Tracing the genetic history of the 'Cañaris' from Ecuador and Peru using uniparental DNA markers.

BACKGROUND: According to history, in the pre-Hispanic period, during the conquest and Inka expansion in Ecuador, many Andean families of the Cañar region would have been displaced to several places of Tawantinsuyu, including Kañaris, a Quechua-speaking community located at the highlands of the Province of Ferreñafe, Lambayeque (Peru). Other families were probably taken from the Central Andes to a place close to Kañaris, named Inkawasi. Evidence of this migration comes from the presence near the Kañaris-Inkawasi communities of a village, a former Inka camp, which persists until the present day. This scenario could explain these toponyms, but it is still controversial. To clarify this historical question, the study presented here focused on the inference of the genetic relationship between 'Cañaris' populations, particularly of Cañar and Ferreñafe, compared to other highland populations. We analysed native patrilineal Y chromosome haplotypes composed of 15 short tandem repeats, a set of SNPs, and maternal mitochondrial DNA haplotypes of control region sequences. RESULTS: After the genetic comparisons of local populations-three from Ecuador and seven from Peru-, Y chromosome analyses (n = 376) indicated that individuals from the Cañar region do not share Y haplotypes with the Kañaris, or even with those of the Inkawasi. However, some Y haplotypes of Ecuadorian 'Cañaris' were associated with haplotypes of the Peruvian populations of Cajamarca, Chivay (Arequipa), Cusco and Lake Titicaca, an observation that is congruent with colonial records. Within the Kañaris and Inkawasi communities there are at least five clans in which several individuals share haplotypes, indicating that they have recent common ancestors. Despite their relative isolation, most individuals of both communities are related to those of the Cajamarca and Chachapoyas in Peru, consistent with the spoken Quechua and their geographic proximity. With respect to mitochondrial DNA haplotypes (n = 379), with the exception of a shared haplotype of the D1 lineage between the Cañar and Kañaris, there are no genetic affinities. CONCLUSION: Although there is no close genetic relationship between the Peruvian Kañaris (including Inkawasi) and Ecuadorian Cañar populations, our results showed some congruence with historical records.

Pharmacogenomics, biomarker network, and allele frequencies in colorectal cancer.

Colorectal cancer is one of the leading causes of cancer death worldwide. Over the last decades, several studies have shown that tumor-related genomic alterations predict tumor prognosis, drug response, and toxicity. These observations have led to the development of several therapies based on individual genomic profiles. As part of these approaches, pharmacogenomics analyses genomic alterations which may predict an efficient therapeutic response. Studying these mutations as biomarkers for predicting drug response is of a great interest to improve precision medicine. We conduct a comprehensive review of the main pharmacogenomics biomarkers and genomic alterations affecting enzyme activity, transporter capacity, channels, and receptors; and therefore the new advances in CRC precision medicine to select the best therapeutic strategy in populations worldwide, with a focus on Latin America.

A quick guide for using Microsoft OneNote as an electronic laboratory notebook.

Scientific data recording and reporting systems are of a great interest for endorsing reproducibility and transparency practices among the scientific community. Current research generates large datasets that can no longer be documented using paper lab notebooks (PLNs). In this regard, electronic laboratory notebooks (ELNs) could be a promising solution to replace PLNs and promote scientific reproducibility and transparency. We previously analyzed five ELNs and performed two survey-based studies to implement an ELN in a biomedical research institute. Among the ELNs tested, we found that Microsoft OneNote presents numerous features related to ELN best functionalities. In addition, both surveyed groups preferred OneNote over a scientifically designed ELN (PerkinElmer Elements). However, OneNote remains a general note-taking application and has not been designed for scientific purposes. We therefore provide a quick guide to adapt OneNote to an ELN workflow that can also be adjusted to other nonscientific ELNs.

Gene Prioritization through Consensus Strategy, Enrichment Methodologies Analysis, and Networking for Osteosarcoma Pathogenesis.

