Biology subjects

Armendariz-Castillo, I.

Publications and source records attributed to Armendariz-Castillo, I..

7 recordsLinked to original sources

bioRxiv2020

Characterization Of Ancestral Origin Of Cystic Fibrosis Of Patients With New Reported Mutations In CFTR

The incidence of Cystic fibrosis (CF) and the frequency of the variants for CFTR depend on the population; furthermore, CF symptomatology is characterized by obstructive lung disease, pancreatic insufficiency among others, reliant on the individual genotype. Ecuadorian population is a mixture of Native Americans, Europeans, and Africans. That population admixture could be the reason for the new mutations reported in a previous study by Ruiz et al. (2019). A panel of 46 Ancestry Informative Markers was used to estimate the ancestral proportions of each available sample (12 samples in total). As a result, the Native American ancestry proportion was the most prevalent in almost all individuals, except for three patients from Guayaquil with the mutation [c.757G>A:p.Gly253Arg; c.1352G>T:p.Gly451Val] who had the highest European composition.

genetics↗

bioRxiv2020

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 have the ability to switch from a telomerase-dependent mechanism to ALT, in fact, the co-existence between telomerase and the ALT pathway have been observed in a variety of cancer types. Despite different elements in the ALT pathway have been uncovered, the molecular mechanism and other factors are still poorly understood, which difficult the detection and treatment of ALT-positive cells, which are known to present poor prognosis. Therefore, with the aim to identify potential molecular markers to be used in the study of ALT, we combined simplistic in silico approaches in 411 telomere maintenance (TM) genes which have been previously validated or predicted to be involved in the ALT pathway. In consequence, we conducted a genomic analysis of these genes in 31 Pan-Cancer Atlas studies (n=9,282) from The Cancer Genome Atlas in the cBioPortal and found 325,936 genomic alterations, being mRNA high and low the top alterations with 65.8% and 10.7% respectively. Moreover, we analyzed the highest frequency means of genomics alterations, identified and proposed 20 genes, which are highly mutated and up and down regulated in the cancer studies and could be used for future analysis in the study of ALT. Finally, we made a protein-protein interaction network and enrichment analysis to obtain an insight into the main pathways these genes are involved. We could observe their role in main processes related to the ALT mechanism like homologous recombination, homology directed repair (HDR), HDR through homologous recombination and telomere maintenance and organization.. Overall, due to the lack of understanding of the molecular mechanisms and detection of ALT-positive cancers, we identified and proposed more molecular targets that can be used for expression analysis and additional ex vivo assays to validate them as new potential therapeutic markers in the study of the ALT mechanism.

cancer biology↗

bioRxiv2020

Metastatic signaling of hypoxia-related genes across TCGA Pan-Cancer types

Many primary-tumor subregions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis. Metastatic disease is the leading cause of cancer-related deaths and involves critical interactions between tumor cells and the microenvironment. Here we focused on elucidating the molecular hallmarks of tumor hypoxia that remains poorly defined. To fill this gap, we analyzed the genomic alterations and hypoxia score of 233 hypoxia-related genes of 6,343 individuals across 17 TCGA Pan-Cancer types. In addition, we analyzed a protein-protein interactome (PPi) network and the shortest paths from hypoxic proteins to metastasis. As results, mRNA high alteration was prevalent in all cancer types. Genomic alterations and hypoxia score presented a highest frequency in tumor stage 4 and positive metastasis status in all cancer types. The most significant signaling pathways were HIF-1, ErbB, PI3K-Akt, FoxO, mTOR, Ras and VEGF. The PPi network revealed a strong association among hypoxic proteins, cancer driver proteins and metastasis driver proteins. The analysis of shortest paths revealed 99 ways to spread metastasis signaling from hypoxic proteins. Additionally, we proposed 62 hypoxic genes strongly associated with metastasis and 27 of them with high amount of genomic alterations. Overall, tumor hypoxia may drive aggressive molecular features across cancer types. Hence, we identified potential biomarkers and therapeutic targets regulated by hypoxia that could be incorporated into strategies aimed at improving novel drug development and treating metastasis.

cancer biology↗

bioRxiv2020

In silico analyses reveal new putative Breast Cancer RNA-binding proteins

Breast cancer (BC) is the leading cause of cancer-associated death among women worldwide. Despite treatment efforts, advanced BC with distant organ metastases is considered incurable. A better understanding of BC molecular processes is therefore of great interest to identify new therapeutic targets. Although large-scale efforts, such as The Cancer Genome Atlas (TCGA), have completely redefined cancer drug development, diagnosis, and treatment, additional key aspects of tumor biology remain to be discovered. In that respect, post-transcriptional regulation of tumorigenesis represents an understudied aspect of cancer research. As key regulators of this process, RNA-binding proteins (RBPs) are emerging as critical modulators of tumorigenesis but only few have defined roles in BC. To unravel new putative BC RBPs, we have performed in silico analyses of all human RBPs in three major cancer databases (TCGA-Breast Invasive Carcinoma, the Human Protein Atlas, and the Cancer Dependency Map project) along with complementary bioinformatics resources (STRING protein-protein interactions and the Network of Cancer Genes 6.0). Thus, we have identified six putative BC progressors (MRPL13, SCAMP3, CDC5L, DARS2, PUF60, and PLEC), and five BC suppressors RBPs (SUPT6H, MEX3C, UPF1, CNOT1, and TNKS1BP1). These proteins have never been studied in BC but show similar cancer-associated features than well-known BC proteins. Further research should focus on the mechanisms by which these proteins promote or suppress breast tumorigenesis, holding the promise of new therapeutic pathways along with novel drug development strategies.

