with the Kaplan-Meier method and compared with the log-rank test; and the Cox model was applied for the multivariate analysis., Results: We included 1291 patients with LACC treated from 2005 to 2014, of which 1154 (89·4%) had SCC and 137 (10·6%) had AC. Complete response to treatment was achieved in 933 (80·8%) patients with SCC and 113 (82·5%) patients with AC. Recurrence of the disease was reported in 29·9% of SCC patients and 31·9% of AC patients. Five-year DFS was 70% for SCC and 62·2% for AC. The five-year OS rates were 74·3% and 60% for SCC and AC, respectively. The mean DFS was 48·8 months for SCC vs 46·10 for AC (p = 0·043), the mean OS was 50·8 for SCC and 47·0 for AC (p = 0·002)., Conclusion: Our findings support the hypothesis that SCC and AC are different clinical entities., Trial Registration: NCT04537273 ., (© 2022. The Author(s).)

Squamous cell carcinoma of the uterine cervix is considered the most common histologic variant of cervical cancer, with well-established treatment protocols and prognosis. An infrequent histologic variant of cervical squamous cell carcinoma is the acantholytic variant (ASCC), which is characterized by discohesive cells that result in a pseudoglandular and/or angiomatoid pattern of growth. This variant of squamous cell carcinoma has been regarded as having a poor prognosis at certain anatomic sites such as the head and neck and vulva. In the uterine cervix, the importance of this variant has not been yet established. A ten-year retrospective review of squamous cell carcinoma of the uterine cervix was performed to identify this variant and correlate it with clinical characteristics to better define its prognostic implications. During the study period 19 cases were identified containing from 10 to 80% acantholytic component. Mean age at diagnosis was 49 years. Clinical stages were 1A2 (1 case), Ib1 (16), and IIA1 (2). Median follow-up was 92 months. When compared with controls, ASCC were larger in size (1.4 vs 3.5 cm), had deeper involvement of the cervical stroma (21 vs 47%), had more lymph node metastasis (8 vs 26%), more frequent recurrences (4 vs 15%) and a shorter disease-free survival; however, no statistical differences were identified in overall survival. ASCC is an infrequent variant of cervical cancer which seems to have an impact on disease-free survival but no in overall survival., (Copyright © 2021. Published by Elsevier Inc.)

Lymph node metastasis (LNM) is an important prognostic factor in cervical cancer (CC). In early stages, the risk of LNM is approximately 3.7 to 21.7%, and the 5-year overall survival decreases from 80% to 53% when metastatic disease is identified in the lymph nodes. Few reports have analyzed the relationship between miRNA expression and the presence of LNM. The aim of this study was to identify a subset of miRNAs related to LNM in early-stage CC patients. Formalin-fixed paraffin-embedded tissue blocks were collected from patients with early-stage CC treated by radical hysterectomy with lymphadenectomy. We analyzed samples from two groups of patients-one group with LNM and the other without LNM. Global miRNA expression was identified by microarray analysis, and cluster analysis was used to determine a subset of miRNAs associated with LNM. Microarray expression profiling identified a subset of 36 differentially expressed miRNAs in the two groups (fold change (FC) ≥ 1.5 and p < 0.01). We validated the expression of seven miRNAs; miR-487b, miR-29b-2-5p, and miR-195 were underexpressed, and miR-92b-5p, miR-483-5p, miR-4534, and miR-548ac were overexpressed according to the microarray experiments. This signature exhibited prognostic value for identifying early-stage CC patients with LNM. These findings may help detect LNM that cannot be observed in imaging studies.

Background: Novel prognostic factors in patients with diffuse large B-cell lymphoma (DLBCL) are required in the era of Rituximab., Objective: The objective of the study was to study the prognostic impact of exon-16 enhancer-of-zeste homolog-2 (EZH2) mutations in patients with DLBCL., Methods: In a cohort of patients with DLBCL treated between 2015 and 2017, we analyzed the presence of EZH2 mutations and their association with clinical response (CR), relapse, progression-free survival (PFS), and overall survival (OS)., Results: A total of 198 patients were included; of them, 30 (15.2%) had mutations at codon 641, in exon 16 of EZH2. Response was achieved in 151 patients (76.3%), and 43 (21.7%) relapsed or progressed during follow-up. EZH2 mutations were associated with relapse/progression (risk ratio [RR] 1.18; 95% confidence interval [CI] 0.98-1.42; p = 0.031), while a trend for not achieving a complete response was observed (RR: 0.876; 95%CI 0.74-1.038; p = 0.071). Of note, Tyr641His and Tyr641Ser EZH2 mutations were associated with shorter PFS (hazard ratio 3.234; 95% CI 1.149-9.1; p = 0.026)., Conclusion: The presence of EZH2 mutations was negatively associated with relapse/progression and showed a trend for lack of complete response. Further studies are needed to define better the prognostic significance of these mutations in Mexican-Mestizo DLBCL patients.

