Chromothripsis-like chromosomal rearrangements induced by ionizing radiation using proton microbeam irradiation system

Morishita, Maki; Muramatsu, Tomoki; Suto, Yumiko; Hirai, Momoki; Konishi, Teruaki; Hayashi, Shin Ichi; Shigemizu, Daichi; Tsunoda, Tatsuhiko; Moriyama, Keiji; Inazawa, Johji

doi:10.18632/oncotarget.7186

Cited by 46 publications

(35 citation statements)

References 44 publications

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“…Another factor in the induction of chromothripsis is physical chromosomal damage, such as that caused by ionizing radiation [43]. A pulse of ionizing radiation induces DNA double-strand breaks, leading to the unfettered circulation of hundreds of shards of genomic DNA in the nucleus.…”

Section: The Genomic Landscape Of Osteosarcomamentioning

confidence: 99%

Molecular genetics of osteosarcoma

Rickel

Fang

Tao

2017

Bone

204

179

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Osteosarcoma is the predominant form of bone cancer, affecting mostly adolescents. Recent progress made in molecular genetic studies of osteosarcoma has changed our view on the cause of the disease and ongoing therapeutic approaches for patients. As we draw closer to gaining more complete catalogues of candidate cancer driver genes in common forms of cancer, the landscape of somatic mutations in osteosarcoma is emerging from its first phase. In this review, we summarize recent whole genome and/or whole exome genomic studies, and then put these findings in the context of genetic hallmarks of somatic mutations and mutational processes in human osteosarcoma. One of the lessons learned here is that the extent of somatic mutations and complexity of the osteosarcoma genome are similar to that of common forms of adult cancer. Thus, a much higher number of samples than those currently obtained are needed to complete the catalogue of driver mutations in human osteosarcoma. In parallel, genetic studies in other species have revealed candidate driver genes and their roles in the genesis of osteosarcoma. This review also summarizes newly identified drivers in genetically engineered mouse models (GEMMs) and discusses our understanding of the impact of nature and number of drivers on tumor latency, subtypes, and metastatic potentials of osteosarcoma. It is becoming apparent that a synergistic team composed of three drivers (one ‘first driver’ and two ‘synergistic drivers’) may be required to generate an animal model that recapitulates aggressive osteosarcoma with a short latency. Finally, new cancer therapies are urgently needed to improve survival rate and quality of life for osteosarcoma patients. Several vulnerabilities in osteosarcoma are illustrated in this review to exemplify the opportunities for next generation molecularly targeted therapies. However, much work remains in order to complete our understanding of the somatic mutation basis of osteosarcoma, to develop reliable animal models of human disease, and to apply this information to guide new therapeutic approaches for reducing morbidity and mortality of this rare disease.

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Section: The Genomic Landscape Of Osteosarcomamentioning

confidence: 99%

Molecular genetics of osteosarcoma

Rickel

Fang

Tao

2017

Bone

204

179

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“…The mechanism of chromothripsis remains elusive but several hypotheses are described such as the formation of micronuclei, premature chromosome compaction (PCC), TP53 mutations and breakage‐fusion bridge cycles or irradiation . The formation of chromothripsis involving telomere regions and 1 chromosome arm is described and supports the hypothesis that events during the cell cycle are involved in the formation of these chromosomal rearrangements .…”

Section: Introductionmentioning

confidence: 81%

Chromosomal rearrangements in uveal melanoma: Chromothripsis

Poppelen

Yavuzyigitoglu

Smit

et al. 2018

Genes Chromosomes & Cancer

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Uveal melanoma (UM) is the most common primary intraocular malignancy in the Western world. Recurrent mutations in GNAQ, GNA11, CYSLTR2, PLCB4, BAP1, EIF1AX, and SF3B1 are described as well as non‐random chromosomal aberrations. Chromothripsis is a rare event in which chromosomes are shattered and rearranged and has been reported in a variety of cancers including UM. SNP arrays of 249 UM from patients who underwent enucleation, biopsy or endoresection were reviewed for the presence of chromothripsis. Chromothripsis was defined as ten or more breakpoints per chromosome involved. Genetic analysis of GNAQ, GNA11, BAP1, SF3B1, and EIF1AX was conducted using Sanger and next‐generation sequencing. In addition, immunohistochemistry for BAP1 was performed. Chromothripsis was detected in 7 out of 249 tumors and the affected chromosomes were chromosomes 3, 5, 6, 8, 12, and 13. The mean total of fragments per chromosome was 39.8 (range 12‐116). In 1 UM, chromothripsis was present in 2 different chromosomes. GNAQ, GNA11 or CYSLTR2 mutations were present in 6 of these tumors and 5 tumors harbored a BAP1 mutation and/or lacked BAP1 protein expression by immunohistochemistry. Four of these tumors metastasized and for the fifth only short follow‐up data are available. One of these metastatic tumors harbored an SF3B1 mutation. No EIF1AX mutations were detected in any of the tumors. To conclude, chromothripsis is a rare event in UM, occurring in 2.8% of samples and without significant association with mutations in any of the common UM driver genes.

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“…Что же касается тонких молекулярных механизмов, они различными исследо-вательскими группами трактуются по-разному. На наш взгляд, к настоящему времени лучше всего сформули-рована концепция, согласно которой возникновение хромотрипсиса связано с образованием микроядер [1,30,37,[77][78][79]. Не ставится также под сомнение и воз-можность возникновения хромотрипсиса вследствие воздействия на ДНК и митоз клеток ионизирующего излучения и свободных радикалов [4,14,33,73,80].…”

Section: основные механизмы хромотрипсисаunclassified

Chromothripsis in Oncology: Literature Review and Case Report

Мамаев¹,

Гиндина²,

Бойченко³

2017

Клиническая онкогематология

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The article presents a clinical case and literature review dwelling on the recently discovered chromothripsis phenomenon in oncology. Chromothripsis is a type of complex genome changes when a chromosome is first torn into dozens and even thousands of fragments, and then these fragments are bound in a random manner. Sometimes, several chromosomes are involved in the restructuring. As a result, genome mutant zones are formed which trigger malignancies and congenital diseases. In other words, the use of certain methodological approaches (multicolor fluorescence in situ hybridization, SKY technique, and some others) permits to observe under a microscope the splitting of two or more chromosomes and further reunification of these fragments into new unusual two- or multicolor structures, chromosomal markers. Chromothripsis is a rare phenomenon with a peculiar pattern observed in clones of cells of various tumors including hematopoietic and lymphoid tissue malignancies. There are published data on a higher incidence of this phenomenon in patients with myelodysplastic syndromes and bone tumors. TP53 gene mutations play an important role in the development of chromothripsis. The use of paired-sequencing DNA or SNP approaches in oncology is promising both in theoretical and clinical application. The first subject cohort should include patients with TP53 and MLL gene mutations, complex chromosomal aberrations, EVI-1 gene overexpression, and some others. The article presents the chromothripsis phenomenon in an 8-month-old girl with M7 acute myeloid leukemia.

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Chromothripsis-like chromosomal rearrangements induced by ionizing radiation using proton microbeam irradiation system

Cited by 46 publications

References 44 publications

Molecular genetics of osteosarcoma

Molecular genetics of osteosarcoma

Chromosomal rearrangements in uveal melanoma: Chromothripsis

Chromothripsis in Oncology: Literature Review and Case Report

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