Molecular profile of Hürthle cell carcinomas: recurrent mutations in the Wnt/β-catenin pathway

Objective Genomic alterations in Hürthle cell carcinomas (HCC) include chromosomal losses, mitochondrial DNA mutations, and changes in the expression profile of the PI3K-AKT-mTOR and Wnt/β-catenin pathways. This study aimed at characterizing the mutational profile of HCC. Methods Next-generation sequencing (NGS) of 40 HCC using a 102-gene panel including, among others, the MAPK, PI3K-AKT-mTOR, Wnt/β-catenin, and Notch pathways. HCC was widely invasive in 57.5%, and lymph node and distant metastases were diagnosed in 5% and 7.5% of cases. During follow-up, 10% of patients presented with persistent/recurrent disease, but there were no cancer-related deaths. Results Genetic alterations were identified in 47.5% of HCC and comprised 190 single-nucleotide variants and 5 insertions/deletions. The Wnt/β-catenin pathway was most frequently affected (30%), followed by MAPK (27.5%) and PI3K-AKT-mTOR (25%). FAT1 and APC were the most frequently mutated genes and present in 17.5%. RAS mutations were present in 12.5% but no BRAF mutation was found. There was no association between the mutational profile and clinicopathological features. Conclusions This series of HCC presents a wide range of mutations in the Wnt/β-catenin, MAPK and PI3K-AKT-mTOR pathways. The recurrent involvement of Wnt/β-catenin pathway, particularly mutations in APC and FAT1, are of particular interest. The data suggest that mutated FAT1 may represent a potential novel driver in HCC tumorigenesis and that the Wnt/β-catenin pathway plays a critical role in this distinct thyroid malignancy.

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Gene Copy Number Changes in Myeloid Leukemias.

Blood ◽

10.1182/blood.v112.11.sci-37.sci-37 ◽

2008 ◽

Vol 112 (11) ◽

pp. sci-37-sci-37

Author(s):

James R. Downing

Keyword(s):

Copy Number ◽

B Lymphocyte ◽

Lymphoblastic Leukemia ◽

Point Mutations ◽

Leukemia Cell ◽

Genetic Alterations ◽

Gene Copy ◽

Recurrent Mutations ◽

Wide Range ◽

Development And Differentiation

Abstract A wide range of genetic alterations contribute to the formation of leukemia. These alterations include, but are not limited to, point mutations, gene rearrangements, deletions, amplifications, and a diverse array of epigenetic changes that influence gene expression. Unfortunately, using present methodologies, the identification of all mutations within a leukemia cell is cost prohibitive. Therefore, a more measured approach is needed. In previous work on pediatric acute lymphoblastic leukemia (ALL), we demonstrated the power of genome-wide copy number analysis for the identification of recurrent mutations. Our analyses revealed deletion, amplification, point mutation, and structural rearrangement in genes encoding key regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL. PAX5 was the most frequent target of somatic mutation, being altered in 30% of cases. Deletions were also detected in E2A, EBF1, LEF1, Ikaros, and Aiolos. These findings suggest that direct disruption of pathways controlling B cell development and differentiation contributes to ALL pathogenesis. We have now extended our analysis to pediatric acute myeloid leukemia (AML). This analysis revealed a mean number of somatic copy number abnormalities (CNA) of 2.38 per cases, with gains equal to losses. Strikingly, the most frequent recurrent CNA were at the breakpoints of known chromosomal translocations, including t(8;21) and inv(16). Based on this observation, we examined genes with CNA in their 5’ or 3’ regions for their possible involvement in cryptic translocations. Using this approach, two cryptic translocations were identified: t(5;11) [NUP98-NSD1] in four cases, and t(6;11)[MLL-MLLT4] in two cases. A number of other genes were identified as the target of recurrent abnormalities, including amplification of CCDC26, ABCC4, and deletion of FAM20C, BCOR. The most frequent abnormality was the amplification of CCDC26 at 8q24.21 (N=15; focal in four cases, broad in 11 cases), which encodes a putative mediator of retinoic acid receptor signaling. The other recurrent lesions occurred in two or fewer cases. Thus many fewer recurrent lesions were identified in AML than in ALL. In addition to the CNA, we also sequenced genes previously shown to be mutated in AML including NRAS, KRAS, PTPN11, BRAF, SOS1, FLT3, CEPBA, NPM1, AML1, CKIT, ERG, TP53, PTEN, and GATA1. Mutations were identified in all genes except BRAF, or SOS1, with the frequency of mutations varying across the different AML genetic subtypes. FAB M7 cases had the highest frequency of CNA but had sequence mutations limited to GATA1. Mutations of FLT3, CEPBA, and NPM1 were most frequent in cases with no or miscellaneous cytogenetic abnormalities, whereas NRAS mutations were most frequent in t(8;21) and inv(16) cases. Importantly, approximately 20% of the cases with recurring translocations had no other sequence or numerical abnormalities. Collectively, these data demonstrate a marked difference in the spectrum of genetic lesions between AML and ALL, with AML having fewer CNA per cases, a lower frequency of recurrent lesions, and a higher frequency of cases lacking any CNA. These data suggest a fundamental difference in the type of collaborating mutations between AML and ALL.

