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Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma.

ABSTRACT: INTRODUCTION:Malignant pleural mesothelioma is a disease primarily associated with exposure to the carcinogen asbestos. Whereas other carcinogen-related tumors are associated with a high tumor mutation burden, mesothelioma is not. We sought to resolve this discrepancy. METHODS:We used mate-pair (n = 22), RNA (n = 28), and T cell receptor sequencing along with in silico predictions and immunologic assays to understand how structural variants of chromosomes affect the transcriptome. RESULTS:We observed that inter- or intrachromosomal rearrangements were present in every specimen and were frequently in a pattern of chromoanagenesis such as chromoplexy or chromothripsis. Transcription of rearrangement-related junctions was predicted to result in many potential neoantigens, some of which were proven to bind patient-specific major histocompatibility complex molecules and to expand intratumoral T cell clones. T cells responsive to these predicted neoantigens were also present in a patient's circulating T cell repertoire. Analysis of genomic array data from the mesothelioma cohort in The Cancer Genome Atlas suggested that multiple chromothriptic-like events negatively impact survival. CONCLUSIONS:Our findings represent the discovery of potential neoantigen expression driven by structural chromosomal rearrangements. These results may have implications for the development of novel immunotherapeutic strategies and the selection of patients to receive immunotherapies.

SUBMITTER: Mansfield AS

PROVIDER: S-EPMC6348045 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma.

Mansfield Aaron S AS Peikert Tobias T Smadbeck James B JB Udell Julia B M JBM Garcia-Rivera Enrique E Elsbernd Laura L Erskine Courtney L CL Van Keulen Virginia P VP Kosari Farhad F Murphy Stephen J SJ Ren Hongzheng H Serla Vishnu V VV Schaefer Klein Janet L JL Karagouga Giannoula G Harris Faye R FR Sosa Carlos C Johnson Sarah H SH Nevala Wendy W Markovic Svetomir N SN Bungum Aaron O AO Edell Eric S ES Dong Haidong H Cheville John C JC Aubry Marie Christine MC Jen Jin J Vasmatzis George G

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 20181010 2

<h4>Introduction</h4>Malignant pleural mesothelioma is a disease primarily associated with exposure to the carcinogen asbestos. Whereas other carcinogen-related tumors are associated with a high tumor mutation burden, mesothelioma is not. We sought to resolve this discrepancy.<h4>Methods</h4>We used mate-pair (n = 22), RNA (n = 28), and T cell receptor sequencing along with in silico predictions and immunologic assays to understand how structural variants of chromosomes affect the transcriptome. ...[more]

PMID: 30316012

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Project description:ObjectiveComplex chromosome rearrangements (CCR) are rare structural abnormalities involving at least three breakpoints, categorized into three types based on their structure: type A (three-way rearrangements), type B (double two-way translocations), and type C (exceptional CCR). However, thus far, limited data exists on preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR) in CCR carriers. This study aims to evaluate the clinical outcomes and influencing factors of PGT-SR in couples with CCR.MethodsFifteen couples with unique CCR recruited from 793 couples following PGT-SR between January 2017 and May 2023. In addition, a total of 54 CCR cases, 39 previously reported as well as 15 newly added, were included in the analysis of factors associate with normal/balanced embryos.ResultsA total of 100 blastocysts were biopsied and analyzed in 15 CCR couples after 17 PGT-SR cycles, with 16.0% being euploid, 78.0% aneuploid and 6.0% mosaic. 11 normal/balanced embryos and one mosaic embryo were transferred, resulting in eight live births. Furthermore, based on the combined data from 54 CCR carriers, the proportion of normal/balanced embryos was 10.8%, with a significant decrease observed among female carriers compared to male heterozygotes (6.5% vs. 15.5%, p = 0.002). Type B exhibited the lowest rate of euploid embryos at only 6.7%, followed by type A at 11.6% and type C at 14.0%, although the differences were not significant (p = 0.182). After completing the multivariate generalized estimating equation (GEE) analysis, type B (p = 0.014) and female carrier (p = 0.002) were identified as independent risk factors for fewer euploid embryos.ConclusionThe occurrence of balanced CCR in patients with reproductive abnormalities may be more frequent than we expected. Despite the proportion of normal/balanced embryos being significantly low, which can be influenced by CCR type and carrier's sex, PGT-SR may improve the reproductive outcomes among CCR cases. These findings can optimize the clinical management and genetic counseling of CCR carriers seeking assisted reproductive technology (ART).