The resistance that Triple-Negative Breast Cancer (TNBC), the most aggressive breast cancer subtype, develops against radiotherapy is a complex phenomenon involving several regulators of cell metabolism and gene expression; understanding it is the only way to overcome it. We focused this review on the contribution of the two leading classes of regulatory non-coding RNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), against ionizing radiation-based therapies. We found that these regulatory RNAs are mainly associated with DNA damage response, cell death, and cell cycle regulation, although they regulate other processes like cell signaling and metabolism. Several regulatory RNAs regulate multiple pathways simultaneously, such as miR-139-5p, the miR-15 family, and the lncRNA HOTAIR. On the other hand, proteins such as CHK1 and WEE1 are targeted by several regulatory RNAs simultaneously. Interestingly, the study of miRNA/lncRNA/mRNA regulation axes increases, opening new avenues for understanding radioresistance. Many of the miRNAs and lncRNAs that we reviewed here can be used as molecular markers or targeted by upcoming therapeutic options, undoubtedly contributing to a better prognosis for TNBC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Aranza-Martínez, Sánchez-Pérez, Brito-Elias, López-Camarillo, Cantú de León, Pérez-Plasencia and López-Urrutia.)

Background: In Cervical cancer (CC), in addition to HPV infection, the most relevant alteration during CC initiation and progression is the aberrant activation of Wnt/β-catenin pathway. Several inhibitory drugs of this pathway are undergoing preclinical and clinical studies. Long non-coding RNAs (lncRNAs) are associated with resistance to treatments. In this regard, understanding the efficiency of drugs that block the Wnt/β-catenin pathway in CC is of relevance to eventually propose successful target therapies in patients with this disease., Methods: We analyzed the levels of expression of 249 components of the Wnt/β-catenin pathway in a group of 109 CC patients. Three drugs that blocking specific elements of Wnt/β-catenin pathway (C59, NSC668036 and ICRT14) by TOP FLASH assays and qRT-PCR were tested in vitro in CC cells., Results: 137 genes of the Wnt/β-catenin pathway were up-regulated and 112 down-regulated in CC patient's samples, demonstrating that this pathway is dysregulated. C59 was an efficient drug to inhibit Wnt/β-catenin pathway in CC cells. NSC668036, was not able to inhibit the transcriptional activity of the Wnt/β-catenin pathway. Strikingly, ICRT14 was neither able to inhibit this pathway in HeLa cells, due to HOTAIR interaction with β-catenin, maintaining the Wnt/β-catenin pathway activated., Conclusions: These results demonstrate a mechanism by which HOTAIR evades the effect of ICRT14, a Wnt/β-catenin pathway inhibitory drug, in HeLa cell line. The emergence of these mechanisms reveals new scenarios in the design of target therapies used in cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Trujano-Camacho, Cantú-de León, Delgado-Waldo, Coronel-Hernández, Millan-Catalan, Hernández-Sotelo, López-Camarillo, Pérez-Plasencia and Campos-Parra.)

Aberrant metabolism is arising interest in the scientific community not only because of the role it plays in the development and establishment of the tumor mass but also the possibility of drug poisoning of key enzymes overexpressed in tumor cells. Moreover, tumor metabolism provides key molecules to maintain the epigenetic changes that are also an undisputed characteristic of each tumor type. This metabolic change includes the Warburg effect and alterations in key pathways involved in glutaminolysis, pentose phosphate, and unsaturated fatty acid biosynthesis. Modifications in all these pathways have consequences that impact genetics and epigenetics processes such as DNA methylation patterns, histone post-translational modifications, triggering oncogenes activation, and loss in tumor suppressor gene expression to lead the tumor establishment. In this review, we describe the metabolic rearrangement and its association with epigenetic regulation in breast cancer, as well as its implication in biological processes involved in cancer progression. A better understanding of these processes could help to find new targets for the diagnosis, prognosis, and treatment of this human health problem., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Coronel-Hernández, Pérez-Yépez, Delgado-Waldo, Contreras-Romero, Jacobo-Herrera, Cantú-De León and Pérez-Plasencia.)

Purpose: Increasingly epidemiological evidence supports that environmental factors are associated with breast cancer (BC) outcomes after a BC diagnosis. Although evidence suggests that air pollution exposure is associated with higher mortality in women with BC, studies investigating potential mechanisms have been lacking., Methods: We evaluated women with BC (N = 151) attended at the National Cancer Institute-Mexico from 2012 to 2015. We calculated 1-year average exposures to particulate matter < 2.5 μm (PM 2.5 ) at home address before diagnosis. We used linear and logistic regression models to determine the associations between PM 2.5 exposure and BC aggressiveness (tumor size, molecular phenotype)., Results: Average annual PM 2.5 exposure of this population was 23.0 μg/m 3 [standard deviation (SD)]: 1.90 μg/m 3 ]. PM 2.5 levels were positively correlated with tumor size at diagnosis (r = 0.22; p = 0.007). Multivariable linear models had a similar inference [risk ratio (RR): 1.32; 95% confidence interval (95% CI): 1.04, 1.674]. We did not observe differences in this association by age or menopause status. Further, women with triple-negative BC (TNBC) had significantly higher PM 2.5 levels compared with other phenotypes (p = 0.015). Multivariable-adjusted logistic regression models assessing the association between PM 2.5 and tumor size had a similar inference (RR 1.41; 95% CI 1.05, 1.89) overall for all ages and also for women who were ≤ 50 years old at diagnosis (RR 1.63; 95% CI 1.036, 2.57)., Conclusions: Our findings suggest a significant association between long-term PM 2.5 exposure and BC aggressiveness based on tumor size and phenotype, as well as a worse outcome.

Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide in both sexes. Current therapies include surgery, chemotherapy, and targeted therapy; however, prolonged exposure to chemical agents induces toxicity in patients and drug resistance. So, we implemented a therapeutic strategy based on the combination of doxorubicin, metformin, and sodium oxamate called triple therapy (Tt). We found that Tt significantly reduced proliferation by inhibiting the mTOR/AKT pathway and promoted apoptosis and autophagy in CRC derived cells compared with doxorubicin. Several autophagy genes were assessed by western blot; ULK1, ATG4, and LC3 II were overexpressed by Tt. Interestingly, ULK1 was the only one autophagy-related protein gradually overexpressed during Tt administration. Thus, we assumed that there was a post-transcriptional mechanism mediating by microRNAs that regulate UKL1 expression during autophagy activation. Through bioinformatics approaches, we ascertained that ULK1 could be targeted by mir-26a, which is overexpressed in advanced stages of CRC. In vitro experiments revealed that overexpression of mir-26a decreased significantly ULK1, mRNA, and protein expression. Contrariwise, the Tt recovered ULK1 expression by mir-26a decrease. Due to triple therapy repressed mir-26a expression, we hypothesized this drug combination could be involved in mir-26a transcription regulation. Consequently, we analyzed the mir-26a promoter sequence and found two HIF-1α transcription factor recognition sites. We developed two different HIF-1α stabilization models. Both showed mir-26a overexpression and ULK1 reduction in hypoxic conditions. Immunoprecipitation experiments were performed and HIF-1α enrichment was observed in mir-26a promoter. Surprisingly, Tt diminished HIF-1α detection and restored ULK1 mRNA expression. These results reveal an important regulation mechanism controlled by the signaling that activates HIF-1α and that in turn regulates mir-26a transcription., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a shared affiliation with the authors at the time of review., (Copyright © 2021 Coronel-Hernández, Salgado-García, Cantú-De León, Jacobo-Herrera, Millan-Catalan, Delgado-Waldo, Campos-Parra, Rodríguez-Morales, Delgado-Buenrostro and Pérez-Plasencia.)

Colorectal cancer (CRC) is among the top three most deadly cancers worldwide. The survival rate for this disease has not been reduced despite the treatments, the reason why the search for therapeutic alternatives continues to be a priority issue in oncology. In this research work, we tested our successful pharmacological combination of three drugs, metformin, doxorubicin, and sodium oxamate (triple therapy, or TT), as an autophagy inducer. Firstly, we employed western blot (WB) assays, where we observed that after 8 h of stimulation with TT, the proteins Unc-51 like autophagy activating kinase 1(ULK1), becline-1, autophagy related 1 protein (Atg4), and LC3 increased in the CRC cell lines HCT116 and SW480 in contrast to monotherapy with doxorubicin. The overexpression of these proteins indicated the beginning of autophagy flow through the activation of ULK1 and the hyperlipidation of LC3 at the beginning of this process. Moreover, we confirm that ULK1 is a bona fide target of hsa-miR-106a-5p (referred to from here on as miR-106a) in HCT116. We also observed through the GFP-LC3 fusion protein that in the presence of miR-106a, the accumulation of autophagy vesicles in cells stimulated with TT is inhibited. These results show that the TT triggered autophagy to modulate miR-106a/ULK1 expression, probably affecting different cellular pathways involved in cellular proliferation, survivance, metabolic maintenance, and cell death. Therefore, considering the importance of autophagy in cancer biology, the study of miRNAs that regulate autophagy in cancer will allow a better understanding of malignant tumors and lead to the development of new disease markers and therapeutic strategies.

Objective: Our main objective was to assess the association between the markers p16 and Ki-67 and recurrence of disease in patients previously treated for cervical high-grade squamous intraepithelial lesion (HSIL)., Design: This is a case-control study at the National Cancer Institute conducted between 2005 and 2015. Of the patients with a pathologically confirmed diagnosis of HSIL, 107 cases were selected. They were divided into 2 groups: 28 cases with recurrence after treatment and a control group of 79 patients without recurrence. We identified clinical, pathological, and treatment variables., Methods: Two experienced pathologists performed immunohistochemical analysis of biomarkers; they agreed on their interpretation, and we calculated the odds ratios (ORs) associated with recurrence. For group comparisons, we used the Wilcoxon signed-rank, χ2, or Fisher's exact test, depending on the type of variable. We conducted logistic regression models to estimate ORs and determine the factors associated with recurrence. The recurrence-free period was defined as the time frame between conization and either recurrence of disease or the last date the patient was seen. We used Kaplan-Meier plots to visualize survival curves and log-rank tests to compare the curves. We established a p value <0.05 as statistically significant., Results: After pathologists performed immunohistochemical analysis, they achieved an agreement level of 83.7% for p16 and 60% for Ki-67. We did not find an association between recurrence and either p16 expression (p = 0.69) or the percentage of Ki-67 expression (p = 0.71). The recurrence-free period analysis did not reveal a difference in p16 expression (p = 0.57) nor in the percentage of Ki-67 expression in the 3-tiered scale (p = 0.56)., Limitations: Our main limitation was a reduced sample size., Conclusion: We found no association between p16 and Ki-67 positivity and the risk of recurrence in previously treated HSIL., (© 2021 S. Karger AG, Basel.)