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Identification of Genetic Alterations Associated with Mutant IL7Ralpha in T-ALL

Blood ◽

10.1182/blood.v128.22.5272.5272 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5272-5272

Author(s):

Gisele O. L. Rodrigues ◽

Wenqing Li ◽

Sarah Cramer ◽

Livia W. Campos ◽

Priscila P. Zenatti ◽

...

Keyword(s):

T Cell ◽

Exome Sequencing ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Genetic Alterations ◽

Single Nucleotide Variants ◽

Gamma Chain ◽

Genetic Changes ◽

Recurrent Mutations ◽

Agilent Sureselect

Abstract The IL7/IL7R mediated signaling is essential for normal development and homeostasis of T cell precursors. Early studies have shown that around 10% of patients with Acute lymphoblastic leukemia T cell (T-ALL) have mutations in the alpha chain of the receptor for IL7 (IL-7Ralpha) driving constitutive signaling via JAK1 and independent of IL-7, gamma-chain or JAK3. Some genetic changes are important factors to initiate leukemia, but in many cases these changes are insufficient to achieve the complete leukemic phenotype, suggesting that collaborative oncogenic mutations may be present. To identify candidate mutations that work in collaboration with the oncogenic IL7R, we performed exome sequencing and SNP-CNV-Array assay on a group of eight primary T-ALL samples carrying the IL7R mutation (T-ALL-IL7Rmut). The microarray was performed using Cytoscan HD - Affymetrix and CNVs were detected by ChAs software, version 2.0.1.2. For exome sequencing we used Illumina Hiseq2000 platform and Agilent SureSelect V4 51M Capture kit (mean sequencing depths of 80X / 50X for leukemia and remission samples, respectively). Somatic Single Nucleotide Variants (SNVs) and Small Insertion/Deletion (InDels) were detected using VarScan, and mutations were functionally annotated using ANNOVAR. All somatic mutations detected were manually curated. We found 17 genes recurrently mutated (in ≥ 2 cases) and chose five of them for further analyses due to their previous involvement in ALL (PHF6, RB1, CTCF, SGK223 and DNM2). Ongoing experiments are being conducted to determine whether these recurrent mutations can collaborate functionally with mutIL7R by co-transfection into immature murine thymocytes, transplanting into mice and determining incidence of leukemia. Disclosures No relevant conflicts of interest to declare.

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The genomic landscape of metastasis in treatment-naïve breast cancer models

10.1101/777904 ◽

2019 ◽

Author(s):

Christina Ross ◽

Karol Szczepanek ◽

Maxwell Lee ◽

Howard Yang ◽

Tinghu Qiu ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Metastasis ◽

Primary Tumour ◽

Genetic Alterations ◽

Breast Cancer Metastasis ◽

Single Nucleotide Variants ◽

Somatic Evolution ◽

Recurrent Mutations ◽

Number Variation ◽

Treatment Naïve

AbstractMetastasis remains the principle cause of mortality for breast cancer and presents a critical challenge because secondary lesions are often refractory to conventional treatments. While specific genetic alterations are tightly linked to primary tumour development and progression, the role of genetic alteration in the metastatic process is not well-understood. To investigate how somatic evolution might contribute to breast cancer metastasis, we performed exome, whole genome, and RNA sequencing of matched metastatic and primary tumours from pre-clinical mouse models of breast cancer. Here we show that in a treatment-naïve setting, recurrent single nucleotide variants and copy number variation, but not gene fusion events, play key metastasis-driving roles in breast cancer. For instance, we identified recurrent mutations in Kras, a known driver of tumorigenesis that has not been previously implicated in breast cancer metastasis. The strategy presented here represents a novel framework to identify actionable metastasis-targeted therapies.