Project description:BackgroundBalanced complex chromosome rearrangements (BCCR) are balanced chromosomal structural aberrations that involve two or more chromosomes and at least three breakpoints. It is very rare in the population. The objective is to explore the difference of influence of three types of BCCR on early embryonic development and molecular karyotype.ResultsTwelve couples were recruited including four couples of three-way rearrangements carriers (group A), three couples of double two-way translocations carriers (group B) and five couples of exceptional CCR carriers (group C). A total of 243 oocytes were retrievedin the seventeen preimplantation genetic testing (PGT) cycles, and 207 of these were available for fertilization. After intracytoplasmic sperm injection, 181oocytes normally fertilized. The rates of embryos forming on day3 in three groups were 87.88, 97.78 and77.14%, which was significantly different (P = 0.01). Compared with group B, the rate of embryo formation was statistically significantly lower in group C (P = 0.01). Furthermore, the rates of high-quality blastocysts in three group were 14.71, 48.15 and 62.96%, respectively, which was significantly different (P = 0.00). Compared with group B andC, the rate of high-quality blastocysts in group A was statistically significantly lower (P = 0.00;P = 0.00). Comprehensive chromosome analysis was performed on 83 embryos, including 75 trophectodermcellsand 8 blastomeres. Except 7 embryos failed to amplify, 9.01%embryos were diagnosed as euploidy, and 90.91% were diagnosed as abnormal. As for group A, the euploid embryo rate was 10.71%and the abnormal embryo rate was 89.29%. In group B,the euploid embryo rate was 3.85%, the abnormal embryo rate was 96.15%. The euploid embryo rate was 13.04%, the abnormal embryo rate was 86.96% in group C. There were no significant differences among the three groups (P = 0.55).ConclusionsThe lowest rate of high quality blastocysts has been for three-way rearrangements and the lowest rate of euploidy has been for double two-way translocations, although no significant difference. Different types of BCCR maybe have little effect on the embryonic molecular karyotype. The difference of influence of BCCR on early embryonic developmentandmolecular karyotypeshould be further studied.

Project description:BackgroundNuclear protein in testis (NUT) midline carcinoma (NMC) is a rare aggressive malignancy often occurring in the tissues of midline anatomical structures. Except for the pathognomonic BRD3/4-NUT rearrangement, the comprehensive landscape of genomic alterations in NMCs has been unexplored.Patients and methodsWe investigated three NMC cases, including two newly diagnosed NMC patients in Seoul National University Hospital, and a previously reported cell line (Ty-82). Whole-genome and transcriptome sequencing were carried out for these cases, and findings were validated by multiplex fluorescence in situ hybridization and using individual fluorescence probes.ResultsHere, we present the first integrative analysis of whole-genome sequencing, transcriptome sequencing and cytogenetic characterization of NUT midline carcinomas. By whole-genome sequencing, we identified a remarkably similar pattern of highly complex genomic rearrangements (previously denominated as chromoplexy) involving the BRD3/4-NUT oncogenic rearrangements in two newly diagnosed NMC cases. Transcriptome sequencing revealed that these complex rearrangements were transcribed as very simple BRD3/4-NUT fusion transcripts. In Ty-82 cells, we also identified a complex genomic rearrangement involving the BRD4-NUT rearrangement underlying the simple t(15;19) karyotype. Careful inspections of rearrangement breakpoints indicated that these rearrangements were likely attributable to single catastrophic events. Although the NMC genomes had >3000 somatic point mutations, canonical oncogenes or tumor suppressor genes were rarely affected, indicating that they were largely passenger events. Mutational signature analysis showed predominant molecular clock-like signatures in all three cases (accounting for 54%-75% of all base substitutions), suggesting that NMCs may arise from actively proliferating normal cells.ConclusionTaken together, our findings suggest that a single catastrophic event in proliferating normal cells could be sufficient for neoplastic transformation into NMCs.

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Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma.

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Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma.

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