Comprehensive omic characterization of breast cancer in Mexican-Hispanic women.

Breast cancer is a heterogeneous pathology, but the genomic basis of its variability remains poorly understood in populations other than Caucasians. Here, through DNA and RNA portraits we explored the molecular features of breast cancers in a set of Hispanic-Mexican (HM) women and compared them to public multi-ancestry datasets. HM patients present an earlier onset of the disease, particularly in aggressive clinical subtypes, compared to non-Hispanic women. The age-related COSMIC signature 1 was more frequent in HM women than in those from other ancestries. We found the AKT1E17K hotspot mutation in 8% of the HM women and identify the AKT1/PIK3CA axis as a potentially druggable target. Also, HM luminal breast tumors present an enhanced immunogenic phenotype compared to Asiatic and Caucasian tumors. This study is an initial effort to include patients from Hispanic populations in the research of breast cancer etiology and biology to further understand breast cancer disparities.

LINC00460 Is a Dual Biomarker That Acts as a Predictor for Increased Prognosis in Basal-Like Breast Cancer and Potentially Regulates Immunogenic and Differentiation-Related Genes.

Breast cancer (BRCA) is a serious public health problem, as it is the most frequent malignant tumor in women worldwide. BRCA is a molecularly heterogeneous disease, particularly at gene expression (mRNAs) level. Recent evidence shows that coding RNAs represent only 34% of the total transcriptome in a human cell. The rest of the 66% of RNAs are non-coding, so we might be missing relevant biological, clinical or regulatory information. In this report, we identified two novel tumor types from TCGA with LINC00460 deregulation. We used survival analysis to demonstrate that LINC00460 expression is a marker for poor overall (OS), relapse-free (RFS) and distant metastasis-free survival (DMFS) in basal-like BRCA patients. LINC00460 expression is a potential marker for aggressive phenotypes in distinct tumors, including HPV-negative HNSC, stage IV KIRC, locally advanced lung cancer and basal-like BRCA. We show that the LINC00460 prognostic expression effect is tissue-specific, since its upregulation can predict poor OS in some tumors, but also predicts an improved clinical course in BRCA patients. We found that the LINC00460 expression is significantly enriched in the Basal-like 2 (BL2) TNBC subtype and potentially regulates the WNT differentiation pathway. LINC00460 can also modulate a plethora of immunogenic related genes in BRCA, such as SFRP5, FOSL1, IFNK, CSF2, DUSP7 and IL1A and interacts with miR-103-a-1, in-silico, which, in turn, can no longer target WNT7A. Finally, LINC00460:WNT7A ratio constitutes a composite marker for decreased OS and DMFS in Basal-like BRCA, and can predict anthracycline therapy response in ER-BRCA patients. This evidence confirms that LINC00460 is a master regulator in BRCA molecular circuits and influences clinical outcome.

Application of chemoresistive gas sensors and chemometric analysis to differentiate the fingerprints of global volatile organic compounds from diseases. Preliminary results of COPD, lung cancer and breast cancer.

BACKGROUND: Analysis of volatile organic compounds (VOCs) in exhaled breath has been proposed as a screening method that discriminates between disease and healthy subjects, few studies evaluate whether these chemical fingerprints are specific when compared between diseases. We evaluated global VOCs and their discrimination capacity in chronic obstructive pulmonary disease (COPD), lung cancer, breast cancer and healthy subjects by chemoresistive sensors and chemometric analysis. METHODS: A cross-sectional study was conducted with the participation of 30 patients with lung cancer, 50 with breast cancer, 50 with COPD and 50 control subjects. Each participant's exhaled breath was analyzed with the electronic nose. A multivariate analysis was carried: principal component analysis (PCA) and, canonical analysis of principal coordinates (CAP). Twenty single-blind samples from the 4 study groups were evaluated by CAP. RESULTS: A separation between the groups of patients to the controls was achieved through PCA with explanations of >90% of the data and with a correct classification of 100%. In the CAP of the 4 study groups, discrimination between the diseases was obtained with 2 canonical axes with a correct general classification of 91.35%. This model was used for the prediction of the single-blind samples resulting in correct classification of 100%. CONCLUSIONS: The application of chemoresistive gas sensors and chemometric analysis can be used as a useful tool for a screening test for lung cancer, breast cancer and COPD since this equipment detects the set of VOCs present in the exhaled breath to generate a characteristic chemical fingerprint of each disease.

