Important role of indels in somatic mutations of human cancer genes

Clustered somatic mutations are common in cancer genomes with prior analyses revealing several types of clustered single-base substitutions, including doublet- and multi-base substitutions, diffuse hypermutation termed omikli, and longer strand-coordinated events termed kataegis. Here, we provide a comprehensive characterization of clustered substitutions and clustered small insertions and deletions (indels) across 2,583 whole-genome sequenced cancers from 30 cancer types. While only 3.7% of substitutions and 0.9% of indels were found to be clustered, they contributed 8.4% and 6.9% of substitution and indel drivers, respectively. Multiple distinct mutational processes gave rise to clustered indels including signatures enriched in tobacco smokers and homologous-recombination deficient cancers. Doublet-base substitutions were caused by at least 12 mutational processes, while the majority of multi-base substitutions were generated by either tobacco smoking or exposure to ultraviolet light. Omikli events, previously attributed to the activity of APOBEC3 deaminases, accounted for a large proportion of clustered substitutions. However, only 16.2% of omikli matched APOBEC3 patterns with experimental validation confirming additional mutational processes giving rise to omikli. Kataegis was generated by multiple mutational processes with 76.1% of all kataegic events exhibiting AID/APOBEC3-associated mutational patterns. Co-occurrence of APOBEC3 kataegis and extrachromosomal-DNA (ecDNA) was observed in 31% of samples with ecDNA. Multiple distinct APOBEC3 kataegic events were observed on most mutated ecDNA. ecDNA containing known cancer genes exhibited both positive selection and kataegic hypermutation. Our results reveal the diversity of clustered mutational processes in human cancer and the role of APOBEC3 in recurrently mutating and fueling the evolution of ecDNA.

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A Dual Proto-Oncogenic and Tumor Suppressive Role of LRF/POKEMON In Hemopoietic Malignancies through Control of Cell Fate Decision

Blood ◽

10.1182/blood.v116.21.sci-14.sci-14 ◽

2010 ◽

Vol 116 (21) ◽

pp. SCI-14-SCI-14

Author(s):

Pier Paolo Pandolfi

Keyword(s):

Cell Fate ◽

Cellular Differentiation ◽

Conflicts Of Interest ◽

Human Cancer ◽

Cellular Transformation ◽

Related Factor ◽

Cancer Genes ◽

Cell Fate Decisions

Abstract Abstract SCI-14 LRF (Leukemia/lymphoma-related factor, also known as POKEMON) is a member of the POZ and Kruppel (POK) family of transcription factors. LRF has been shown to play an essential role in embryonic development and to act as a master regulator of cellular differentiation in virtually any tissue where it is found expressed, including the hemopoietic compartment. As we will discuss, LRF inactivation in the mouse blocks cellular differentiation in both myeloid/erythroid and lymphoid compartments. On the other hand, LRF has been shown to possess a potent proto-oncogenic activity both in vitro and in vivo. In fact, LRF itself can transform primary cells in combination with known oncogenes and is also essential for cellular transformation of mouse embryonic fibroblasts. In addition, overexpression of LRF in immature B and T progenitor cells in vivo in the mouse lead to lethal precursor T-cell lymphoblastic lymphoma/leukemia. In agreement with this notion, LRF is aberrantly expressed in a variety of human cancers, including diffuse large B cell and follicular lymphomas, but also ovarian and breast cancers. Further, the LRF gene is found amplified in a subset of non-small cell lung cancers (NSCLCs), illustrating a direct role in human cancer. However, we speculated that due to the key role of LRF in cell fate decisions, LRF/POKEMON loss could also contribute to tumorigenesis by blocking cellular differentiation. We will discuss provocative in vivo data in support of the notion that LRF/POKEMON can indeed act as a bona fide tumor suppressor representing a compelling example of two-faced cancer genes. Disclosures: No relevant conflicts of interest to declare.

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Profiling of Somatic Mutations in Phaeochromocytoma and Paraganglioma by Targeted Next Generation Sequencing Analysis

International Journal of Endocrinology ◽

10.1155/2015/138573 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 33

Author(s):

Andrea Luchetti ◽

Diana Walsh ◽

Fay Rodger ◽

Graeme Clark ◽

Tom Martin ◽

...