Background: Ovarian cancer is the most lethal gynecologic cancer. Although most patients respond adequately to the first-line therapy, up to 85% experience a recurrence of disease, which carries a poor prognosis. Mitotic arrest deficiency 1 is a protein that helps in the assembly of the mitotic spindle assembly checkpoint by preventing anaphase until all chromatids are properly aligned. A single-nucleotide polymorphism in the MAD1L1 gene is prevalent in patients with advanced epithelial ovarian cancer and alters the way in which it responds to chemotherapy., Objective: The objective of the study was to study the relationship between the rs1801368 polymorphism of MAD1L1 and prognosis of ovarian adenocarcinoma., Methods: A total of 118 patients in whom the MAD1L1 gene was sequenced were analyzed using descriptive and comparative statistics., Results: Patients carrying the wild-type genotype had a higher distribution of early-stage disease. Having a MAD1L1 polymorphic allele increased the risk of being non-sensitive to chemotherapy. The median disease-free survival for patients with the wild-type MAD1L1 was 46.93 months, compared to 10.4 months for patients with at least one polymorphic allele., Conclusions: The rs1801368 polymorphism of MAD1L1 gene worsens prognosis in patients with ovarian adenocarcinoma. Traditional therapy for ovarian cancer might not be optimal in patients carrying this polymorphism.

Background: Endometrial carcinoma is the most common gynecologic malignancy in developed countries. Grade 2 carcinoma is associated with pelvic lymph-node metastasis, depending on selected risk factors. Intraoperative assessment (IOA) can identify patients at risk for lymph node metastasis who should undergo staging surgery. Our objective was to establish the diagnostic precision of IOA in determining the need for surgical staging in grade 2 endometrioid endometrial carcinoma., Methods: Two hundred twenty-two patients underwent IOA. Results were compared to the final pathology report. The accuracy of the IOA parameters was calculated. Variables were evaluated in patients with positive versus negative IOA. Overall and disease-free survivals were calculated according to IOA, lymphadenectomy, and nodal metastasis., Results: IOA was positive in 80 patients. It showed an accuracy of 76.13% when compared with the postoperative assessment. The best individual parameter was myometrial invasion. Nodal metastasis was observed in 16 patients in the positive IOA group and 7 patients in the negative group. Patients with lymph node metastasis had a 5-year overall survival rate of 80.9%, whereas patients without metastasis had a 5-year overall survival rate of 97.9%., Conclusions: IOA is an adequate tool to identify high-risk patients in grade 2 endometrial carcinoma. Myometrial invasion is the individual parameter that yields the highest diagnostic precision.

Background: Serine Threonine Kinase 11 (STK11), also known as LKB1, is a tumor suppressor gene that regulates several biological processes such as apoptosis, energetic metabolism, proliferation, invasion, and migration. During malignant progression, different types of cancer inhibit STK11 function by mutation or epigenetic inactivation. In Head and Neck Cancer, it is unclear what mechanism is involved in decreasing STK11 levels. Thus, the present work aims to determine whether STK11 expression might be regulated through epigenetic or post-translational mechanisms., Methods: Expression levels and methylation status for STK11 were analyzed in 59 cases of head and neck cancer and 10 healthy tissue counterparts. Afterward, we sought to identify candidate miRNAs exerting post-transcriptional regulation of STK11. Then, we assessed a luciferase gene reporter assay to know if miRNAs directly target STK11 mRNA. The expression levels of the clinical significance of mir-100-3p, -5p, and STK11 in 495 HNC specimens obtained from the TCGA database were further analyzed. Finally, the Kaplan-Meier method was used to estimate the prognostic significance of the miRNAs for Overall Survival, and survival curves were compared through the log-rank test., Results: STK11 was under-expressed, and its promoter region was demethylated or partially methylated. miR-17-5p, miR-106a-5p, miR-100-3p, and miR-100-5p could be negative regulators of STK11. Our experimental data suggested evidence that miR-100-3p and -5p were over-expressed in analyzed tumor patient samples. Luciferase gene reporter assay experiments showed that miR-100-3p targets and down-regulates STK11 mRNA directly. With respect to overall survival, STK11 expression level was significant for predicting clinical outcomes., Conclusion: This is, to our knowledge, the first report of miR-100-3p targeting STK11 in HNC. Together, these findings may support the importance of regulation of STK11 through post-transcriptional regulation in HNC and the possible contribution to the carcinogenesis process in this neoplasia.