Osteosarcoma is the most common subtype of primary bone cancer, affecting mostly adolescents. In recent years, several studies have focused on elucidating the molecular mechanisms of this sarcoma; however, its molecular etiology has still not been determined with precision. Therefore, we applied a consensus strategy with the use of several bioinformatics tools to prioritize genes involved in its pathogenesis. Subsequently, we assessed the physical interactions of the previously selected genes and applied a communality analysis to this protein-protein interaction network. The consensus strategy prioritized a total list of 553 genes. Our enrichment analysis validates several studies that describe the signaling pathways PI3K/AKT and MAPK/ERK as pathogenic. The gene ontology described TP53 as a principal signal transducer that chiefly mediates processes associated with cell cycle and DNA damage response It is interesting to note that the communality analysis clusters several members involved in metastasis events, such as MMP2 and MMP9, and genes associated with DNA repair complexes, like ATM, ATR, CHEK1, and RAD51. In this study, we have identified well-known pathogenic genes for osteosarcoma and prioritized genes that need to be further explored.

The Genetic History of Peruvian Quechua-Lamistas and Chankas: Uniparental DNA Patterns among Autochthonous Amazonian and Andean Populations.

This study focuses on the genetic history of the Quechua-Lamistas, inhabitants of the Lamas Province in the San Martin Department, Peru, who speak their own distinct variety of the Quechua family of languages. It has been suggested that different pre-Columbian ethnic groups from the Peruvian Amazonia, like the Motilones or "shaven heads", assimilated the Quechua language and then formed the current native population of Lamas. However, many Quechua-Lamistas claim to be direct descendants of the Chankas, a famous pre-Columbian indigenous group that escaped from Inca rule in the Andes. To investigate the Quechua-Lamistas and Chankas' ancestries, we compared uniparental genetic profiles (17 STRs of Q-M3 Y-chromosome and mtDNA complete control region haplotypes) among autochthonous Amazonian and Andean populations from Peru, Bolivia and Ecuador. The phylogeographic and population genetic analyses indicate a fairly heterogeneous ancestry for the Quechua-Lamistas, while they are closely related to their neighbours who speak Amazonian languages, presenting no direct relationships with populations from the region where the ancient Chankas lived. On the other hand, the genetic profiles of self-identified Chanka descendants living in Andahuaylas (located in the Apurimac Department, Peru, in the Central Andes) were closely related to those living in Huancavelica and the assumed Chanka Confederation area before the Inca expansion.

New native South American Y chromosome lineages.

Many single-nucleotide polymorphisms (SNPs) in the non-recombining region of the human Y chromosome have been described in the last decade. High-coverage sequencing has helped to characterize new SNPs, which has in turn increased the level of detail in paternal phylogenies. However, these paternal lineages still provide insufficient information on population history and demography, especially for Native Americans. The present study aimed to identify informative paternal sublineages derived from the main founder lineage of the Americas-haplogroup Q-L54-in a sample of 1841 native South Americans. For this purpose, we used a Y-chromosomal genotyping multiplex platform and conventional genotyping methods to validate 34 new SNPs that were identified in the present study by sequencing, together with many Y-SNPs previously described in the literature. We updated the haplogroup Q phylogeny and identified two new Q-M3 and three new Q-L54*(xM3) sublineages defined by five informative SNPs, designated SA04, SA05, SA02, SA03 and SA29. Within the Q-M3, sublineage Q-SA04 was mostly found in individuals from ethnic groups belonging to the Tukanoan linguistic family in the northwest Amazon, whereas sublineage Q-SA05 was found in Peruvian and Bolivian Amazon ethnic groups. Within Q-L54*, the derived sublineages Q-SA03 and Q-SA02 were exclusively found among Coyaima individuals (Cariban linguistic family) from Colombia, while Q-SA29 was found only in Maxacali individuals (Jean linguistic family) from southeast Brazil. Furthermore, we validated the usefulness of several published SNPs among indigenous South Americans. This new Y chromosome haplogroup Q phylogeny offers an informative paternal genealogy to investigate the pre-Columbian history of South America.Journal of Human Genetics advance online publication, 31 March 2016; doi:10.1038/jhg.2016.26.