cancer biology↗

bioRxiv2019

Pharmacogenomics, biomarker network and allele frequencies in colorectal cancer

Colorectal cancer (CRC) 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 a number of precision therapies based on individual genomic profiles. As part of these approaches, pharmacogenomics analyses genomic alterations that may predict an efficient therapeutic response. Studying these mutations as biomarkers for predicting drug response is of a great interest to improve precision medicine. Here 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.

genomics↗

bioRxiv2019

Genomic, Ancestral and Networking Analyses of a High-Altitude Native American Ecuadorian Patient with Congenital Insensitivity to Pain with Anhidrosis

Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder characterized by insensitivity to pain, inability to sweat and intellectual disability. CIPA is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) that encodes the high-affinity receptor of nerve growth factor (NGF). Patients with CIPA lack the primary afferents and sympathetic postganglionic neurons leading to lack of pain sensation and the presence of anhidrosis, respectively. Herein, we conducted a genomic analysis of 4,811 genes and 18,933 variants, including 54 mutations of NTRK1 in a high-altitude indigenous Ecuadorian patient with CIPA. As results, the patient presented 87.8% of Native American ancestry, 6.6% of African ancestry and 5.6% of European ancestry. The mutational analysis of the kinase domain of NTRK1 showed two pathogenic mutations, rs80356677 (Asp674Tyr) and rs763758904 (Arg602*). The genomic analysis showed 68 pathogenic and/or likely pathogenic variants in 45 genes, and two variants of uncertain significance in CACNA2D1 (rs370103843) and TRPC4 (rs80164537) genes involved in the pain matrix. The GO enrichment analysis showed 28 genes with relevant mutations involved in several biological processes, cellular components and molecular functions. In addition, the protein-protein interaction (PPi) networking analysis showed that NTRK1, SPTBN2 and GRM6 interact with several proteins of the pain matrix. In conclusion, this is the first time that a study associates genomic, ancestral and networking data in a high-altitude Native American Ecuadorian patient with consanguinity background in order to better understand CIPA pathogenesis.

genetics↗

bioRxiv2017

Inherited chromosomally integrated human herpesvirus 6 genomes are ancient, intact and potentially able to reactivate from telomeres

Human herpesviruses 6A and 6B (HHV6-A and HHV-6B; species Human herpesvirus 6A and Human herpesvirus 6B) have the capacity to integrate into telomeres, the essential capping structures of chromosomes that play roles in cancer and ageing. About 1% of people worldwide are carriers of chromosomally integrated HHV-6 (ciHHV-6), which is inherited as a genetic trait. Understanding the consequences of integration for the evolution of the viral genome, for the telomere and for the risk of disease associated with carrier status is hampered by a lack of knowledge about ciHHV-6 genomes. Here, we report an analysis of 28 ciHHV-6 genomes and show that they are significantly divergent from the few modern non-integrated HHV-6 strains for which complete sequences are currently available. In addition ciHHV-6B genomes in Europeans are more closely related to each other than to ciHHV-6B genomes from China and Pakistan, suggesting regional variation of the trait. Remarkably, at least one group of European ciHHV-6B carriers has inherited the same ciHHV-6B genome, integrated in the same telomere allele, from a common ancestor estimated to have existed 24,500 {+/-}10,600 years ago. Despite the antiquity of some, and possibly most, germline HHV-6 integrations, the majority of ciHHV-6B (95%) and ciHHV-6A (72%) genomes contain a full set of intact viral genes and therefore appear to have the capacity for viral gene expression and full reactivation.\n\nIMPORTANCEInheritance of HHV-6A or HHV-6B integrated into a telomere occurs at a low frequency in most populations studied to date but its characteristics are poorly understood. However, stratification of ciHHV-6 carriers in modern populations due to common ancestry is an important consideration for genome-wide association studies that aim to identify disease risks for these people. Here we present full sequence analysis of 28 ciHHV-6 genomes and show that ciHHV-6B in many carriers with European ancestry most likely originated from ancient integration events in a small number of ancestors. We propose that ancient ancestral origins for ciHHV-6A and ciHHV-6B are also likely in other populations. Moreover, despite their antiquity, all of the ciHHV-6 genomes appear to retain the capacity to express viral genes and most are predicted to be capable of full viral reactivation. These discoveries represent potentially important considerations in immune-compromised patients, in particular in organ transplantation and in stem cell therapy.

evolutionary biology↗