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Divergent molecular profile of PIK3CA gene in arsenic-associated bladder carcinoma

Mutagenesis ◽

10.1093/mutage/geaa031 ◽

2021 ◽

Author(s):

Mukta Basu ◽

Balarko Chakraborty ◽

Sabnam Ghosh ◽

Sudip Samadder ◽

Sankhadeep Dutta ◽

...

Keyword(s):

Bladder Carcinoma ◽

Expression Profiles ◽

Genetic Alterations ◽

Molecular Profile ◽

Strong Impact ◽

Pik3ca Gene ◽

Recurrent Mutations ◽

Number Variation ◽

Exon 9 ◽

Impact Of Arsenic

Abstract The activation of PIK3CA in bladder carcinoma (BlCa) with its recurrent mutations in exon 9 and 20 were well reported. But the association of arsenic on the activation of the pathway is not well elucidated. Therefore, we aimed to analyse the effect of arsenic on the genetic (copy number variation/mutation) and expression profiles of PIK3CA in primary BlCa samples. Infrequent amplification (16%) of the PIK3CA locus was observed, with higher frequency among the arsenic-high (AsH) than arsenic-low (AsL) samples. Frequent (54%) tumour-specific mutations in exon 9 and 20 of PIK3CA were observed in the BlCa samples with prevalent (47%) C>T transition mutations. Exon 9 and 20 harboured 48% and 73% of the total mutations, respectively, with 37% in E542K/E545K and 25% of the mutation in H1047Y/R. Though mutation frequency in AsH and AsL was found to be comparable, we observed some arsenic-specific mutation at c.1633G>A, c.1634A>C (E545K) and c.2985C>T and c.3130G>T mutations, as well as prevalent transverse mutations of A>C and G>T in AsH group. Furthermore, 73% of the BlCa samples showed overexpression (mRNA/protein) of PIK3CA with genetic alterations (amplification/mutation), significantly (P = 0.01) higher in AsH group. However, 36% of the samples showed overexpressed PIK3CA, independent of mutation or amplification, signifying a transcriptional upregulation of PIK3CA gene. Therefore, the expression status of NFκB, a transcription factor of PIK3CA, was assessed and found to be significantly correlated with the overexpression of PIK3CA (mRNA/protein) in AsH group. Similarly, the expression pattern of pAKT1 (Thr 308) was also found to be significantly correlated with PIK3CA overexpression. Finally, AsH patients with the overexpression of PIK3CA or NFκB had the worst overall survival, signifying a strong impact of arsenic on this pathway and outcome of the patients. Thus, our study showed that the arsenic-associated differential molecular profile of PIK3CA/AKT1/NFkB in BlCa has an important role in the molecular pathogenesis of the disease.

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Shooting a Tiger

10.1093/oso/9780199489381.001.0001 ◽

2018 ◽

Author(s):

Vijaya Ramadas Mandala

Keyword(s):

Critical Role ◽

Late Nineteenth Century ◽

Way Of Life ◽

Colonial India ◽

British Raj ◽

Early Colonial ◽

Wide Range ◽

Forest Legislation ◽

Imperial Governance ◽

North And South

The main contention of Shooting a Tiger is that hunting during the colonial period was not merely a recreational activity, but a practice intimately connected with imperial governance. The book positions shikar or hunting at the heart of colonial rule by demonstrating that, for the British in India, it served as a political, practical, and symbolic apparatus in the consolidation of power and rule during the nineteenth and early twentieth centuries. The book analyses early colonial hunting during the Company period, and then surveys different aspects of hunting during the high imperial decades in the later nineteenth and early twentieth centuries. The book draws upon an impressive array of archival material and uses a wide range of evidence to support its contentions. It examines hunting at a variety of social and ethnic levels—military, administrative, elite, princely India, Indian professional hunters, and in terms of Indian auxiliaries and (sometimes) resisters. It also deals with different geographical contexts—the plains, the mountains, north and south India. The exclusive privilege of hunting exercised by the ruling classes, following colonial forest legislation, continued to be extended to the Indian princes who played a critical role in sustaining the lavish hunts that became the hallmark of the late nineteenth-century British Raj. Hunting was also a way of life in colonial India, undertaken by officials and soldiers alike alongside their everyday duties, necessary for their mental sustenance and vital for the smooth operation of the colonial administration. There are also two final chapters on conservation, particularly the last chapter focusing on two British hunter-turned-conservationists, Jim Corbett and Colonel Richard Burton.

