Atypical UV Photoproducts Induce Non-canonical Mutation Classes Associated with Driver Mutations in Melanoma

The genomic characterization of acute myeloid leukemia (AML) by DNA sequencing has illuminated subclasses of the disease, with distinct driver mutations, that might be responsive to targeted therapies. Approximately 15-23% of AML genomes harbor mutations in one of two isoforms of isocitrate dehydrogenase (IDH1 or IDH2). These enzymes are constitutive mediators of basic cellular metabolism, but their mutated forms in cancer synthesize an abnormal metabolite, 2- hydroxyglutarate, that in turn acts as a competitive inhibitor of multiple gene regulatory enzymes. As a result, leukemic IDH mutations cause changes in genome structure and gene activity, culminating in an arrest of normal myeloid differentiation. These discoveries have motivated the development of a new class of selective small molecules with the ability to inhibit the mutant IDH enzymes while sparing normal cellular metabolism. These agents have shown promising anti-leukemic activity in animal models and early clinical trials, and are now entering Phase 3 study. This review will focus on the growing preclinical and clinical data evaluating IDH inhibitors for the treatment of IDH-mutated AML. These data suggest that inducing cellular differentiation is central to the mechanism of clinical efficacy for IDH inhibitors, while also mediating toxicity for patients who experience IDH Differentiation Syndrome. Ongoing trials are studying the efficacy of IDH inhibitors in combination with other AML therapies, both to evaluate potential synergistic combinations as well as to identify the appropriate place for IDH inhibitors within existing standard-of-care regimens.

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Therapeutic Approaches for the Treatment of Epidermal Growth Factor Receptor Mutated Lung Cancer

Current Cancer Drug Targets ◽

10.2174/1568009617666170623123848 ◽

2018 ◽

Vol 18 (8) ◽

pp. 773-791

Author(s):

Dhaval Sanchala ◽

Lokesh K. Bhatt ◽

Kedar S. Prabhavalkar

Keyword(s):

Lung Cancer ◽

Clinical Trial ◽

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Growth Factor Receptor ◽

Driver Mutations ◽

Therapeutic Approaches ◽

Epidermal Growth ◽

Egfr Mutant

Lung cancer surfaces to be the predominant determinant of mortality worldwide constituting 13% and 19% of all new cancer cases and deaths related to cancer respectively. Molecular profiling has now become a regular trend in lung cancer to identify the driver mutations. Epidermal Growth Factor Receptor (EGFR) is the most regular driver mutation encountered in Non-Small Cell Lung Cancer (NSCLC). Targeted therapies are now available for the treatment of EGFR mutant NSCLC. EGFR mutation is more frequently expressed in adenocarcinoma than squamous cell carcinoma. This article presents a detailed molecular insight of the therapeutic approaches for the treatment of EGFR mutant lung cancer. The article delineates molecular mechanism of the drugs that are approved, the drugs that are in clinical trial and the drugs that have not entered a clinical trial but shows promising future in the treatment of EGFR mutant lung cancer. Furthermore, this article provides concise information on relevant combinational or monotherapy clinical trials that have been completed for various approaches.

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Mutation Mechanisms of Breast Cancer among the Female Population in China

Current Bioinformatics ◽

10.2174/1574893615666191220141548 ◽

2020 ◽

Vol 15 (3) ◽

pp. 253-259

Author(s):

Asmaa Amer ◽

Ahmed Nagah ◽

Tianhai Tian ◽

Xinan Zhang

Keyword(s):

Breast Cancer ◽

Gene Mutations ◽

Driver Mutations ◽

Human Breast ◽

Breast Epithelium ◽

Female Population ◽

Multistage Model ◽

The Usa ◽

Intermediate Cells ◽

Mutation Mechanisms

Background: Cancer is a genetic disease caused by the accumulation of gene mutations. It is important to derive the number of driver mutations that are needed for the development of human breast cancer, which may provide insights into the tumor diagnosis and therapy. Objective: This work is designed to investigate whether there is any difference for the mutation mechanism of breast cancer between the patients in the USA and those in China. We study the mechanisms of breast cancer development in China, and then compare these mechanisms with those in the USA. Methods: This work designed a multistage model including both gene mutation and clonal expansion of intermediate cells to fit the dataset of breast cancer in China from 2004 to 2009. Results: Our simulation results show that the maximum number of driver mutations for breast epithelium stem cells of females in China is 13 which is less than the 14 driver mutations of females in the USA. In addition, the two-hit model is the optimal one for the tumorigenesis of females in China, which is also different from the three-hit model that was predicted as the optimal model for the tumorigenesis of females in the USA. Conclusion: The differences of the mutation mechanisms between China and the USA reflect a variety of lifestyle, genetic influences, environmental exposure, and the availability of mammography screening.

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Exomic Sequencing of Medullary Thyroid Cancer Reveals Dominant and Mutually Exclusive Oncogenic Mutations in RET and RAS

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2012-2703 ◽

2013 ◽

Vol 98 (2) ◽

pp. E364-E369 ◽

Cited By ~ 120

Author(s):

Nishant Agrawal ◽

Yuchen Jiao ◽

Mark Sausen ◽

Rebecca Leary ◽

Chetan Bettegowda ◽

...

Keyword(s):

Thyroid Cancer ◽

Somatic Mutations ◽

Medullary Thyroid Cancer ◽

Driver Mutations ◽

High Confidence ◽

Kras Mutations ◽

Protein Coding ◽

Medullary Thyroid ◽

Oncogenic Mutations ◽

Independent Cohort

Abstract Context: Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome. Objective: To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs. Patients and Design: We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC. Results: We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons. Conclusions: Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.

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Targetable driver mutations in multicentric reticulohistiocytosis

Haematologica ◽

10.3324/haematol.2019.218735 ◽

2019 ◽

Vol 105 (2) ◽

pp. e61-e64 ◽

Cited By ~ 3

Author(s):

Norihiro Murakami ◽

Tomohisa Sakai ◽

Eisuke Arai ◽

Hideki Muramatsu ◽

Daisuke Ichikawa ◽

...

Keyword(s):

Driver Mutations ◽

Multicentric Reticulohistiocytosis

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Clonal approaches to understanding the impact of mutations on hematologic disease development

Blood ◽

10.1182/blood-2018-11-835405 ◽

2019 ◽

Vol 133 (13) ◽

pp. 1436-1445 ◽

Cited By ~ 6

Author(s):

Jyoti Nangalia ◽

Emily Mitchell ◽

Anthony R. Green

Keyword(s):

Somatic Mutations ◽

Clonal Selection ◽

Single Cells ◽

Driver Mutations ◽

Great Promise ◽

Tumor Evolution ◽

Disease Development ◽

Hematopoietic Tissue ◽

The Impact

Abstract Interrogation of hematopoietic tissue at the clonal level has a rich history spanning over 50 years, and has provided critical insights into both normal and malignant hematopoiesis. Characterization of chromosomes identified some of the first genetic links to cancer with the discovery of chromosomal translocations in association with many hematological neoplasms. The unique accessibility of hematopoietic tissue and the ability to clonally expand hematopoietic progenitors in vitro has provided fundamental insights into the cellular hierarchy of normal hematopoiesis, as well as the functional impact of driver mutations in disease. Transplantation assays in murine models have enabled cellular assessment of the functional consequences of somatic mutations in vivo. Most recently, next-generation sequencing–based assays have shown great promise in allowing multi-“omic” characterization of single cells. Here, we review how clonal approaches have advanced our understanding of disease development, focusing on the acquisition of somatic mutations, clonal selection, driver mutation cooperation, and tumor evolution.

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