Molecular Characterization and Clinical Relevance of ALDH2 in Human Cancers

Background: Aldehyde dehydrogenase 2 (ALDH2) is well-known to be a key enzyme in alcohol metabolism. However, a comprehensive understanding of ALDH2 across human cancers is lacking.Methods: A systematic and comprehensive analysis of the molecular alterations and clinical relevance for ALDH2 in more than 10,000 samples from 33 cancer types was performed. qRT-PCR was performed on 60 cancer and 60 paired nontumor tissues.Results: It was observed that ALDH2 was generally downregulated in most cancers, which was mainly driven by DNA hypermethylation rather than mutations or copy number variations. Besides, ALDH2 was closely related to the inhibition and activation of tumor pathways and a variety of potential targeted agents had been discovered in our research. Last but not least, ALDH2 had the best prediction efficacy in assessing immunotherapeutic response compared with PD-L1, PD-1, CTLA4, CD8, and tumor mutation burden (TMB) in cutaneous melanoma. According to the analysis of large-scale public data and 60 pairs of clinical cancer samples, we found the downregulation of ALDH2 expression tends to suggest the malignant phenotypes and adverse prognosis, which might enhance the precise diagnosis and timely intervention of cancer patients.Conclusion: This study advanced the understanding of ALDH2 across cancers, and provided important insight into chemotherapy, immunotherapy and prognosis of patients with cancer.

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Genome diversity in Ukraine

GigaScience ◽

10.1093/gigascience/giaa159 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Taras K Oleksyk ◽

Walter W Wolfsberger ◽

Alexandra M Weber ◽

Khrystyna Shchubelka ◽

Olga T Oleksyk ◽

...

Keyword(s):

Sequence Data ◽

Copy Number Variations ◽

Genomic Variation ◽

High Coverage ◽

Genome Data ◽

New Information ◽

Genome Wide ◽

Public Data ◽

Genome Wide Data ◽

Multiple Samples

Abstract Background The main goal of this collaborative effort is to provide genome-wide data for the previously underrepresented population in Eastern Europe, and to provide cross-validation of the data from genome sequences and genotypes of the same individuals acquired by different technologies. We collected 97 genome-grade DNA samples from consented individuals representing major regions of Ukraine that were consented for public data release. BGISEQ-500 sequence data and genotypes by an Illumina GWAS chip were cross-validated on multiple samples and additionally referenced to 1 sample that has been resequenced by Illumina NovaSeq6000 S4 at high coverage. Results The genome data have been searched for genomic variation represented in this population, and a number of variants have been reported: large structural variants, indels, copy number variations, single-nucletide polymorphisms, and microsatellites. To our knowledge, this study provides the largest to-date survey of genetic variation in Ukraine, creating a public reference resource aiming to provide data for medical research in a large understudied population. Conclusions Our results indicate that the genetic diversity of the Ukrainian population is uniquely shaped by evolutionary and demographic forces and cannot be ignored in future genetic and biomedical studies. These data will contribute a wealth of new information bringing forth a wealth of novel, endemic and medically related alleles.

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The Peptide Functionalized Inorganic Nanoparticles for Cancer-Related Bioanalytical and Biomedical Applications

Molecules ◽

10.3390/molecules26113228 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3228

Author(s):

Xiaotong Li ◽

Minghong Jian ◽

Yanhong Sun ◽

Qunyan Zhu ◽

Zhenxin Wang

Keyword(s):

Drug Delivery ◽

Large Scale ◽

Amino Acid Sequences ◽

Inorganic Nanoparticles ◽

Metallic Ions ◽

Therapeutic Function ◽

Precise Diagnosis ◽

The Subject ◽

Targeting Ability ◽

Guided Therapy

In order to improve their bioapplications, inorganic nanoparticles (NPs) are usually functionalized with specific biomolecules. Peptides with short amino acid sequences have attracted great attention in the NP functionalization since they are easy to be synthesized on a large scale by the automatic synthesizer and can integrate various functionalities including specific biorecognition and therapeutic function into one sequence. Conjugation of peptides with NPs can generate novel theranostic/drug delivery nanosystems with active tumor targeting ability and efficient nanosensing platforms for sensitive detection of various analytes, such as heavy metallic ions and biomarkers. Massive studies demonstrate that applications of the peptide–NP bioconjugates can help to achieve the precise diagnosis and therapy of diseases. In particular, the peptide–NP bioconjugates show tremendous potential for development of effective anti-tumor nanomedicines. This review provides an overview of the effects of properties of peptide functionalized NPs on precise diagnostics and therapy of cancers through summarizing the recent publications on the applications of peptide–NP bioconjugates for biomarkers (antigens and enzymes) and carcinogens (e.g., heavy metallic ions) detection, drug delivery, and imaging-guided therapy. The current challenges and future prospects of the subject are also discussed.

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Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Nature Communications ◽

10.1038/s41467-020-18723-y ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Tianyun Wang ◽

◽

Kendra Hoekzema ◽

Davide Vecchio ◽

Huidan Wu ◽

...