A study of the molecular variants associated with lactase persistence in different Ecuadorian ethnic groups.

OBJECTIVE: Lactase persistence (LP) is an adaptive trait that certain human populations have acquired in response to lactose consumption in adulthood. The T-13910 variant has been reported as a causal polymorphism in Europeans. The Ecuadorian population has been described as multicultural and multiethnic, comprised of three main ethnic groups (Mestizo, Native Amerindian, and Afro-Ecuadorian). The aim of the study was to identify the molecular basis of LP in these admixed populations for the first time and determine the association between the T-13910 marker and the European ancestry proportion of each ethnic group. METHODS: Genotyping was performed in 741 Ecuadorian individuals by sequencing a 576 bp region around the -13910 position upstream of the LCT gene. The ancestry proportions of Mestizo, Afro-Ecuadorian, and Native Amerindians were calculated using Ancestry Informative Markers and were compared with the diversity panel of the Human Genome Diversity Project. RESULTS: LP prevalence calculated from T-13910 allele frequency in Mestizo, Afro-Ecuadorian, and Native Amerindians was 24.4%, 16%, and 12.5%, respectively. The ancestry percentage correlated to the admixture proportion of each ethnic group, and the C/T-13910 genotype frequency was influenced by the European ancestry proportion. CONCLUSIONS: The presence of the T-13910 polymorphism in the Ecuadorian population suggested that LP was a trait introduced by European migration and inherited by admixture that occurred during the colonization of South America. This variant was not fixed in a population with a history of admixture, and its allele frequency was proportional to the ancestry proportion of each Ecuadorian ethnic group. Am. J. Hum. Biol. 28:774-781, 2016. © 2016Wiley Periodicals, Inc.

Breast cancer risk associated with gene expression and genotype polymorphisms of the folate-metabolizing MTHFR gene: a case-control study in a high altitude Ecuadorian mestizo population.

Breast cancer (BC) is the leading cause of cancer-related death among women in 2014. Methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and MTR reductase (MTRR) are enzymes that play an important role in folate metabolism. The single nucleotide polymorphisms, MTHFR C677T, A1298C, MTR A2756G, and MTRR A66G, alter plasmatic folate and homocysteine concentrations, causing problems during the repairment, synthesis, and methylation of the genetic material. Therefore, it is essential to know how BC risk is associated with histopathological and immunohistochemical characteristics, genotype polymorphisms, and gene expression in a high altitude Ecuadorian mestizo population. DNA was extracted from 195 healthy and 114 affected women. Genotypes were determined by restriction enzymes and genomic sequencing. mRNA was extracted from 26 glandular breast tissue samples, both from cancerous tissue and healthy tissue adjacent to the tumor. Relative gene expression was determined with the comparative Livak method (2(-ΔΔCT)). We found significant association between the rs1801133 (A222V) genotypes and an increased risk of BC development: C/T (odds ratio [OR] = 1.8; 95 % confidence interval [CI] = 1.1-3.2; P = 0.039), T/T (OR = 2.9; 95 % CI = 1.2-7.2; P = 0.025), and C/T + T/T (OR = 1.9; 95 % CI = 1.1-3.3; P = 0.019). Regarding relative gene expression, we found significant mRNA subexpression between the combined genotypes C/T + T/T (rs1801133) and triple negative breast cancer (TNBC) (P = 0.034). In brief, the MTHFR gene and its protein could act as potential predictive biomarkers of BC, especially TNBC among the high altitude Ecuadorian mestizo population.

Harmonization of QSAR Best Practices and Molecular Docking Provides an Efficient Virtual Screening Tool for Discovering New G-Quadruplex Ligands.

