How do molecular aberrations guide therapy in MDS?

2021 ◽  
pp. 101324
Author(s):  
Rafael Bejar
Keyword(s):  
Molecular Aberrations

scholarly journals Analysis of the genomic landscape of yolk sac tumors reveals mechanisms of evolution and chemoresistance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xuan Zong ◽  
Ying Zhang ◽  
Xinxin Peng ◽  
Dongyan Cao ◽  
Mei Yu ◽  
...  
Keyword(s):  
Copy Number Alteration ◽  
Germ Cell Tumors ◽  
Gonadal Development ◽  
Yolk Sac ◽  
Mutational Signatures ◽  
Whole Exome ◽  
Genomic Landscape ◽  
Yolk Sac Tumors ◽  
Molecular Aberrations

AbstractYolk sac tumors (YSTs) are a major histological subtype of malignant ovarian germ cell tumors with a relatively poor prognosis. The molecular basis of this disease has not been thoroughly characterized at the genomic level. Here we perform whole-exome and RNA sequencing on 41 clinical tumor samples from 30 YST patients, with distinct responses to cisplatin-based chemotherapy. We show that microsatellite instability status and mutational signatures are informative of chemoresistance. We identify somatic driver candidates, including significantly mutated genes KRAS and KIT and copy-number alteration drivers, including deleted ARID1A and PARK2, and amplified ZNF217, CDKN1B, and KRAS. YSTs have very infrequent TP53 mutations, whereas the tumors from patients with abnormal gonadal development contain both KRAS and TP53 mutations. We further reveal a role of OVOL2 overexpression in YST resistance to cisplatin. This study lays a critical foundation for understanding key molecular aberrations in YSTs and developing related therapeutic strategies.

scholarly journals MODL-21. INTEGRATIVE APPROACHES IN FUNCTIONAL GENOMICS TO IDENTIFY GENETIC DEPENDENCIES IN PEDIATRIC BRAIN CANCER

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii415-iii415
Author(s):  
Claire Sun ◽  
Caroline Drinkwater ◽  
Dhanya Sooraj ◽  
Gabrielle Bradshaw ◽  
Claire Shi ◽  
...  
Keyword(s):  
Functional Genomics ◽  
Precision Medicine ◽  
Brain Cancer ◽  
Human Genomes ◽  
Pediatric Cancer Patients ◽  
Crispr Screen ◽  
The Central Nervous System ◽  
Molecular Aberrations ◽  
Genetic Profiles ◽  
Pediatric Brain

Abstract The precise decoding of human genomes facilitated by the advancements in next-generation sequencing has led to a better understanding of genetic underpinnings of pediatric brain cancers. Indeed, it is now evident that tumours of the same type harbour distinct driving mutations and molecular aberrations that can result in different prognosis and treatment outcomes. The profounder insight into the the identity, amount and types of molecular aberrations has paved the way for the advent of targeted therapies in precision medicine. Nevertheless, less than 10% of pediatric cancer patients harbour actionable mutations. Strictly limited therapeutic options that are firstly available for brain cancers and secondly acceptable for children’s development further impede the breakthrough in the survival rate in pediatric brain cancers. This underscores a desperate need to delve beyond genomic sequencing to identify biomarker coupled therapies that not only featured with treatment efficacy in the central nervous system but also acceptable side effects for children. The Hudson-Monash Paediatric Precision Medicine (HMPPM) Program focuses on utilising genetic profiles of patients’ tumour models to identify new therapeutic targets and repurpose existing ones using high-throughput functional genomics screens (2220 drugs and CRISPR screen of 300 oncogenic genes). Using a large compendium of over sixty patient derived paediatric brain cancer models, we provide proof-of-concept data that shows an integrative pipeline for functional genomics with multi-omics datasets to perform genotype-phenotype correlations and, therefore, identify genetic dependencies. Herein, using several examples in ATRT, DIPG and HGG, we show how functional interrogations can better define molecular subclassification of tumours and identify unique vulnerabilities.

scholarly journals The FGF/FGFR System in Breast Cancer: Oncogenic Features and Therapeutic Perspectives

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3029
Author(s):  
Maria Francesca Santolla ◽  
Marcello Maggiolini
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Kinase Inhibitors ◽  
Point Mutations ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Transduction Mechanisms ◽  
Molecular Landscape ◽  
Molecular Aberrations

One of the major challenges in the treatment of breast cancer is the heterogeneous nature of the disease. With multiple subtypes of breast cancer identified, there is an unmet clinical need for the development of therapies particularly for the less tractable subtypes. Several transduction mechanisms are involved in the progression of breast cancer, therefore making the assessment of the molecular landscape that characterizes each patient intricate. Over the last decade, numerous studies have focused on the development of tyrosine kinase inhibitors (TKIs) to target the main pathways dysregulated in breast cancer, however their effectiveness is often limited either by resistance to treatments or the appearance of adverse effects. In this context, the fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system represents an emerging transduction pathway and therapeutic target to be fully investigated among the diverse anti-cancer settings in breast cancer. Here, we have recapitulated previous studies dealing with FGFR molecular aberrations, such as the gene amplification, point mutations, and chromosomal translocations that occur in breast cancer. Furthermore, alterations in the FGF/FGFR signaling across the different subtypes of breast cancer have been described. Next, we discussed the functional interplay between the FGF/FGFR axis and important components of the breast tumor microenvironment. Lastly, we pointed out the therapeutic usefulness of FGF/FGFR inhibitors, as revealed by preclinical and clinical models of breast cancer.