Keyword(s):

Neurodevelopmental Disorders ◽

Large Scale ◽

De Novo ◽

Targeted Sequencing ◽

Published Data ◽

De Novo Mutations ◽

Risk Genes ◽

Mutation Burden ◽

Number Of Patients ◽

Significant Burden

Abstract Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E−06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E−07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype–genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

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Carcinosarcoma of the prostate: case report with molecular and histological characterization

The International Journal of Biological Markers ◽

10.1177/1724600818791463 ◽

2018 ◽

Vol 33 (4) ◽

pp. 540-544 ◽

Cited By ~ 3

Author(s):

Samanta Salvi ◽

Valentina Casadio ◽

Filippo Martignano ◽

Giorgia Gurioli ◽

Maria Maddalena Tumedei ◽

...

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Copy Number Variations ◽

Molecular Characteristics ◽

Glutathione S Transferase ◽

Molecular Alterations ◽

Positive Expression ◽

Molecular Pattern ◽

Programmed Death ◽

Number Variation

Background: We report a case of prostatic carcinosarcoma, a rare variant of prostatic cancer, which is composed of a mixture of epithelial and mesenchymal components with a generally poor outcome. Aims and methods: We aim to identify molecular alterations, in particular copy number variations of AR and c -MYC genes, methylation and expression of glutathione S-transferase P1 (GSTP1), programmed death-ligand 1 (PD-L1), AR, and phosphorylated AR expression. Results: We found a distinct molecular pattern between adenocarcinoma and carcinosarcoma, which was characterized by high AR copy number variation gain; positive expression of PD-L1, AR, and phosphorylated AR; low espression of GSTP1 in epithelial component. The sarcomatoid component had a lower gain of the AR gene, and no expression of PD-L1, AR, phosphorylated AR, or GSTP1. Both components had a gain of c-MYC copy number variation. Conclusions: Our findings suggest that carcinosarcoma has specific molecular characteristics that could be indicative for early diagnosis and treatment selection.

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Molecular alterations and clinical relevance in cervical carcinoma and precursors (Review)

Oncology Reports ◽

10.3892/or.2020.7804 ◽

2020 ◽

Vol 44 (6) ◽

pp. 2397-2405

Author(s):

Jiayi Sheng ◽

Yi Xiang ◽

Li Shang ◽

Qiongqiong He

Keyword(s):

Cervical Carcinoma ◽

Clinical Relevance ◽

Molecular Alterations

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Genetic characterization of colorectal cancer using a next generation sequencing approach to identify a specific pattern of somatic alterations in tumors arising from different anatomic sites

10.7287/peerj.preprints.1658 ◽

2016 ◽

Author(s):

Carmelo Laudanna ◽

Gianluca Santamaria ◽

Simona Migliozzi ◽

Duarte Mendes Oliveira ◽

Donatella Malanga ◽

...

Keyword(s):

Colorectal Cancer ◽

Copy Number ◽

Treatment Options ◽

Copy Number Variations ◽

Specific Pattern ◽

Surgical Approaches ◽

Anatomical Location ◽

Molecular Alterations ◽

Somatic Alterations ◽

Novel Biomarkers

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide, with nearly 1.4 million new cases diagnosed in 2012. CRC results from the accumulation of multiple genetic and epigenetic aberrations. Tumor localization in the large intestine tract determines different surgical approaches and treatment options. Considering the heterogeneous nature of these tumors we hypothesized that different patterns of molecular alterations could be associated with a specific anatomical location. To identify distinct genomic alterations (e.g, copy number variations and mutations) associated to different CRC anatomical sites we sequenced 32 CRCs samples from different location (right-sided, left-sided etc.) using the Ion AmpliSeq™ Comprehensive Cancer Panel that covered the whole coding sequence of 409 tumor suppressor genes and oncogenes frequently altered in cancer. Interestingly left-sided tumors were generally more altered respect to right-sided ones. Cluster analysis of all samples allowed the identification of 21-gene core that were significantly mutated in all sample groups. As expected, KRAS and APC mutations were frequently in the tumors resected from different anatomical localizations. Unsupervised analysis of copy number variations reveals a core of 160-gene significantly altered. In addition to the expected SRC, MYC and CEBPA, we found interestingly genes in validation status. Despite missing a significant number of cases, gene panel provides a solid alternative approach to WES in order to characterize a signature of alterations correlated with CRC tumor and the identification of novel biomarkers in colorectal carcinoma that could be used as potential clinical target.

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A large-scale survey of genetic copy number variations among Han Chinese residing in Taiwan

BMC Genetics ◽

10.1186/1471-2156-9-92 ◽

2008 ◽

Vol 9 (1) ◽

pp. 92 ◽

Cited By ~ 17

Author(s):

Chien-Hsing Lin ◽

Ling-Hui Li ◽

Sheng-Feng Ho ◽

Tzu-Po Chuang ◽

Jer-Yuarn Wu ◽

...