Telomeres and telomerase are key players in tumorogenesis. Among the various strategies proposed for telomerase inhibition or telomere uncapping, the stabilization of telomeric G-quadruplex (G4) structures is a very promising one. Additionally, G4 stabilizing ligands also act over tumors mediated by the alternative elongation of telomeres. Accordingly, the discovery of novel compounds able to act on telomeres and/or inhibit the telomerase enzyme by stabilizing DNA telomeric G4 structures as well as the development of approaches efficiently prioritizing such compounds constitute active areas of research in computational medicinal chemistry and anticancer drug discovery. In this direction, we applied a virtual screening strategy based on the rigorous application of QSAR best practices and its harmonized integration with structure-based methods. More than 600,000 compounds from commercial databases were screened, the first 99 compounds were prioritized, and 21 commercially available and structurally diverse candidates were purchased and submitted to experimental assays. Such strategy proved to be highly efficient in the prioritization of G4 stabilizer hits, with a hit rate of 23.5%. The best G4 stabilizer hit found exhibited a shift in melting temperature from FRET assay of +7.3 °C at 5 µM, while three other candidates also exhibited a promising stabilizing profile. The two most promising candidates also exhibited a good telomerase inhibitory ability and a mild inhibition of HeLa cells growth. None of these candidates showed antiproliferative effects in normal fibroblasts. Finally, the proposed virtual screening strategy proved to be a practical and reliable tool for the discovery of novel G4 ligands which can be used as starting points of further optimization campaigns.

Alterations and chromosomal variants in the Ecuadorian population.

Medical genetics is a field marked by fast progress. Even though it was at one point confined to a group of relatively rare diseases, today it has become a central component in the understanding of disorders and it is the subject of interest for all medical specialties. This paper, shares data on the chromosomal alterations and variations that have been diagnosed in Ecuadorian patients since 1998. A total of 2,636 individual cases have been analyzed by G-banding technique until February 2012. The present work shows this collection of data and the important findings that have appeared throughout these years in hopes that it can contribute to have a deeper understanding of the incidence of chromosomal aberrations and alterations in the Ecuadorian population.

A new subhaplogroup of native American Y-Chromosomes from the Andes.

The human Y chromosome contains highly informative markers for making historical inferences about the pre-Columbian peopling of Americas. However, the scarcity of these markers has limited its use in the inference of shared ancestry and past migrations relevant to the origin of the culturally and biologically diverse Native Americans. To identify new single nucleotide polymorphisms (SNPs) and increase the phylogenetic resolution of the major haplogroup Q found in the Americas, we have performed a search for new polymorphisms based on sequencing divergent Y chromosomes identified by microsatellite haplotype analysis. Using this approach, a new Y-SNP (SA01) has been identified in the Andean populations of South America, allowing for the detection of a new sublineage of Q1a3a. This sublineage displays a less complex phylogeographic network of associated microsatellites and more restricted geographic occurrence, and is given the designation Q1a3a4. This result indicates that our approach can be successfully used to identify sublineages of interest in a specific region that allow the investigation of particular histories of human populations.

Baseline determination in social, health, and genetic areas in communities affected by glyphosate aerial spraying on the northeastern Ecuadorian border.

The northeastern Ecuadorian border has undergone aerial spraying with an herbicide mix that contains surfactants and adjuvants, executed by the Colombian Government. The purpose of this study was to diagnose social, health, and genetic aspects of the people affected by glyphosate. For this objective to be achieved, 144 people were interviewed, and 521 medical diagnoses and 182 peripheral blood samples were obtained. Genotyping of GSTP1 Ile105Val, GPX-1 Pro198Leu, and XRCC1 Arg399Gln polymorphisms were analyzed, using PCR-RFLP technique. The assessment of chromosomal aberrations was performed, obtaining 182 karyotypes. Malnutrition in children was 3%. Of the total population, 7.7% had children with malformations, and the percentage of abortions was 12.7%. Concerning genotyping, individuals with GSTP1 Val/Val obtained an odds ratio of 4.88 (p < 0.001), and Ile/Val individuals, together with Val/Val individuals, had an odds ratio of 2.6 (p < 0.05). In addition, GPX-1 Leu/Leu individuals presented an odds ratio (OR) of 8.5 (p < 0.05). Regarding karyotyping, the 182 individuals had normal karyotypes. In conclusion, the study population did not present significant chromosomal and DNA alterations. The most important social impact was fear. We recommend future prospective studies to assess the communities.