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Proteomic Analysis of Zeb1 Interactome in Breast Carcinoma Cells

Molecules ◽

10.3390/molecules26113143 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3143

Author(s):

Sergey E. Parfenyev ◽

Sergey V. Shabelnikov ◽

Danila Y. Pozdnyakov ◽

Olga O. Gnedina ◽

Leonid S. Adonin ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Epithelial To Mesenchymal Transition ◽

Critical Role ◽

Malignant Neoplasm ◽

Malignant Neoplasms ◽

Breast Cancer Patients ◽

Survival Prognosis ◽

Mesenchymal Transition ◽

Wide Range

Breast cancer is the most frequently diagnosed malignant neoplasm and the second leading cause of cancer death among women. Epithelial-to-mesenchymal Transition (EMT) plays a critical role in the organism development, providing cell migration and tissue formation. However, its erroneous activation in malignancies can serve as the basis for the dissemination of cancer cells and metastasis. The Zeb1 transcription factor, which regulates the EMT activation, has been shown to play an essential role in malignant transformation. This factor is involved in many signaling pathways that influence a wide range of cellular functions via interacting with many proteins that affect its transcriptional functions. Importantly, the interactome of Zeb1 depends on the cellular context. Here, using the inducible expression of Zeb1 in epithelial breast cancer cells, we identified a substantial list of novel potential Zeb1 interaction partners, including proteins involved in the formation of malignant neoplasms, such as ATP-dependent RNA helicase DDX17and a component of the NURD repressor complex, CTBP2. We confirmed the presence of the selected interactors by immunoblotting with specific antibodies. Further, we demonstrated that co-expression of Zeb1 and CTBP2 in breast cancer patients correlated with the poor survival prognosis, thus signifying the functionality of the Zeb1–CTBP2 interaction.

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Development of cancer metabolism as a therapeutic target: new pathways, patient studies, stratification and combination therapy

British Journal of Cancer ◽

10.1038/s41416-019-0666-4 ◽

2019 ◽

Vol 122 (1) ◽

pp. 1-3 ◽

Cited By ~ 4

Author(s):

Adrian L. Harris

Keyword(s):

Metabolic Pathways ◽

Trial Design ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Critical Role ◽

Therapeutic Approaches ◽

Preclinical Models ◽

Wide Range ◽

Patient Studies

AbstractCancer metabolism has undergone a resurgence in the last decade, 70 years after Warburg described aerobic glycolysis as a feature of cancer cells. A wide range of techniques have elucidated the complexity and heterogeneity in preclinical models and clinical studies. What emerges are the large differences between tissues, tumour types and intratumour heterogeneity. However, synergies with inhibition of metabolic pathways have been found for many drugs and therapeutic approaches, and a critical role of window studies and translational trial design is key to success.

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Determinants of vitamin D status in Kenyan calves

Scientific Reports ◽

10.1038/s41598-020-77209-5 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Rebecca Callaby ◽

Emma Hurst ◽

Ian Handel ◽

Phil Toye ◽

Barend M. de C. Bronsvoort ◽

...