Intracystic Papillary Breast Cancer in a 16-Year-Old Patient.

BACKGROUND: Primary breast cancer in the pediatric population is rare. To our knowledge, no cases of intracystic papillary carcinoma have been reported in patients younger than 21 years. CASE: A 16-year-old patient presented with a retroareolar mass and bloody nipple discharge in her left breast. A biopsy established papillary intracystic carcinoma. The patient was treated surgically and a risk reduction strategy developed in a multidisciplinary session was implemented.

Mitochondrial DNA Mutation Analysis in Breast Cancer: Shifting From Germline Heteroplasmy Toward Homoplasmy in Tumors.

Studies have suggested a potential role of somatic mitochondrial mutations in cancer development. To analyze the landscape of somatic mitochondrial mutation in breast cancer and to determine whether mitochondrial DNA (mtDNA) mutational burden is correlated with overall survival (OS), we sequenced whole mtDNA from 92 matched-paired primary breast tumors and peripheral blood. A total of 324 germline variants and 173 somatic mutations were found in the tumors. The most common germline allele was 663G (12S), showing lower heteroplasmy levels in peripheral blood lymphocytes than in their matched tumors, even reaching homoplasmic status in several cases. The heteroplasmy load was higher in tumors than in their paired normal tissues. Somatic mtDNA mutations were found in 73.9% of breast tumors; 59% of these mutations were located in the coding region (66.7% non-synonymous and 33.3% synonymous). Although the CO1 gene presented the highest number of mutations, tRNA genes (T,C, and W), rRNA 12S, and CO1 and ATP6 exhibited the highest mutation rates. No specific mtDNA mutational profile was associated with molecular subtypes of breast cancer, and we found no correlation between mtDNA mutational burden and OS. Future investigations will provide insight into the molecular mechanisms through which mtDNA mutations and heteroplasmy shifting contribute to breast cancer development.

FAM83H-AS1 is a potential modulator of cancer driver genes across different tumors and a prognostic marker for ER/PR + BRCA patients.

Breast cancer (BRCA) is a serious public health problem, as it is the most frequent malignant tumor in women worldwide. BRCA is a molecularly heterogenic disease, particularly at gene expression (mRNAs) level. Recent evidence shows that coding RNAs represent only 34% of the total transcriptome in a human cell. The rest of the 66% of RNAs are non-coding, so we might be missing relevant biological, clinical or regulatory information. In this report, we identified nine novel tumor types from TCGA with FAM83H-AS1 deregulation. We used survival analysis to demonstrate that FAM83H-AS1 expression is a marker for poor survival in IHC-detected ER and PR positive BRCA patients and found a significant correlation between FAM83H-AS1 overexpression and tamoxifen resistance. Estrogen and Progesterone receptor expression levels interact with FAM83H-AS1 to potentiate its effect in OS prediction. FAM83H-AS1 silencing impairs two important breast cancer related pathways: cell migration and cell death. Among the most relevant potential FAM83H-AS1 gene targets, we found p63 and claudin 1 (CLDN1) to be deregulated after FAM83H-AS1 knockdown. Using correlation analysis, we show that FAM83H-AS1 can regulate a plethora of cancer-related genes across multiple tumor types, including BRCA. This evidence suggests that FAM83H-AS1 is a master regulator in different cancer types, and BRCA in particular.

A lncRNA landscape in breast cancer reveals a potential role for AC009283.1 in proliferation and apoptosis in HER2-enriched subtype.