INFECTION DYNAMICS OF BATRACHOCHYTRIUM DENDROBATIDIS IN TWO FROG SPECIES INHABITING QUITO'S METROPOLITAN GUANGÜILTAGUA PARK, ECUADOR.

Batrachochytrium dendrobatidis (Bd) infection is one of the principal causes of amphibian declines worldwide. The presence of Bd has been determined in Gastrotheca riobambae tadpoles that inhabit ponds in Quito's Metropolitan Guangüiltagua Park, Ecuador. This study sought to determine whether these tadpoles are infected and to determine the presence of chytridiomycosis in another frog species, Pristimantis unistrigatus, which also inhabits the park and has different reproductive biology and distinct behavioral habits. We used end-point and real-time PCR techniques to detect and quantify Bd infection. At 1 yr, samples were taken from the skin of P. unistrigatus using swabs and were also taken from the mouthparts of G. riobambae tadpoles. It was found that the two species were infected with a Bd prevalence of 39% (53/135) in G. riobambae tadpoles and 15% (57/382) in P. unistrigatus frogs. The two types of samples (tissue and swabs) from mouthparts showed differences in the zoospores per microliter loads (x̄=1,376.7±3,450.2 vs. x̄=285.0±652.3). Moreover, a correlation (r2=0.621) was discovered between the monthly mean maximum temperature of the pond with disease prevalence in G. riobambae tadpoles. Infection levels in the P. unistrigatus population varied significantly over time, and distance to the pond was a determinant factor for infection intensity.

In silico Analyses of Immune System Protein Interactome Network, Single-Cell RNA Sequencing of Human Tissues, and Artificial Neural Networks Reveal Potential Therapeutic Targets for Drug Repurposing Against COVID-19.

Background: There is pressing urgency to identify therapeutic targets and drugs that allow treating COVID-19 patients effectively. Methods: We performed in silico analyses of immune system protein interactome network, single-cell RNA sequencing of human tissues, and artificial neural networks to reveal potential therapeutic targets for drug repurposing against COVID-19. Results: We screened 1,584 high-confidence immune system proteins in ACE2 and TMPRSS2 co-expressing cells, finding 25 potential therapeutic targets significantly overexpressed in nasal goblet secretory cells, lung type II pneumocytes, and ileal absorptive enterocytes of patients with several immunopathologies. Then, we performed fully connected deep neural networks to find the best multitask classification model to predict the activity of 10,672 drugs, obtaining several approved drugs, compounds under investigation, and experimental compounds with the highest area under the receiver operating characteristics. Conclusion: After being effectively analyzed in clinical trials, these drugs can be considered for treatment of severe COVID-19 patients. Scripts can be downloaded at https://github.com/muntisa/immuno-drug-repurposing-COVID-19.

Population history, phylogeography, and conservation genetics of the last Neotropical mega-herbivore, the lowland tapir (Tapirus terrestris).