Molecular determinants of therapy response of venetoclax-based combinations in acute myeloid leukemia

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Philipp Makowka ◽  
Verena Stolp ◽  
Karoline Stoschek ◽  
Hubert Serve
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Current Knowledge ◽  
Therapy Response ◽  
Secondary Resistance ◽  
Molecular Alterations ◽  
Molecular Features ◽  
Slow Progress ◽  
Molecular Aberrations ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous, highly malignant disease of the bone marrow. After decades of slow progress, recent years saw a surge of novel agents for its treatment. The most recent advancement is the registration of the Bcl-2 inhibitor ventoclax in combination with a hypomethylating agent (HMA) in the US and Europe for AML patients not eligible for intensive chemotherapy. Treatment of newly diagnosed AML patients with this combination results in remission rates that so far could only be achieved with intensive treatment. However, not all AML patients respond equally well, and some patients relapse early, while other patients experience longer periods of complete remission. A hallmark of AML is its remarkable genetic, molecular and clinical heterogeneity. Here, we review the current knowledge about molecular features of AML that help estimate the probability of response to venetoclax-containing therapies. In contrast to other newly developed AML therapies that target specific recurrent molecular alterations, it seems so far that responses are not specific for a certain subgroup. One exception is spliceosome mutations, where good response has been observed in clinical trials with venetoclax/azacitidine. These mutations are rather associated with a more unfavorable outcome with chemotherapy. In summary, venetoclax in combination with hypomethylating agents represents a significant novel option for AML patients with various molecular aberrations. Mechanisms of primary and secondary resistance seem to overlap with those towards chemotherapy.

Molecular Profiling and the Reclassification of Cancer: Divide and Conquer

2013 ◽  
pp. 127-134 ◽  
Author(s):  
Javier Munoz ◽  
Charles Swanton ◽  
Razelle Kurzrock
Keyword(s):  
Growth Factor Receptor ◽  
Molecular Profiling ◽  
Small Cell ◽  
Divide And Conquer ◽  
Egfr Mutations ◽  
Diagnostic Process ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
The Right ◽  
Molecular Aberrations

Cancer is one of the leading causes of mortality in the world. Choosing the best treatment is dependent on making the right diagnosis. The diagnostic process has been based on light microscopy and the identification of the organ of tumor origin. Yet we now know that cancer is driven by molecular processes, and that these do not necessarily segregate by organ of origin. Fortunately, revolutionary changes in technology have enabled rapid genomic profiling. It is now apparent that neoplasms classified uniformly (e.g., non-small cell lung cancer) are actually comprised of up to 100 different molecular entities. For instance, tumors bearing ALK alterations make up about 4% of non-small cell lung cancers, and tumors bearing epidermal growth factor receptor (EGFR) mutations, approximately 5% to 10%. Importantly, matching patients to therapies targeted against their driver molecular aberrations has resulted in remarkable response rates. There is now a wealth of evidence supporting a divide-and-conquer strategy. Herein, we provide a concise primer on the current state-of-the-art of molecular profiling in the cancer clinic.

scholarly journals Analysis of molecular aberrations of Wnt pathway gladiators in colorectal cancer in the Kashmiri population

2011 ◽  
Vol 5 (5) ◽  
pp. 441 ◽  
Author(s):  
A Sameer ◽  
Zaffar A Shah ◽  
Safiya Abdullah ◽  
Nissar A Chowdri ◽  
Mushtaq A Siddiqi
Keyword(s):  
Colorectal Cancer ◽  
Wnt Pathway ◽  
Kashmiri Population ◽  
Molecular Aberrations

scholarly journals EMT-Inducing Molecular Factors in Gynecological Cancers

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Loredana Campo ◽  
Catherine Zhang ◽  
Eun-Kyoung Breuer
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Signs And Symptoms ◽  
Therapeutic Interventions ◽  
Gynecologic Cancers ◽  
Papilloma Virus ◽  
Mesenchymal Transition ◽  
Metastatic Relapse ◽  
Immunodeficiency Virus ◽  
Common Risk Factors ◽  
Molecular Aberrations

Gynecologic cancers are the unregulated growth of neoplastic cells that arise in the cervix, ovaries, fallopian tubes, uterus, vagina, and vulva. Although gynecologic cancers are characterized by different signs and symptoms, studies have shown that they share common risk factors, such as smoking, obesity, age, exposure to certain chemicals, infection with human immunodeficiency virus (HIV), and infection with human papilloma virus (HPV). Despite recent advancements in the preventative, diagnostic, and therapeutic interventions for gynecologic cancers, many patients still die as a result of metastasis and recurrence. Since mounting evidence indicates that the epithelial-mesenchymal transition (EMT) process plays an essential role in metastatic relapse of cancer, understanding the molecular aberrations responsible for the EMT and its underlying signaling should be given high priority in order to reduce cancer morbidity and mortality.

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