Breast cancer is the most commonly diagnosed neoplasm in women worldwide with a well-recognized heterogeneous pathology, classified into four molecular subtypes: Luminal A, Luminal B, HER2-enriched and Basal-like, each one with different biological and clinical characteristics. Long non-coding RNAs (lncRNAs) represent 33% of the human transcriptome and play critical roles in breast carcinogenesis, but most of their functions are still unknown. Therefore, cancer research could benefit from continued exploration into the biology of lncRNAs in this neoplasm. We characterized lncRNA expression portraits in 74 breast tumors belonging to the four molecular subtypes using transcriptome microarrays. To infer the biological role of the deregulated lncRNAs in the molecular subtypes, we performed co-expression analysis of lncRNA-mRNA and gene ontology analysis. We identified 307 deregulated lncRNAs in tumor compared to normal tissue and 354 deregulated lncRNAs among the different molecular subtypes. Through co-expression analysis between lncRNAs and protein-coding genes, along with gene enrichment analysis, we inferred the potential function of the most deregulated lncRNAs in each molecular subtype, and independently validated our results taking advantage of TCGA data. Overexpression of the AC009283.1 was observed in the HER2-enriched subtype and it is localized in an amplification zone at chromosome 17q12, suggesting it to be a potential tumorigenic lncRNA. The functional role of lncRNA AC009283.1 was examined through loss of function assays in vitro and determining its impact on global gene expression. These studies revealed that AC009283.1 regulates genes involved in proliferation, cell cycle and apoptosis in a HER2 cellular model. We further confirmed these findings through ssGSEA and CEMITool analysis in an independent HER2-amplified breast cancer cohort. Our findings suggest a wide range of biological functions for lncRNAs in each breast cancer molecular subtype and provide a basis for their biological and functional study, as was conducted for AC009283.1, showing it to be a potential regulator of proliferation and apoptosis in the HER2-enriched subtype.

Identification of profiles of volatile organic compounds in exhaled breath by means of an electronic nose as a proposal for a screening method for breast cancer: a case-control study.

The objective of the present study was to identify volatile prints from exhaled breath, termed breath-print, from breast cancer (BC) patients and healthy women by means of an electronic nose and to evaluate its potential use as a screening method. A cross-sectional study was performed on 443 exhaled breath samples from women, of whom 262 had been diagnosed with BC by biopsy and 181 were healthy women (control group). Breath-print analysis was performed utilizing the Cyranose 320 electronic nose. Group data were evaluated by principal component analysis (PCA), canonical discriminant analysis (CDA), and support vector machine (SVM), and the test's diagnostic power was evaluated by means of receiver operating characteristic (ROC) curves. The results obtained using the model generated from the CDA, which best describes the behavior of the assessed groups, indicated that the breath-print of BC patients was different from that of healthy women and that they presented with a variability of up to 98.8% and a correct classification of 98%. The sensitivity, specificity, negative predictive value, and positive predictive value reached 100% according to the ROC curve. The present study demonstrates the capability of the electronic nose to separate between healthy subjects and BC patients. This research could have a beneficial impact on clinical practice as we consider that this test could probably be used at the first point before the application of established gold tests (mammography, ultrasound, and biopsy) and substantially improve screening tests in the general population.

Expression of long non-coding RNA ENSG00000226738 (LncKLHDC7B) is enriched in the immunomodulatory triple-negative breast cancer subtype and its alteration promotes cell migration, invasion, and resistance to cell death.