BACKGROUND: Understanding the forces that shaped Neotropical diversity is central issue to explain tropical biodiversity and inform conservation action; yet few studies have examined large, widespread species. Lowland tapir (Tapirus terrrestris, Perissodactyla, Tapiridae) is the largest Neotropical herbivore whose ancestors arrived in South America during the Great American Biotic Interchange. A Pleistocene diversification is inferred for the genus Tapirus from the fossil record, but only two species survived the Pleistocene megafauna extinction. Here, we investigate the history of lowland tapir as revealed by variation at the mitochondrial gene Cytochrome b, compare it to the fossil data, and explore mechanisms that could have shaped the observed structure of current populations. RESULTS: Separate methodological approaches found mutually exclusive divergence times for lowland tapir, either in the late or in the early Pleistocene, although a late Pleistocene divergence is more in tune with the fossil record. Bayesian analysis favored mountain tapir (T. pinchaque) paraphyly in relation to lowland tapir over reciprocal monophyly, corroborating the inferences from the fossil data these species are sister taxa. A coalescent-based analysis rejected a null hypothesis of allopatric divergence, suggesting a complex history. Based on the geographic distribution of haplotypes we propose (i) a central role for western Amazonia in tapir diversification, with a key role of the ecological gradient along the transition between Andean subcloud forests and Amazon lowland forest, and (ii) that the Amazon river acted as an barrier to gene flow. Finally, the branching patterns and estimates based on nucleotide diversity indicate a population expansion after the Last Glacial Maximum. CONCLUSIONS: This study is the first examining lowland tapir phylogeography. Climatic events at the end of the Pleistocene, parapatric speciation, divergence along the Andean foothill, and role of the Amazon river, have similarly shaped the history of other taxa. Nevertheless further work with additional samples and loci is needed to improve our initial assessment. From a conservation perspective, we did not find a correspondence between genetic structure in lowland tapir and ecogeographic regions proposed to define conservation priorities in the Neotropics. This discrepancy sheds doubt into this scheme's ability to generate effective conservation planning for vagile species.

Frequency of polymorphisms pro198leu in GPX-1 gene and ile58thr in MnSOD gene in the altitude Ecuadorian population with bladder cancer.

Bladder cancer represents 8% of all malignancies diagnosed in men and 3% in women. The risk factors for developing bladder cancer, including the incidence rate, morbidity, and mortality, vary according to the ethnic group, exposition rate at work, age, gender, and tobacco consumption. Moreover, there is a risk of developing this carcinoma due to dietary conditions, demonstrating that certain enzymes neutralize oxidative compound derivative of carcinogens, which if not degraded, accumulate in the body and destroy epithelial cells of the bladder, causing an increase in the risk of developing this disease. The detoxifying enzymes inactivate dangerous chemical compounds and anions for the cell; that is, why it is important to know if the polymorphisms pro198leu in GPX-1 and ile58thr in MnSOD are associated with bladder cancer. In this study, 120 individuals were analyzed as controls and 97 individuals with previously diagnosed bladder cancer. In the case of polymorphism pro198leu, highly significant differences were observed and individuals with this polymorphism presented a probability of developing bladder cancer 3.8 times greater than controls (OR = 3.8; 95% CI 2.16-6.78; p < 0.001). No significant differences in polymorphism ile58thr of MnSOD gene occurred when we compared the study population (OR = 2.1; 95% CI 1.26-3.49; p > 0.05). The results indicate that polymorphism of GPX-1 gene influences the risk of developing bladder cancer in the Ecuadorian population, suggesting that more research on detoxifying genes in bladder cancer should be conducted.

TCGA Pan-Cancer Genomic Analysis of Alternative Lengthening of Telomeres (ALT) Related Genes.

Telomere maintenance mechanisms (TMM) are used by cancer cells to avoid apoptosis, 85-90% reactivate telomerase, while 10-15% use the alternative lengthening of telomeres (ALT). Due to anti-telomerase-based treatments, some tumors switch from a telomerase-dependent mechanism to ALT; in fact, the co-existence between both mechanisms has been observed in some cancers. Although different elements in the ALT pathway are uncovered, some molecular mechanisms are still poorly understood. Therefore, with the aim to identify potential molecular markers for the study of ALT, we combined in silico approaches in a 411 telomere maintenance gene set. As a consequence, we conducted a genomic analysis of these genes in 31 Pan-Cancer Atlas studies from The Cancer Genome Atlas and found 325,936 genomic alterations; from which, we identified 20 genes highly mutated in the cancer studies. Finally, we made a protein-protein interaction network and enrichment analysis to observe the main pathways of these genes and discuss their role in ALT-related processes, like homologous recombination and homology directed repair. Overall, due to the lack of understanding of the molecular mechanisms of ALT cancers, we proposed a group of genes, which after ex vivo validations, could represent new potential therapeutic markers in the study of ALT.

