David Cantú de León

Human Papillomavirus (HPV) in breast tumors: prevalence in a group of Mexican patients

BackgroundBreast cancer is one of the main health problems in developed countries, occupying first place in mortality in women. It is well-known that there are risk factors associated with breast cancer development. Nonetheless, in 50–80% of cases known risk factors have not been identified, this has generated the attempt to identify new factors related with this neoplasia as viral infections. The aim of this work is investigate the prevalence of HPV DNA in patients with breast lesions at the Instituto Nacional de Cancerologia de Mexico.MethodsFifty-one cases of breast cancer were selected from the files of the institute and compared by age and tumor size with 43 cases of non malignant breast lesions (fibroadenoma, fibrocystic disease and phyllodes tumor). Paraffin embedded specimens were selected, HPV DNA was analyzed by polymerase chain reaction (PCR) and sequenced for different types of HPV in case of positivity for HPV-DNA. Descriptive analysis of clinical and pathological variables was performed and comparisons between positive and negative cases was done.ResultsAll patients were mexican, mean age was 53.3, median age of menarche was 13 and median tumor size 9 cms. Cervicovaginal cytology was performed to all patients, 1 patient (1.9%) of cancer group had HPV and none in the other group, no cases were diagnosed with cervical dysplasia. In the group of carcinomas 36 (70.5%) were negative and 15 (29.4%) were positive to HPV-DNA, 10(66.6%) were positive for HPV 16, 3(20%) for HPV 18, two cases (13.4%) were positive for both. In the group of benign conditions all were negative to HPV-DNA.ConclusionPresence of HPV in breast cancer in our group of cases is high in comparison to other authors; larger numbers of cases need to be analyzed in order to establish the exact role of this virus in the pathogenesis of breast cancer.

Primary retroperitoneal mucinous cystadenocarcinoma: report of two cases.

BackgroundRetroperitoneal cystadenocarcinomas are rare lesions, the majority of cases presented as one-patient reports.MethodsWe present two cases of retroperitoneal cystadenocarcinoma, both in women of reproductive age: one with aggressive behavior, and the remaining case, with a more indolent clinical evolution.ResultsOne case presented as pelvic tumor, was treated with surgical resection of the disease, but manifested with recurrent disease a few months later despite use of chemotherapy. The second case involved a patient with diagnosis of abdominal tumor; during laparotomy, a retroperitoneal tumor was found and was totally removed. At follow-up, the patient is disease-free with no other treatment.ConclusionThe behavior and treatment of retroperitoneal cystadenocarcinoma are controversial. We suggest aggressive surgery including radical hysterectomy and bilateral salpingoopherectomy with adjuvant chemotherapy in these cases.

The role of the histone demethylase KDM4A in cancer

Histone posttranslational modifications are important components of epigenetic regulation. One extensively studied modification is the methylation of lysine residues. These modifications were thought to be irreversible. However, several proteins with histone lysine demethylase functions have been discovered and characterized. Among these proteins, KDM4A is the first histone lysine demethylase shown to demethylate trimethylated residues. This enzyme plays an important role in gene expression, cellular differentiation, and animal development. Recently, it has also been shown to be involved in cancer. In this review, we focus on describing the structure, mechanisms, and function of KDM4A. We primarily discuss the role of KDM4A in cancer development and the importance of KDM4A as a potential therapeutic target.

MicroRNAs in cervical cancer: evidences for a miRNA profile deregulated by HPV and its impact on radio-resistance.

Cervical carcinoma (CC) is one of the most common cancers and a leading cause of mortality in women worldwide. Epidemiologic and experimental data have clearly demonstrated a causal role of high-risk Human Papillomavirus (HR-HPV) types in CC initiation and progression, affecting the cellular processes by targeting and inactivating p53 and pRB host proteins. HR-HPV E5, E6 and E7 oncoproteins have the ability to deregulate several cellular processes, mostly apoptosis, cell cycle control, migration, immune evasion, and induction of genetic instability, which promote the accumulation of mutations and aneuploidy. In this scenario, genomic profiles have shown that aberrant expression of cellular oncogenic and tumor suppressive miRNAs have an important role in CC carcinogenesis. It has been stated that HPV infection and E6/E7 expression are essential but not sufficient to lead to CC development; hence other genetic and epigenetic factors have to be involved in this complex disease. Recent evidence suggests an important level of interaction among E6/E7 viral proteins and cellular miRNA, and other noncoding RNAs. The aim of the current review is to analyze recent data that mainly describe the interaction between HR-HPV established infections and specific cellular miRNAs; moreover, to understand how those interactions could affect radio-therapeutic response in tumor cells.