Triple negative breast cancer (TNBC) represents an aggressive phenotype with poor prognosis compared with ER, PR, and HER2-positive tumors. TNBC is a heterogeneous disease, and gene expression analysis has identified seven molecular subtypes. Accumulating evidence demonstrates that long non-coding RNA (lncRNA) are involved in regulation of gene expression and cancer biology, contributing to essential cancer cell functions. In this study, we analyzed the expression profile of lncRNA in TNBC subtypes from 156 TNBC samples, and then characterized the functional role of LncKLHDC7B (ENSG00000226738). A total of 710 lncRNA were found to be differentially expressed between TNBC subtypes, and a subset of these altered lncRNA were independently validated. We discovered that LncKLHDC7B (ENSG00000226738) acts as a transcriptional modulator of its neighboring coding gene KLHDC7B in the immunomodulatory subtype. Furthermore, LncKLHDC7B knockdown enhanced migration and invasion, and promoted resistance to cellular death. Our findings confirmed the contribution of LncKLHDC7B to induction of apoptosis and inhibition of cell migration and invasion, suggesting that TNBC tumors with enrichment of LncKLHDC7B may exhibit distinct regulatory activity, or that this may be a generalized process in breast cancer. Additionally, in silico analysis confirmed for the first time that the low expression of KLHDC7B and LncKLHDC7B is associated with poor prognosis in patients with breast cancer.

Complete sequence of the ATP6 and ND3 mitochondrial genes in breast cancer tissue of postmenopausal women with different body mass indexes.

Due to the fact that mitochondrial defects and oxidative stress have been related with obesity and breast cancer is more aggressive in women with obesity, we investigated if postmenopausal Mexican-Mestizo women with breast cancer presented somatic mutations in the sequence of the ATP6 and/or ND3 genes. Twenty one postmenopausal Mexican-Mestizo women with breast cancer who underwent mastectomy or breast conserving surgery were studied. Height and weight were used to calculate body mass index. DNA from tumor tissue samples and blood leukocytes was amplified by polymerase chain reaction and sequenced the ATP6 and ND3 mitochondrial genes. Ages ranged from 46 to 82. According to World Health Organization criteria among the 21 women, 7 had a normal BMI, 7 were overweight and 7 had obesity. In regard to the molecular study, after sequencing the coding region of ATP6 and ND3 genes of the DNA obtained from both leukocytes and tumor tissue, we did not find somatic mutations. All of the changes that we found in both genes were polymorphisms: in ATP6, we identified in ten patients 3 non-synonymous nucleotide changes and in ND3 we observed that six patients presented polymorphisms, three of them were synonymous and two non-synonymous. To our knowledge, this constitutes the first report where the complete sequence of the ATP6 and ND3 genes has been analyzed in postmenopausal Mexican-Mestizo women with breast cancer and diverse BMI. Our results differ with those reported in Caucasian and Asian populations, possibly due to ethnic differences.

Asociación entre telorragia y cáncer de mama en una unidad médica de alta concentración / Association between telorragia and breast cancer in a high concentration medical unit

Resumen OBJETIVO: Determinar la asociación entre telorragia y cáncer de mama en población mexicana atendida en una unidad médica de alta concentración. MATERIALES Y MÉTODOS: Estudio observacional, retrospectivo y analítico efectuado en pacientes con telorragia atendidas entre enero de 2007 y diciembre de 2016 en la Fundación de Cáncer de Mama (FUCAM). Se efectuó el cálculo de proporciones y un subanálisis "tipo nodo" entre telorragia más nódulo versus telorragia sola, mediante χ2, riesgo relativo e intervalo de confianza al 95% con el paquete estadístico SPSS 23.0. RESULTADOS: Se estudiaron 169 pacientes, 42 de ellas con diagnóstico definitivo de cáncer de mama. La telorragia se asoció en 24.8% con cáncer, y cuando estuvo asociada con un nódulo la probabilidad de malignidad fue de 63%. Al comparar los subgrupos: telorragia más nódulo vs telorragia sola, se encontró una razón de momios de 4.2 para el primer grupo (IC95%: 2.5-6.8; p < 0.001). CONCLUSIONES: Este estudio demostró que la probabilidad de malignidad en los casos de telorragia sola en población mexicana, en un hospital de referencia, se encuentra en el límite alto en relación con el histórico mundial, y cuando se asocia con un nódulo la probabilidad es significativamente mayor.