Background: Although important achievements have been done in type 2 diabetes mellitus (T2D) treatment and glycemic control, new strategies may take advantage of non-pharmacological approaches and of other potential determinants of health (e.g., socioeconomic status, education, diabetes knowledge, physical activity, and self-care behavior). However, the relationships between these factors are not totally clear and have not been studied in the context of large urban settings. This study aimed to explore the relationship between these determinants of glycemic control (GC) in a low-income urban population from Mexico City, focused in exploring potential the mediation of self-care behaviors in the association between diabetes knowledge and GC., Methods: A multicenter cross-sectional study was conducted in patients with type 2 diabetes (T2D) from 28 primary care outpatient centers located in Mexico City. Using multivariable-adjusted models, we determined the associations between diabetes knowledge, self-care behaviors, and GC. The mediation analyses to determine the pathways on glycemic control were done using linear regression models, where the significance of indirect effects was calculated with bootstrapping., Results: The population (N = 513) had a mean age of 53.8 years (standard deviation: 11.3 yrs.), and 65.9% were women. Both socioeconomic status and level of education were directly associated with diabetes knowledge. Using multivariable-adjusted linear models, we found that diabetes knowledge was associated with GC (β: -0.102, 95% Confidence Interval [95% CI] -0.189, - 0.014). Diabetes knowledge was also independently associated with self-care behavior (for physical activity: β: 0.181, 95% CI 0.088, 0.273), and self-care behavior was associated with GC (for physical activity: β: -0.112, 95% CI -0.194, - 0.029). The association between diabetes knowledge and GC was not observed after adjustment for self-care behaviors, especially physical activity (β: -0.084, 95% CI -0.182, 0.014, p-value: 0.062). Finally, the mediation models showed that the effect of diabetes knowledge on GC was 17% independently mediated by physical activity (p-value: 0.049)., Conclusions: Socioeconomic and educational gradients influence diabetes knowledge among primary care patients with type 2 diabetes. Self-care activities, particularly physical activity, mediated the effect of diabetes knowledge on GC. Our results indicate that diabetes knowledge should be reinforced in low-income T2D patients, with an emphasis on the benefits physical activity has on improving GC.

Breast cancer is the neoplasm with the highest number of deaths in women. Although the molecular mechanisms associated with the development of this tumor have been widely described, metastatic disease has a high mortality rate. In recent years, several studies show that microRNAs or miRNAs regulate complex processes in different biological systems including cancer. In the present work, we describe a group of 61 miRNAs consistently over-expressed in breast cancer (BC) samples that regulate the breast cancer transcriptome. By means of data mining from TCGA, miRNA and mRNA sequencing data corresponding to 1091 BC patients and 110 normal adjacent tissues were downloaded and a miRNA-mRNA network was inferred. Calculations of their oncogenic activity demonstrated that they were involved in the regulation of classical cancer pathways such as cell cycle, PI3K-AKT, DNA repair, and k-Ras signaling. Using univariate and multivariate analysis, we found that five of these miRNAs could be used as biomarkers for the prognosis of overall survival. Furthermore, we confirmed the over-expression of two of them in 56 locally advanced BC samples obtained from the histopathological archive of the National Cancer Institute of Mexico, showing concordance with our previous bioinformatic analysis.

Background: When endometrial carcinoma invades the cervical stroma, overall survival and disease-free survival decrease. However, it is still controversial whether patients in suspected stage II should be treated with radical hysterectomy. The goal of this study is to describe the role of radical hysterectomy in patients with endometrial carcinoma and cervical involvement., Methods: This was a retrospective cohort study were a total of 239 patients with endometrial carcinoma with cervical involvement from Mexico City's National Cancer Institute were divided according to the type of hysterectomy, and the outcomes were compared using statistical analysis., Results: The 5-year overall survival was 75.76% for the simple hysterectomy group and 89.19% for the radical hysterectomy group, without achieving statistical significance. The 5-year disease-free survival was 72.95% for the simple hysterectomy group and 64.31% for the radical hysterectomy group, without achieving statistical significance. Radicality was associated with longer surgical times, intraoperative complications, and bleeding over 500 ml., Conclusions: In patients with endometrial carcinoma with cervical involvement, radical hysterectomy does not improve prognosis or alter adjuvant therapy.