Multiple human papillomavirus infections are highly prevalent in the anal canal of human immunodeficiency virus-positive men who have sex with men

BackgroundAnal cancer has become one of the most common non-AIDS-defined tumors among Human Immunodeficiency Virus-positive (HIV+) individuals, and a rise in its incidence among HIV+ Men who have Sex with Men (MSM) has been shown, despite the introduction of Highly Active Anti-Retroviral Therapy (HAART). Human Papillomavirus (HPV) infections are highly prevalent among HIV+ MSM and recent studies have shown high rates of HPV-associated anal intraepithelial neoplasia (AIN) and anal cancer among this population.MethodsIn the present study we determined the prevalence and nature of HPV co-infections in the anal canal of 324 HIV+ MSM attending a high specialty medical center in Mexico City, DNA extraction and amplification with generic primers for HPV was performed, followed by detection of specific types and co-infections with INNO-Lipa, and identification of variants by amplification and sequencing of the E6 and LCR region of HPV 16.ResultsWe found a very high prevalence of HPV infections among this cohort (86%), with more than one fourth of them (28%) positive for type 16. Among HPV16-positive patients, European variants were the most prevalent, followed by Asian-American ones. Among these individuals (HPV-16+), we identified co-infections with other 21 HPV types namely; 11, 51, 52, 6, 66, 68, 74, 18, 45, 35, 26, 44, 70, 53, 54, 82, 31, 33, 56, 58, 59.ConclusionsHIV+ MSM show a very high rate of HPV infections in the anal canal and those with type 16 exhibited a multiplicity of associated types. This study emphasizes the need for an early detection of HPV infections among HIV+ MSM in order to establish its utility to prevent anal neoplasia and cancer.

Adenocarcinoma metastatic to the uterine cervix: A case series

Aims:  The objectives of this report are, first, to describe the clinical behavior of cases of carcinoma metastatic to the uterine cervix treated at our institution in order to carry out a systematic review to establish the behavioral patterns of the most frequent metastases to the cervix and, second, to generate guidelines for their diagnosis and treatment.

High resolution human leukocyte antigen (HLA) class I and class II allele typing in Mexican mestizo women with sporadic breast cancer: case-control study

BackgroundThe 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.MethodsWe 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.ResultsHLA-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).ConclusionOur 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.

Characterization of cervical cancer stem cell-like cells: phenotyping, stemness, and human papilloma virus co-receptor expression

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.

Adenocarcinoma metastatic to the uterine cervix

Aims:  The objectives of this report are, first, to describe the clinical behavior of cases of carcinoma metastatic to the uterine cervix treated at our institution in order to carry out a systematic review to establish the behavioral patterns of the most frequent metastases to the cervix and, second, to generate guidelines for their diagnosis and treatment.

A microRNA expression signature for clinical response in locally advanced cervical cancer

OBJECTIVE Nearly 50% of patients who are diagnosed with locally advanced cervical cancer have an unfavorable pathological response to conventional treatment. MicroRNAs (miRNAs) are potential biomarkers in cervical cancer; however, their role in identifying patients who do not respond to conventional treatment remains poorly investigated. Here, we identify a set of miRNAs that can be used as molecular markers to predict the pathological response in locally advanced cervical cancer patients receiving radiation and chemotherapy treatment. METHODS Forty-one patients diagnosed with locally advanced cervical cancer were invited to participate in this study and enrolled after they signed an informed consent. Two patient cohorts were randomized for miRNA expression profiling, a discovery cohort (n=10) and a validation cohort (n=31); profiling was performed by means of a miScript miRNA PCR Array. After a median clinical follow-up of 45months, statistical analysis was performed to identify miRNAs that could discriminate non-responders from complete pathological responders to conventional treatment. RESULTS miRNA expression profiling identified 101 miRNAs that showed significant differences between non-responders and complete pathological responders (p<0.05). Seven differentially expressed miRNAs were selected, and their expression patterns were confirmed in the validation phase; thus, miR-31-3p, -3676, -125a-5p, -100-5p, -125b-5p, and -200a-5p and miR-342 were significantly associated with clinical response. Expression of this miRNA signature above the median level was a significant predictor of non-response to standard treatment (p<0.001). CONCLUSIONS These seven validated miRNA signatures could be used as molecular biomarkers of chemo- and radio-resistance in locally advanced cervical cancer patients.