Keyword(s):

Infectious Disease ◽

Vitamin D ◽

Health Outcomes ◽

Critical Role ◽

Subsequent Development ◽

Vitamin D Metabolites ◽

Vitamin D Status ◽

Skeletal Health ◽

A Genome ◽

Wide Range

AbstractVitamin D plays a critical role in calcium homeostasis and in the maintenance and development of skeletal health. Vitamin D status has increasingly been linked to non-skeletal health outcomes such as all-cause mortality, infectious diseases and reproductive outcomes in both humans and veterinary species. We have previously demonstrated a relationship between vitamin D status, assessed by the measurement of serum concentrations of the major vitamin D metabolite 25 hydroxyvitamin D (25(OH)D), and a wide range of non-skeletal health outcomes in companion and wild animals. The aims of this study were to define the host and environmental factors associated with vitamin D status in a cohort of 527 calves from Western Kenya which were part of the Infectious Disease of East African Livestock (IDEAL) cohort. A secondary aim was to explore the relationship between serum 25(OH)D concentrations measured in 7-day old calves and subsequent health outcomes over the following 12 months. A genome wide association study demonstrated that both dietary and endogenously produced vitamin D metabolites were under polygenic control in African calves. In addition, we found that neonatal vitamin D status was not predictive of the subsequent development of an infectious disease event or mortality over the 12 month follow up period.

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A computational method for prioritizing targeted therapies in precision oncology: performance analysis in the SHIVA01 trial

npj Precision Oncology ◽

10.1038/s41698-021-00191-2 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Istvan Petak ◽

Maud Kamal ◽

Anna Dirner ◽

Ivan Bieche ◽

Robert Doczi ◽

...

Keyword(s):

Clinical Benefit ◽

Progressive Disease ◽

Genetic Alterations ◽

Outcome Data ◽

Computational Method ◽

Molecular Profile ◽

Precision Oncology ◽

Driver Genes ◽

Oncology Clinical Trial ◽

Molecularly Targeted Agents

AbstractPrecision oncology is currently based on pairing molecularly targeted agents (MTA) to predefined single driver genes or biomarkers. Each tumor harbors a combination of a large number of potential genetic alterations of multiple driver genes in a complex system that limits the potential of this approach. We have developed an artificial intelligence (AI)-assisted computational method, the digital drug-assignment (DDA) system, to prioritize potential MTAs for each cancer patient based on the complex individual molecular profile of their tumor. We analyzed the clinical benefit of the DDA system on the molecular and clinical outcome data of patients treated in the SHIVA01 precision oncology clinical trial with MTAs matched to individual genetic alterations or biomarkers of their tumor. We found that the DDA score assigned to MTAs was significantly higher in patients experiencing disease control than in patients with progressive disease (1523 versus 580, P = 0.037). The median PFS was also significantly longer in patients receiving MTAs with high (1000+ <) than with low (<0) DDA scores (3.95 versus 1.95 months, P = 0.044). Our results indicate that AI-based systems, like DDA, are promising new tools for oncologists to improve the clinical benefit of precision oncology.

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Wildlife management and the debate on the ethics of animal use. II. A challenge for the animal protection movement.

Pacific Conservation Biology ◽

10.1071/pc120081 ◽

2012 ◽

Vol 18 (2) ◽

pp. 81 ◽

Cited By ~ 9

Author(s):

Daniel Lunney

Keyword(s):

Wildlife Management ◽

Critical Role ◽

Animal Liberation ◽

Ethical Imperative ◽

Animal Protection ◽

Wide Range ◽

Animal Use

How people coexist and interact with animals has become an intensely debated issue in recent times, particularly with the rise of the animal protection movement following the publication of Peter Singer’s book Animal Liberation in 1975. This paper discusses some shortcomings of the philosophical positions taken in this complex debate. Singer has helped put animals on a new footing as a group that cannot morally be ignored, but his focus is mainly on individual, familiar animals that are used or abused by humans. The argument of this paper is that the ethics of managing wildlife hinges on a broader view of animals, and their contexts, than is apparent from Singer’s text. Wildlife managers aim to conserve populations of a wide range of species, and their habitats, but some mechanisms for achieving these aims, such as research and the control of invasive animals, are frequently opposed by elements of the animal protection movement. We need to adapt our attitude to animals, particularly wildlife, away from the traditional legacy of a few familiar species to embrace an ethic that is more ecological and relevant to Australian contexts. The case argued here has been to see the critical role of context — geographical, ecological, historical, relational — as a basis for a degree of reconciliation between conservation-oriented wildlife managers and the rising interest in the ethics of animal use. There is much to be gained for zoologists, wildlife managers and conservation biologists by framing key elements of their case in ethical arguments. Conversely, the challenge for those in the animal protection movement is to expand their philosophical ideas to include the ethical imperative of the conservation of populations of wildlife.

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