Objective: Identify the prevalence of HPV infections in the uterine cervix and oral cavity and HPV16 variants in HIV+ women., Methods: A total of 174 HIV+ women attended an HIV+ specialized clinic in Mexico City. Cells were obtained from the oral cavity and cervix to extract DNA. Polymerase chain reaction (PCR) was used to amplify the HPV sequence with generic primers. We detected specific HPV types using the INNO-LiPA HPV Genotyping Extra II Kit (INNOGENETICS). The identification of variants was studied by sequencing the E6 gene with a Big Dye Terminator Kit and an Applied Biosystems 3500/3500xL genetic analyzer., Results: HPV infection was very high in the uterine cervix (168/174, 96.6%) and oral cavity (161/174, 92.5%). The prevalence of HPV concurrent infections in the cervix and oral cavity was 155/174 (89.1%). We found hrHPVs to be more prevalent than low-risk HPVs (lrHPVs) in the oral cavity (90.2% versus 45.4%) and that infections simultaneously affected the cervix (94.3% versus 36.2%) and oral cavity (85.1% versus 20.1%). Surprisingly, only European variants of HPV type 16 were found in the uterine cervix of women and the oral cavity of all tested samples (52 oral cavity samples and 52 uterine cervix samples)., Conclusions: The high prevalence of HPV, multiple infections and presence of the EP350G intravariant in both anatomical regions are strongly related to the persistence of the virus, which is fundamental for the development of cancer. Therefore, it is very important to control and monitor this high-risk population as well as implement programs for the early detection of HPV and vaccination., Competing Interests: The authors have declared that no competing interests exist.

Metastatic breast cancer (MBC) is a challenge for oncologists, and public efforts should focus on identifying additional molecular markers and therapeutic management to improve clinical outcomes. Among all diagnosed cases of breast cancer (BC; approximately 10%) involve metastatic disease; notably, approximately 40% of patients with early‑stage BC develop metastasis within 5 years. The management of MBC consists of systemic therapy. Despite different treatment options, the 5‑year survival rate is <20%, which may be due to a lack of response with de novo or acquired resistance. MicroRNAs (miRNAs or miRs) are promising biomarkers as they are readily detectable and have a broad spectrum and potential clinical applications. The aim of this study was to identify a miRNA profile for distinguishing patients with MBC who respond to systemic treatment. Patients with MBC were treated according to the National Comprehensive Cancer Network guidelines. We performed miRNA‑Seq on 9 primary tumors using the Thermo Fisher Scientific Ion S5 system. To obtain global miRNA profiles, we carried out differentially expressed gene elimination strategy (DEGES) analysis between the responsive and non‑responsive patients. The results identified a profile of 12 miRNAs associated with the response to systemic treatment. The data were validated in an independent cohort (TCGA database). Based on the results, the upregulation of miR‑342‑3p and miR‑187‑3p was associated with the response to systemic treatment, and with an increased progression‑free survival (PFS) and overall survival (OS); by contrast, the downregulation of miR‑301a‑3p was associated with a higher PFS and OS. On the whole, the findings of this study indicate that these miRNAs may serve as biomarkers for the response to systemic treatment or the prognosis of patients with MBC. However, these data should be validated experimentally in other robust cohorts and using different specimens before implementing these miRNAs as biomarkers in clinical practice to benefit this group of patients.

The presence of germline and somatic deleterious mutations in the BRCA1 and BRCA2 genes has important clinical consequences for breast cancer (BC) patients. Analysis of the mutational status in BRCA genes is not yet common in public Latin American institutions; thus, our objective was to implement high-performance technology with highly reliable results with the possibility of analyzing several patients simultaneously, therefore reducing cost and work time. A prospective cohort of 252 unrelated sporadic breast cancer patients from the Mexican-mestizo population were analyzed using next generation sequencing (NGS) based on ion semiconductor sequencing. We found 28 pathogenic mutations (25 in BRCA1 and 13 in BRCA2 ), 11 of which had not been reported previously in Hispanic or Latin American populations. A total of 38 patients were positive for a pathogenic mutation representing 15% of our Mexican women cohort with breast cancer; 25 for BRCA1 ; and 13 for BRCA2 . Our results revealed that there are mutations not analyzed by mutations panels, and our findings support the suitability of massive sequencing approaches in the public institutions of developing countries. Hence, BRCA screening should be offered to patients with breast cancer regardless of their family history of cancer in order to identify unaffected family carriers.

The identification of prognostic biomarkers is a priority for patients suffering from high-grade serous ovarian cancer (SOC), which accounts for >70% of ovarian cancer (OC) deaths. Meanwhile, borderline ovarian cancer (BOC) is a low malignancy tumor and usually patients undergo surgery with low probabilities of recurrence. However, SOC remains the most lethal neoplasm due to the lack of biomarkers for early diagnosis and prognosis. In this regard, BORIS (CTCFL), a CTCF paralog, is a promising cancer biomarker that is overexpressed and controls transcription in several cancer types, mainly in OC. Studies suggest that BORIS has an important function in OC by altering gene expression, but the effect and extent to which BORIS influences transcription in OC from a genome-wide perspective is unclear. Here, we sought to identify BORIS target genes in an OC cell line (OVCAR3) with potential biomarker use in OC tumor samples. To achieve this, we performed in vitro knockout and knockdown experiments of BORIS in OVCAR3 cell line followed by expression microarrays and bioinformatics network enrichment analysis to identify relevant BORIS target genes. In addition, ex vivo expression data analysis of 373 ovarian cancer patients were evaluated to identify the expression patterns of BORIS target genes. In vitro, we uncovered 130 differentially expressed genes and obtained the BORIS-associated regulatory network, in which the androgen receptor (AR) acts as a major transcription factor. Also, FN1, FAM129A, and CD97 genes, which are related to chemoresistance and metastases in OC, were identified. In SOC patients, we observed that malignancy is associated with high levels of BORIS expression while BOC patients show lower levels. Our study suggests that BORIS acts as a main regulator, and has the potential to be used as a prognostic biomarker and to yield novel drug targets among the genes BORIS controls in SOC patients.