Absract OBJECTIVE: To determine the association between telorragia and breast cancer in a Mexican population in a highly concentrated Medical Unit. MATERIALS AND METHODS: Observational, retrospective, analytical study in patients with telorragia treated at FUCAM from January 2007 to December 2016. Proportion calculation and a "node type" sub-analysis were carried out, between telorragia plus nodule versus telorragia alone, by means of χ2, relative risk, and 95% confidence interval with statistical package SPSS 23.0. RESULTS: 169 patients were studied, 42 of them presented a definitive diagnosis of breast cancer. The telorragia was associated in 24.8% to cancer, and when it was associated with nodule the probability of malignancy was 63%. When comparing the subgroups with more nodule vs telorrhagia alone, an OR of 4.2 was found for the first group (95% CI 2.5-6.8, p <0.001). CONCLUSIONS: This study showed that the probability of malignancy in cases of telorrhagia alone in the Mexican population in a referral hospital is in the high range in relation to the historical world, and is associated with a nodule, the probability is significantly higher.

Phyllodes Tumor of the Breast: 307 Treated Cases, the Largest Mexican Experience at a Single Breast Disease Institution.

BACKGROUND: Phyllodes tumor (PT) of the breast in Hispanic patients is more frequently reported with large tumors and with more borderline/malignant subtypes compared with other populations. The objective of this study was to describe characteristics of patients with PT and to identify differences among subtypes in a Mexican population. METHODS: A retrospective study was conducted on patients with PT. Sociodemographic, histopathologic, and treatment characteristics were compared among subtypes, including only surgically treated cases due the complete surgical-specimen study requirement for appropriate WHO classification. RESULTS: During 10 years, 346 PT were diagnosed; only 307 were included (305 patients), with a mean age of 41.7 yr. Self-detected lump took place in 91.8%, usually discovered 6 months previously, with median tumor size of 4.5 cm. Local wide excisions were done in 213 (69.8%) and mastectomies in 92 (30.1%). Immediate breast reconstruction took place in 38% and oncoplastic procedures in 23%. PT were classified as benign in 222 (72.3%) cases, borderline in 50 (16.2%), and malignant in 35 (11.4%), with pathological tumor size of 4.2, 5.4, and 8.7 cm, respectively (P<0.001). Patients with malignant PT were older (48 yr), with more diabetics (14.3%), less breastfeeding (37.1%), more smokers (17.1%), with more postmenopausal cases (42.9%), and older age at menopause (51.5 years) compared with the remaining subtypes (P<0.05). Relapse occurred in 8.2% of patients with follow-up. CONCLUSION: In comparison with other Hispanic publications, these Mexican patients had similar age, with smaller tumors, modestly higher benign PT, fewer malignant PT, and lower documented relapse cases.

[Feasibility and cosmetic outcome of oncoplastic surgery in breast cancer treatment]. / Factibilidad y resultado estético de la cirugía oncoplástica en el tratamiento de cáncer de mama.

BACKGROUND: Breast cancer is the leading oncological cause of death in Mexican women over 25 years old. Given the need to improve postoperative cosmetic results in patients with breast cancer, oncoplastic surgery has been developed, which allows larger tumour resections and minor cosmetic alterations. OBJECTIVE: To determine the oncological feasibility and cosmetic outcome of oncoplastic surgery at the Instituto de Enfermedades de la Mama, FUCAM, AC. MATERIAL AND METHODS: A review was conducted from January 2010 to July 2013, which included patients with breast cancer diagnosis treated with conventional breast-conserving surgery or with oncoplastic surgery in the Institute of Diseases of the Breast, FUCAM AC. Clinical and histopathological parameters were compared between the two groups, and a questionnaire of cosmetic satisfaction and quality of life was applied. RESULTS: Of the 171 patients included, 95 of them were treated with conventional breast-conserving surgery and 76 with oncoplastic surgery. Pathological tumour size was significantly larger in patients treated with oncoplastic surgery (p = 0.002). There were no differences found between the groups as regards the number of patients with positive surgical margin, the rate of complications, and cosmetic satisfaction. CONCLUSION: This study demonstrates the oncological feasibility and high cosmetic satisfaction of oncoplastic surgery with minimal psycho-social impact on patients.