Keyword(s):

Next Generation Sequencing ◽

Somatic Mutations ◽

Human Cancer ◽

Sequencing Analysis ◽

Cancer Genes ◽

Next Generation ◽

Targeted Next Generation Sequencing ◽

Next Generation Sequencing Analysis ◽

Sequencing Strategy ◽

Generation Sequencing

At least 12 genes (FH, HIF2A, MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127,andVHL) have been implicated in inherited predisposition to phaeochromocytoma (PCC), paraganglioma (PGL), or head and neck paraganglioma (HNPGL) and a germline mutation may be detected in more than 30% of cases. Knowledge of somatic mutations contributing to PCC/PGL/HNPGL pathogenesis has received less attention though mutations inHRAS, HIF2A, NF1, RET,andVHLhave been reported. To further elucidate the role of somatic mutation in PCC/PGL/HNPGL tumourigenesis, we employed a next generation sequencing strategy to analyse “mutation hotspots” in 50 human cancer genes. Mutations were identified forHRAS(c.37G>C; p.G13R and c.182A>G; p.Q61R) in 7.1% (6/85); forBRAF(c.1799T>A; p.V600E) in 1.2% (1/85) of tumours; and forTP53(c.1010G>A; p.R337H) in 2.35% (2/85) of cases. Twenty-one tumours harboured mutations in inherited PCC/PGL/HNPGL genes and noHRAS, BRAF, orTP53mutations occurred in this group. Combining our data with previous reports ofHRASmutations in PCC/PGL we find that the mean frequency ofHRAS/BRAFmutations in sporadic PCC/PGL is 8.9% (24/269) and in PCC/PGL with an inherited gene mutation 0% (0/148) suggesting thatHRAS/BRAFmutations and inherited PCC/PGL genes mutations might be mutually exclusive. We report the first evidence forBRAFmutations in the pathogenesis of PCC/PGL/HNPGL.

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THE ROLE OF PHOSPHATIDYLINOSITOL-3-KINASE IN CARCINOGENESIS

Problems in oncology ◽

10.37469/0507-3758-2017-63-4-545-556 ◽

2017 ◽

Vol 63 (4) ◽

pp. 545-556

Author(s):

Natalya Oskina ◽

Aleksandr Shcherbakov ◽

Maksim Filipenko ◽

Nikolay Kushlinskiy ◽

L. Ovchinnikova

Keyword(s):

Genetic Disease ◽

Intracellular Signaling ◽

Somatic Mutations ◽

Pi3k Pathway ◽

Genetic Alterations ◽

Phosphatidylinositol 3 Kinase ◽

Intracellular Signaling Pathway ◽

Metabolic Activities ◽

Carcinogenic Process

Currently it is established that cancer is a genetic disease and that somatic mutations are the initiators of the carcinogenic process. The PI3K/AKT/mTOR pathway is an important intracellular signaling pathway regulating the cell growth and metabolic activities. Aberrant activation of the PI3K pathway is commonly observed in many different cancers. In this review we analyze the genetic alterations of PI3K pathway in a variety of human malignancies and discuss their possible implications for diagnosis and therapy.

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ACE2/Angiotensin-(1-7)/Mas Receptor Axis in Human Cancer: Potential Role for Pediatric Tumors

Current Drug Targets ◽

10.2174/1389450121666200210124217 ◽

2020 ◽

Vol 21 (9) ◽

pp. 892-901 ◽

Cited By ~ 4

Author(s):

Ana Luiza Ataide Carneiro de Paula Gonzaga ◽

Vitória Andrade Palmeira ◽

Thomas Felipe Silva Ribeiro ◽

Larissa Braga Costa ◽

Karla Emília de Sá Rodrigues ◽

...

Keyword(s):

Clinical Trials ◽

Angiotensin Ii ◽

Pediatric Cancer ◽

Pediatric Patients ◽

Human Cancer ◽

Experimental Studies ◽

At1 Receptor ◽

Pediatric Tumors ◽

Mas Receptor

Background: Pediatric tumors remain the highest cause of death in developed countries. Research on novel therapeutic strategies with lesser side effects is of utmost importance. In this scenario, the role of Renin-Angiotensin System (RAS) axes, the classical one formed by angiotensinconverting enzyme (ACE), Angiotensin II and AT1 receptor and the alternative axis composed by ACE2, Angiotensin-(1-7) and Mas receptor, have been investigated in cancer. Objective: This review aimed to summarize the pathophysiological role of RAS in cancer, evidence for anti-tumor effects of ACE2/Angiotensin-(1-7)/Mas receptor axis and future therapeutic perspectives for pediatric cancer. Methods: Pubmed, Scopus and Scielo were searched in regard to RAS molecules in human cancer and pediatric patients. The search terms were “RAS”, “ACE”, “Angiotensin-(1-7)”, “ACE2”, “Angiotensin II”, “AT1 receptor”, “Mas receptor”, “Pediatric”, “Cancer”. Results: Experimental studies have shown that Angiotensin-(1-7) inhibits the growth of tumor cells and reduces local inflammation and angiogenesis in several types of cancer. Clinical trials with Angiotensin-( 1-7) or TXA127, a pharmaceutical grade formulation of the naturally occurring peptide, have reported promising findings, but not enough to recommend medical use in human cancer. In regard to pediatric cancer, only three articles that marginally investigated RAS components were found and none of them evaluated molecules of the alternative RAS axis. Conclusion: Despite the potential applicability of Angiotensin-(1-7) in pediatric tumors, the role of this molecule was never tested. Further clinical trials are necessary, also including pediatric patients, to confirm safety and efficiency and to define therapeutic targets.