Keyword(s):

Copy Number ◽

Large Scale ◽

Copy Number Variations ◽

Han Chinese ◽

Large Scale Survey

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Abstract 367: Extreme High-Density Lipoprotein Cholesterol Genetics: An Assortment of Large and Small Polygenic Effects

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.367 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Jacqueline S Dron ◽

Jian Wang ◽

Cécile Low-Kam ◽

Sumeet A Khetarpal ◽

John F Robinson ◽

...

Keyword(s):

Large Scale ◽

Genetic Basis ◽

Rare Variants ◽

Association Studies ◽

Density Lipoprotein ◽

Copy Number Variations ◽

Genome Wide Association Studies ◽

Common Variants ◽

Targeted Next Generation Sequencing ◽

Common Genetic Variants

Rationale: Although HDL-C levels are known to have a complex genetic basis, most studies have focused solely on identifying rare variants with large phenotypic effects to explain extreme HDL-C phenotypes. Objective: Here we concurrently evaluate the contribution of both rare and common genetic variants, as well as large-scale copy number variations (CNVs), towards extreme HDL-C concentrations. Methods: In clinically ascertained patients with low ( N =136) and high ( N =119) HDL-C profiles, we applied our targeted next-generation sequencing panel (LipidSeq TM ) to sequence genes involved in HDL metabolism, which were subsequently screened for rare variants and CNVs. We also developed a novel polygenic trait score (PTS) to assess patients’ genetic accumulations of common variants that have been shown by genome-wide association studies to associate primarily with HDL-C levels. Two additional cohorts of patients with extremely low and high HDL-C (total N =1,746 and N =1,139, respectively) were used for PTS validation. Results: In the discovery cohort, 32.4% of low HDL-C patients carried rare variants or CNVs in primary ( ABCA1 , APOA1 , LCAT ) and secondary ( LPL , LMF1 , GPD1 , APOE ) HDL-C–altering genes. Additionally, 13.4% of high HDL-C patients carried rare variants or CNVs in primary ( SCARB1 , CETP , LIPC , LIPG ) and secondary ( APOC3 , ANGPTL4 ) HDL-C–altering genes. For polygenic effects, patients with abnormal HDL-C profiles but without rare variants or CNVs were ~2-fold more likely to have an extreme PTS compared to normolipidemic individuals, indicating an increased frequency of common HDL-C–associated variants in these patients. Similar results in the two validation cohorts demonstrate that this novel PTS successfully quantifies common variant accumulation, further characterizing the polygenic basis for extreme HDL-C phenotypes. Conclusions: Patients with extreme HDL-C levels have various combinations of rare variants, common variants, or CNVs driving their phenotypes. Fully characterizing the genetic basis of HDL-C levels must extend to encompass multiple types of genetic determinants—not just rare variants—to further our understanding of this complex, controversial quantitative trait.

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An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia

Blood ◽

10.1182/blood.2020004834 ◽

2020 ◽

Vol 135 (26) ◽

pp. 2337-2353 ◽

Cited By ~ 8

Author(s):

Tun Kiat Ko ◽

Asif Javed ◽

Kian Leong Lee ◽

Thushangi N. Pathiraja ◽

Xingliang Liu ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tumor Suppressor ◽

Myeloid Leukemia ◽

High Throughput Sequencing ◽

Kinase Inhibitors ◽

Blast Crisis ◽

Chronic Phase ◽

Integrative Model ◽

Dna Hypermethylation ◽

Molecular Alterations

Abstract Targeted therapies against the BCR-ABL1 kinase have revolutionized treatment of chronic phase (CP) chronic myeloid leukemia (CML). In contrast, management of blast crisis (BC) CML remains challenging because BC cells acquire complex molecular alterations that confer stemness features to progenitor populations and resistance to BCR-ABL1 tyrosine kinase inhibitors. Comprehensive models of BC transformation have proved elusive because of the rarity and genetic heterogeneity of BC, but are important for developing biomarkers predicting BC progression and effective therapies. To better understand BC, we performed an integrated multiomics analysis of 74 CP and BC samples using whole-genome and exome sequencing, transcriptome and methylome profiling, and chromatin immunoprecipitation followed by high-throughput sequencing. Employing pathway-based analysis, we found the BC genome was significantly enriched for mutations affecting components of the polycomb repressive complex (PRC) pathway. While transcriptomically, BC progenitors were enriched and depleted for PRC1- and PRC2-related gene sets respectively. By integrating our data sets, we determined that BC progenitors undergo PRC-driven epigenetic reprogramming toward a convergent transcriptomic state. Specifically, PRC2 directs BC DNA hypermethylation, which in turn silences key genes involved in myeloid differentiation and tumor suppressor function via so-called epigenetic switching, whereas PRC1 represses an overlapping and distinct set of genes, including novel BC tumor suppressors. On the basis of these observations, we developed an integrated model of BC that facilitated the identification of combinatorial therapies capable of reversing BC reprogramming (decitabine+PRC1 inhibitors), novel PRC-silenced tumor suppressor genes (NR4A2), and gene expression signatures predictive of disease progression and drug resistance in CP.

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