The SLC5A8 gene encodes Na monocarboxylate transporter 1, which is epigenetically inactivated in various tumour types. This has been attributed to the fact that it prevents the entry of histone deacetylase (HDAC) inhibitors and favours the metabolic reprogramming of neoplastic cells. Nevertheless, its expression and regulation in cervical cancer (CC) have not been elucidated to date. The aim of the present study was to investigate whether SLC5A8 expression is silenced in CC and if epigenetic mechanisms are involved in its regulation. Using RNA and DNA from human CC cell lines and tumour tissues from patients with CC, the expression of SLC5A8 was analysed by reverse transcription polymerase chain reaction and the methylation status of its CpG island (CGI) by bisulphite‑modified sequencing. Additionally, SLC5A8 reactivation was examined in the CC cell lines following treatment with DNA methylation (5‑aza‑2'‑deoxycytidine) and HDAC inhibitors (trichostatin A and pyruvate). All the CC cell lines and a range of tumour tissues (65.5%) exhibited complete or partial loss of SLC5A8 transcription. The bisulphite‑sequencing revealed that hypermethylation of the CGI within SLC5A8 first exon was associated with its downregulation in the majority of cases. The transporter expression was restored in the CC cell lines following exposure to 5‑aza‑2'‑deoxycytidine alone, or in combination with trichostatin A or pyruvate, suggesting that DNA methylation and histone deacetylation contribute to its inhibition in a cell line‑dependent manner. Together, the results of the present study demonstrate the key role of DNA hypermethylation in the repression of SLC5A8 in CC, as well as the involvement of histone deacetylation, at least partially. This allows for research focused on the potential function of SLC5A8 as a tumour suppressor in CC, and as a biomarker or therapeutic target in this malignancy.

Uterine sarcomas are infrequent and heterogeneous mesenchymal tumours, associated with aggressive characteristics and a poor clinical outcome. The aim of the study is to describe the prognostic factors associated with uterine sarcomas. The clinical records between 2000 and 2014 of women diagnosed with uterine sarcomas and initially treated surgically were reviewed. A histological comparison was performed. The overall survival (OS) and disease-free survival (DFS) were calculated and compared. Seventy-three women had surgery (12.3% had endometrial stromal sarcomas, 24.7% undifferentiated endometrial sarcomas, 49.3% leiomyosarcomas and 13.7% other subtypes). Complete cytoreduction had a mean DFS of 25.1 months, while the incomplete cytoreduction averaged in a DFS of 4.33 months (p = .04). The median five-year OS with a complete cytoreduction was not reached; the incomplete cytoreduction OS was 10.1 months (p = .002). Our data suggests that undifferentiated endometrial sarcomas have the lowest DFS (p = .004); while OS was negatively influence by stage IV (p < .001). Impact statement What is already known about this subject? Uterine sarcomas compared with the more common endometrial carcinomas (epithelial neoplasms), behave aggressively and are associated with a poorer prognosis. The rarity of uterine sarcoma has made it difficult to perform large studies to identify risk factors. What do the results of this study add? Complete cytoreduction improves the DFS and OS and may be a valuable prognostic factor. Poorer DFS and OS prognosis was observed in undifferentiated endometrial sarcomas. What are the implications of these findings for clinical practice and/or further research? Our results demonstrate the importance of an early diagnosis, and thus an early identification of disease that benefits from complete cytoreduction regardless of histology. For the advanced clinical stage of uterine sarcomas further research is necessary and participation in clinical trials should be encouraged.

Aim: To determine whether the association of rectal adenocarcinoma with a defective-mismatch repair system (dMMR) was associated with a pathological complete response (pCR) to preoperative chemoradiotherapy., Methods: A case-control study was designed with the aim of determining if patients with rectal adenocarcinoma with dMMR had an associated high pCR rate in response to neoadjuvant chemoradiotherapy (nCRT)., Results: Seventy-two cases with pCR were compared against 144 controls without pCR. Across 216 cases, the mean age was 56.8 years, 140 (64.8%) were men, and 63 (29.2%) demonstrated the dMMR system. The pCR was associated with G1 tumors, dMMR, the absence of vascular invasion, and low tumor budding in the pretreatment biopsy. In a multivariant analysis, the factors associated with pCR were dMMR (OR: 2.61; 95%CI: 1.355-5.040, P = 0.004) and a low degree of tumor budding (OR: 2.52; 95%CI: 1.366-4.894, P = 0.025)., Conclusion: We found an independent association between dMMR and a low rate of tumor budding, with a higher rate of pCR, in the basal biopsies of patients with rectal carcinoma subjected to nCRT., Competing Interests: Conflict-of-interest statement: The authors declared no potential conflicts of interest.