[Impact on quality of life with breast reconstructive surgery after mastectomy for breast cancer]. / Impacto en la calidad de vida con cirugía reconstructiva posterior al tratamiento de cáncer de mama.

BACKGROUND: Breast cancer treatment leads mutilation and destruction of breast shape, with negative effects on body image and self-esteem. OBJECTIVES: Assessment on quality of life after breast reconstruction surgery, impact on sexuality, the cosmetic outcome experienced by the patient, and compare result with patients who refused breast reconstruction. MATERIAL AND METHODS: Retrospective, observational, descriptive, analytic study. We included breast cancer patients treated between April 15 2010 to April 15, 2011. Application of "The Survey Questionnaire short form Health 36" (SF-36) with valid use on Mexican population was conducted to measure quality of life, which uses 8 concepts: physical functioning, physical role, body pain, general health, vitality, social function, emotional role and mental health, the results are transferred to a scale 0 (worst health) to 100 (best health). RESULTS: 37 patients whit breast reconstruction had the inclusion criteria, mean age was 48.4 years. The score of SF-36 questionnaire in reconstructed patients was 76.8, in control group was 85.19 and mastectomy patients without reconstruction was 72.6. Among the items studied those with the greatest difference was the mental health, emotional role and social function, this means that patients with breast reconstruction are less affected in their social and sexual interaction. CONCLUSIONS: The reconstructed patients have a positive impact on quality of life slightly higher, sexuality is significantly worse in patients without breast reconstruction, it is important to inform and offer breast reconstruction because many do not require these procedures for fear or lack of information.

Utilidad de un cuestionario en la detección de individuos con riesgo de diabetes mellitus asintomática / Performance of a questionnaire for screening people with undiagnosed diabetes

Objetivo. Evaluar en población abierta, la utilidad de un cuestionario estructurado para identificar individuos con riesgo elevado de diabetes mellitus asintomática. Material y métodos. Se aplicó a individuos no diabéticos no cuestionario diseñado para identificar personas con riesgo de padecer diabetes, basado en la presencia de factores de riesgo como edad, sobrepeso, sedentarismo, antecedentes familiares de diabetes o personales de macrosomías. A cada participante se le hicieron mediciones antropométricas y se tomó una muestra de sangre capilar para determinación de glucosa mediante tira reactiva y lector óptico portátil. Resultados. Se encuestaron 360 personas, el 28.9 por ciento de las muestras para glucemia se tomaron en ayuno, la edad promedio fue 40.3 años, 34.4 por ciento de los entrevistados tenían familiares en primer grado con diabetes y 53 por ciento tuvieron sobrepeso. De acuerdo al cuestionario, 55.5 por ciento de los encuestados presentaron un perfil de riesgo elevado para diabetes con predominio de las mujeres sobre los hombres (61.9 por ciento vs. 40.7 por ciento, p<0.001). Treinta y ocho (10.5 por ciento) determinaciones de glucosa fueron anormales (tamizaje positivo), de las cuales 31 (81.5 por ciento) correlacionaron con el cuestionario (p>0.01). La sensibilidad y especificidad de cuestionario fueron 81.6 por ciento y 47.5 por ciento respectivamente. El valor predictivo positivo fue 15.5 por ciento y el predictivo negativo 95.6 por ciento. La glucemia en el grupo de alto riesgo por cuestionario fue mayor tanto en ayuno (90.6 vs. 84.2 mg/dL, p=0.015) como postprandial (116.1 vs. 100 mg/dL, p<0.01). Conclusiones. La aplicación del cuestionario evaluado permite distinguir adecuadamente los individuos con mayor probabilidad de una prueba de tamizaje positiva y puede elevar en forma significtiva la tasa de detección de diabetes asintomática en población abierta