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The Role of Sensing Peptides in the Cross-talk between Microbiota and Human Cancer Cells

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557518666180713112119 ◽

2018 ◽

Vol 18 (18) ◽

pp. 1567-1571

Author(s):

Anna Lucia Tornesello ◽

Luigi Buonaguro ◽

Maria Lina Tornesello ◽

Franco M. Buonaguro

Keyword(s):

Cancer Cells ◽

Cross Talk ◽

Human Cancer ◽

Human Cancer Cells ◽

The Cross

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Epigenetic regulation in human cancer: the potential role of epi-drug in cancer therapy

Molecular Cancer ◽

10.1186/s12943-020-01197-3 ◽

2020 ◽

Vol 19 (1) ◽

Cited By ~ 7

Author(s):

Yuanjun Lu ◽

Yau-Tuen Chan ◽

Hor-Yue Tan ◽

Sha Li ◽

Ning Wang ◽

...

Keyword(s):

Cancer Therapy ◽

Epigenetic Regulation ◽

Potential Role ◽

Human Cancer

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New Insights into the Role of miR-29a in Hepatocellular Carcinoma: Implications in Mechanisms and Theragnostics

Journal of Personalized Medicine ◽

10.3390/jpm11030219 ◽

2021 ◽

Vol 11 (3) ◽

pp. 219

Author(s):

Ya-Ling Yang ◽

Yen-Hsiang Chang ◽

Chia-Jung Li ◽

Ying-Hsien Huang ◽

Ming-Chao Tsai ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Microenvironment ◽

Crucial Role ◽

Human Cancer ◽

Metabolic Adaptation ◽

Advanced Hcc ◽

Diagnosis And Prognosis ◽

Competitive Endogenous Rnas ◽

Growing Body

Hepatocellular carcinoma (HCC) remains one of the most lethal human cancer globally. For advanced HCC, curable plan for advanced HCC is yet to be established, and the prognosis remains poor. The detail mechanisms underlying the progression of HCC tumorigenicity and the corruption of tumor microenvironment (TME) is complex and inconclusive. A growing body of studies demonstrate microRNAs (miRs) are important regulators in the tumorigenicity and TME development. Notably, mounting evidences indicate miR-29a play a crucial role in exerting hepatoprotective effect on various types of stress and involved in the progression of HCC, which elucidates their potential theragnostic implications. In this review, we reviewed the advanced insights into the detail mechanisms by which miR-29a dictates carcinogenesis, epigenetic program, and metabolic adaptation, and implicated in the sponging activity of competitive endogenous RNAs (ceRNA) and the TME components in the scenario of HCC. Furthermore, we highlighted its clinical significance in diagnosis and prognosis, as well as the emerging therapeutics centered on the activation of miR-29a.

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Targeting the PI3K and MAPK pathways to improve response to HER2-targeted therapies in HER2-positive gastric cancer

Journal of Translational Medicine ◽

10.1186/s12967-021-02842-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

M. Janusz Mezynski ◽

Angela M. Farrelly ◽

Mattia Cremona ◽

Aoife Carr ◽

Clare Morgan ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Lines ◽

Somatic Mutations ◽

Trastuzumab Resistance ◽

Her2 Positive ◽

Erbb Family ◽

Gastric Tumour ◽

Pi3k Signalling ◽

Trial Setting

Abstract Background Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear. Methods Using mass spectrometry-based genotyping we analysed 105 hotspot, non-synonymous somatic mutations in PIK3CA and ERBB-family (EGFR, ERBB2, ERBB3 and ERBB4) genes in gastric tumour samples from 69 patients. A panel of gastric cell lines (N87, OE19, ESO26, SNU16, KATOIII) were profiled for anti-proliferative response to the PI3K inhibitor copanlisib and the MEK1/2 inhibitor refametinib alone and in combination with anti-HER2 therapies. Results Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months). Mutations in PIK3CA were only identified in HER2-negative tumours, while ERBB-family mutations were identified in HER2-positive and HER2-negative tumours. Copanlisib had anti-proliferative effects in 4/5 cell lines, with IC50s ranging from 23.4 (N87) to 93.8 nM (SNU16). All HER2-positive cell lines except SNU16 were sensitive to lapatinib (IC50s 0.04 µM–1.5 µM). OE19 cells were resistant to trastuzumab. The combination of lapatinib and copanlisib was synergistic in ESO-26 and OE-19 cells (ED50: 0.83 ± 0.19 and 0.88 ± 0.13, respectively) and additive in NCI-N87 cells (ED50:1.01 ± 0.55). The combination of copanlisib and trastuzumab significantly improved growth inhibition compared to either therapy alone in NCI-N87, ESO26 and OE19 cells (p < 0.05). Conclusions PI3K or MEK inhibition alone or in combination with anti-HER2 therapy may represent an improved treatment strategy for some patients with HER2-positive GC, and warrants further investigation in a clinical trial setting.

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