Cervical cancer (CC) is one of the most common cancers diagnosed in women worldwide, and it is estimated that ~500,000 new patients are diagnosed with cervical cancer annually and that ~270,000 deaths occur each year. Patients with cervical cancer are treated with different radiotherapy schedules, either alone or with adjuvant chemotherapy. Unfortunately, nearly 50% of all patients with cervical cancer do not respond to standard treatment due to tumor radioresistance. In this scenario, several microRNAs (miRNAs) have been associated with the acquisition of the radioresistance phenotype. The aim of the present study was to evaluate the possible role of miR‑125a in the acquisition of radioresistance in cervical cancer. The expression of miR‑125a was assessed by means of RT‑qPCR in 30 cervical cancer samples from patients receiving standard treatment and 3 induced radioresistant cervical cancer cell lines. In addition, we employed miR‑125a mimics and inhibitors to evaluate its function in the induction of radioresistance. We showed that miR‑125a was downregulated in patients with cervical cancer who did not respond to standard treatment. Concordantly, radioresistant SiHa, CaSki and HeLa cell lines had low levels of miR‑125a with respect to the sensitive cell lines. Finally, we demonstrated that overexpression of miR‑125a sensitized cervical cancer cells to radiation therapy through the downregulation of CDKN1A. Our data corroborate previously published studies in which it was demonstrated that miRNAs could play a role in the regulation of the process of radioresistance. Additionally, we showed that overexpression of miR‑125a could be used as a radioresistance biomarker in patients with cervical cancer.

Objective: The objective of the present study was to provide genomic and transcriptomic information that may improve clinical outcomes for locally advanced cervical cancer (LACC) patients by searching for therapeutic targets or potential biomarkers through the analysis of significantly altered signaling pathways in LACC., Methods: Microarray-based transcriptome profiling of 89 tumor samples from women with LACC was performed. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, significantly over-expressed genes in LACC were identified; these genes were validated by quantitative reverse transcription-polymerase chain reaction in an independent cohort, and the protein expression data were obtained from the Human Protein Atlas., Results: A transcriptome analysis revealed 7530 significantly over-expressed genes in LACC samples. By KEGG analysis, we found 93 dysregulated signaling pathways, including the JAK-STAT, NOTCH and mTOR-autophagy pathways, which were significantly upregulated. We confirmed the overexpression of the relevant genes of each pathway, such as NOTCH1, JAK2, STAM1, SOS1, ADAM17, PSEN1, NCSTN, RPS6, STK11/LKB1 and MLTS8/GBL in LACC compared with normal cervical tissue epithelia., Conclusions: Through comprehensive genomic and transcriptomic analyses, this work provides information regarding signaling pathways with promising therapeutic targets, suggesting novel target therapies to be considered in future clinical trials for LACC patients., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Cervical cancer (CC) is the most common malignancy throughout developing countries, although considered rare, central nervous system metastasis (CNSm) does occur., Objective: This study aimed to describe our experiences and compare them to other published cases., Materials and Methods: From May 2009 to August 2015, the files of all patients with CC treated at our referral center were reviewed., Results: We found 27 patients with CC and CNSm. Mean age at the time of CNS diagnosis was 50 ± 11 years, mean interval between initial CC and CNSm was 46 months; the most frequent initial International Federation of Gynecology and Obstetrics stage was IIB with 17 patients followed by IB in 4. Fifty-nine percent of patients had lung metastases at the time CNSm were diagnosed. Headache was the most common symptom, followed by weakness, altered mental status, and ataxia/cerebellar. Mean survival was 8.2 months after CNSm was discovered; 3 patients are still alive., Conclusions: The present study describes the largest series of patients with CNSm from CC; this rare complication should be suspected in patients with CC who present with headache, ataxia, cranial nerve palsy, visual disturbance, altered mental status, focal weakness, or other neurological symptom, without other plausible explanation.

Cancer stem cells (CSC) exhibit high tumorigenic capacity in several tumor models. We have now determined an extended phenotype for cervical cancer stem cells. Our results showed increased CK-17, p63+, AII+, CD49f+ expression in these cells, together with higher Aldehyde dehydrogenase (ALDHbright)activity in Cervical CSC (CCSC) enriched in cervospheres. An increase in stem cell markers, represented by OCT-4, Nanog, and β-catenin proteins, was also observed, indicating that under our culture conditions, CCSC are enriched in cervospheres, as compared to monolayer cultures. In addition, we were able to show that an increased ALDHbright activity correlated with higher tumorigenic activity. Flow cytometry and immunflorescence assays demonstrated that CCSC in cervosphere cultures contain a sub-population of cells that contain Annexin II, a Human papillomavirus (HPV) co-receptor. Taken together, under our conditions there is an increase in the number of CCSC in cervosphere cultures which exhibit the following phenotype: CK-17, p63+, AII+, CD49f+ and high ALDH activity, which in turn correlates with higher tumorigenicity. The presence of Annexin II and CD49f in CCSC opens the possibility that normal cervical stem cells could be the initial target of infection by high risk HPV., Competing Interests: The authors declare no conflict of interest.