Oncology and Pharmacogenomics Insights in Polycystic Ovary Syndrome: An Integrative Analysis.

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. Epidemiological findings revealed that women with PCOS are prone to develop certain cancer types due to their shared metabolic and endocrine abnormalities. However, the mechanism that relates PCOS and oncogenesis has not been addressed. Herein, in this review article the genomic status, transcriptional and protein profiles of 264 strongly PCOS related genes (PRG) were evaluated in endometrial cancer (EC), ovarian cancer (OV) and breast cancer (BC) exploring oncogenic databases. The genomic alterations of PRG were significantly higher when compared with a set of non-diseases genes in all cancer types. PTEN had the highest number of mutations in EC, TP53, in OC, and FSHR, in BC. Based on clinical data, women older than 50 years and Black or African American females carried the highest ratio of genomic alterations among all cancer types. The most altered signaling pathways were p53 in EC and OC, while Fc epsilon RI in BC. After evaluating PRG in normal and cancer tissue, downregulation of the differentially expressed genes was a common feature. Less than 30 proteins were up and downregulated in all cancer contexts. We identified 36 highly altered genes, among them 10 were shared between the three cancer types analyzed, which are involved in the cell proliferation regulation, response to hormone and to endogenous stimulus. Despite limited PCOS pharmacogenomics studies, 10 SNPs are reported to be associated with drug response. All were missense mutations, except for rs8111699, an intronic variant characterized as a regulatory element and presumably binding site for transcription factors. In conclusion, in silico analysis revealed key genes that might participate in PCOS and oncogenesis, which could aid in early cancer diagnosis. Pharmacogenomics efforts have implicated SNPs in drug response, yet still remain to be found.

OncoOmics approaches to reveal essential genes in breast cancer: a panoramic view from pathogenesis to precision medicine.

Breast cancer (BC) is the leading cause of cancer-related death among women and the most commonly diagnosed cancer worldwide. Although in recent years large-scale efforts have focused on identifying new therapeutic targets, a better understanding of BC molecular processes is required. Here we focused on elucidating the molecular hallmarks of BC heterogeneity and the oncogenic mutations involved in precision medicine that remains poorly defined. To fill this gap, we established an OncoOmics strategy that consists of analyzing genomic alterations, signaling pathways, protein-protein interactome network, protein expression, dependency maps in cell lines and patient-derived xenografts in 230 previously prioritized genes to reveal essential genes in breast cancer. As results, the OncoOmics BC essential genes were rationally filtered to 140. mRNA up-regulation was the most prevalent genomic alteration. The most altered signaling pathways were associated with basal-like and Her2-enriched molecular subtypes. RAC1, AKT1, CCND1, PIK3CA, ERBB2, CDH1, MAPK14, TP53, MAPK1, SRC, RAC3, BCL2, CTNNB1, EGFR, CDK2, GRB2, MED1 and GATA3 were essential genes in at least three OncoOmics approaches. Drugs with the highest amount of clinical trials in phases 3 and 4 were paclitaxel, docetaxel, trastuzumab, tamoxifen and doxorubicin. Lastly, we collected ~3,500 somatic and germline oncogenic variants associated with 50 essential genes, which in turn had therapeutic connectivity with 73 drugs. In conclusion, the OncoOmics strategy reveals essential genes capable of accelerating the development of targeted therapies for precision oncology.