Phasing analysis of lung cancer genomes using a long read sequencer

Sakamoto, Yoshitaka; Miyake, Shuhei; Oka, Miho; Kanai, Akinori; Kawai, Yosuke; Nagasawa, Satoi; Shiraishi, Yuichi; Tokunaga, Katsushi; Seki, Masahide; Suzuki, Yutaka; Suzuki, Ayako

doi:10.1038/s41467-022-31133-6

Cited by 17 publications

(8 citation statements)

References 85 publications

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“…Importantly, we found that EGFR pathway inhibitors were possibly beneficial for the treatment of tumors with a high CHP score. Seemingly consistent with this finding, chromothripsis is frequently detected in lung cancers driven by EGFR mutations ( 28 ), and mutation of EGFR and ERBB2 is associated with more rearrangement events in LUADs ( 29 ). A correlation between EGFR amplification and chromothripsis has also been detected in glioblastoma ( 30 ).…”

Section: Discussionsupporting

confidence: 68%

Pan-cancer analysis of chromothripsis-related gene expression patterns indicates an association with tumor immune and therapeutic agent responses

Zhang

Yang

et al. 2023

Front. Oncol.

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Chromothripsis is a catastrophic event involving numerous chromosomal rearrangements in confined genomic regions of one or a few chromosomes, causing complex effects on cells via the extensive structural variation. The development of whole-genome sequencing (WGS) has promoted great progress in exploring the mechanism and effect of chromothripsis. However, the gene expression characteristics of tumors undergone chromothripsis have not been well characterized. In this study, we found that the transcriptional profile of five tumor types experiencing chromothripsis is associated with an immune evasion phenotype. A gene set variation analysis (GSVA) was used to develop a CHP score, which is based on differentially expressed gene sets in the TCGA database, revealing that chromothripsis status in multiple cancers is consistent with an abnormal tumor immune microenvironment and immune cell cytotoxicity. Evaluation using four immunotherapy datasets uncovered the ability of the CHP score to predict immunotherapy response in diverse tumor types. In addition, the CHP score was found to be related to resistance against a variety of anti-tumor drugs, including anti-angiogenesis inhibitors and platinum genotoxins, while EGFR pathway inhibitors were found to possibly be sensitizers for high CHP score tumors. Univariate COX regression analysis indicated that the CHP score can be prognostic for several types of tumors. Our study has defined gene expression characteristics of tumors with chromothripsis, supporting the controversial link between chromothripsis and tumor immunity. We also describe the potential value of the CHP score in predicting the efficacy of immunotherapy and other treatments, elevating chromothripsis as a tool in clinical practice.

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Section: Discussionsupporting

confidence: 68%

Pan-cancer analysis of chromothripsis-related gene expression patterns indicates an association with tumor immune and therapeutic agent responses

Zhang

Yang

et al. 2023

Front. Oncol.

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“…However, after the initial report of the human genome and methylome by nanopore sequencing in 2018 and 2017, respectively 10 , 11 , the potential of long-read sequencing in cancer genomics and epigenomics has been only preliminarily explored. Long-reads analyses have clearly shown higher accuracy and sensitivity to detect SVs in the DNA or plasma of a few breast-cancer 12 and lung-carcinoma samples 13 . As well, informative DNA methylation profiles have been obtained in breast cancer cell lines 10 and series of hepatocellular carcinoma 14 and brain-tumor 15 samples.…”

Section: Introductionmentioning

confidence: 99%

High-resolution Nanopore methylome-maps reveal random hyper-methylation at CpG-poor regions as driver of chemoresistance in leukemias

et al. 2023

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Aberrant DNA methylation at CpG dinucleotides is a cancer hallmark that is associated with the emergence of resistance to anti cancer treatment, though molecular mechanisms and biological significance remain elusive. Genome scale methylation maps by currently used methods are based on chemical modification of DNA and are best suited for analyses of methylation at CpG rich regions (CpG islands). We report the first high coverage whole-genome map in cancer using the long read nanopore technology, which allows simultaneous DNA-sequence and -methylation analyses on native DNA. We analyzed clonal epigenomic/genomic evolution in Acute Myeloid Leukemias (AMLs) at diagnosis and relapse, after chemotherapy. Long read sequencing coupled to a novel computational method allowed definition of differential methylation at unprecedented resolution, and showed that the relapse methylome is characterized by hypermethylation at both CpG islands and sparse CpGs regions. Most differentially methylated genes, however, were not differentially expressed nor enriched for chemoresistance genes. A small fraction of under-expressed and hyper-methylated genes at sparse CpGs, in the gene body, was significantly enriched in transcription factors (TFs). Remarkably, these few TFs supported large gene-regulatory networks including 50% of all differentially expressed genes in the relapsed AMLs and highly-enriched in chemoresistance genes. Notably, hypermethylated regions at sparse CpGs were poorly conserved in the relapsed AMLs, under-represented at their genomic positions and showed higher methylation entropy, as compared to CpG islands. Analyses of available datasets confirmed TF binding to their target genes and conservation of the same gene-regulatory networks in large patient cohorts. Relapsed AMLs carried few patient specific structural variants and DNA mutations, apparently not involved in drug resistance. Thus, drug resistance in AMLs can be mainly ascribed to the selection of random epigenetic alterations at sparse CpGs of a few transcription factors, which then induce reprogramming of the relapsing phenotype, independently of clonal genomic evolution.

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“…An analysis of the genetic makeup of 20 patients with NSCLC revealed the presence of chromothripsis regions, where an abnormal accumulation of single nucleotide variations (SNVs) and structural variations (SVs) were observed on a particular haplotype [ 110 ]. Additionally, it is believed that a number of lung cancer driver fusion oncogenes result from chromothripsis [ 111 ].…”

Section: Intratumoral Heterogeneitymentioning

confidence: 99%

Unraveling the Impact of Intratumoral Heterogeneity on EGFR Tyrosine Kinase Inhibitor Resistance in EGFR-Mutated NSCLC

Kobayashi

Tan

2023

IJMS

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The advent of tyrosine kinase inhibitors (TKIs) for treating epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) has been a game changer in lung cancer therapy. However, patients often develop resistance to the drugs within a few years. Despite numerous studies that have explored resistance mechanisms, particularly in regards to collateral signal pathway activation, the underlying biology of resistance remains largely unknown. This review focuses on the resistance mechanisms of EGFR-mutated NSCLC from the standpoint of intratumoral heterogeneity, as the biological mechanisms behind resistance are diverse and largely unclear. There exist various subclonal tumor populations in an individual tumor. For lung cancer patients, drug-tolerant persister (DTP) cell populations may have a pivotal role in accelerating the evolution of tumor resistance to treatment through neutral selection. Cancer cells undergo various changes to adapt to the new tumor microenvironment caused by drug exposure. DTP cells may play a crucial role in this adaptation and may be fundamental in mechanisms of resistance. Intratumoral heterogeneity may also be precipitated by DNA gains and losses through chromosomal instability, and the role of extrachromosomal DNA (ecDNA) may play an important role. Significantly, ecDNA can increase oncogene copy number alterations and enhance intratumoral heterogeneity more effectively than chromosomal instability. Additionally, advances in comprehensive genomic profiling have given us insights into various mutations and concurrent genetic alterations other than EGFR mutations, inducing primary resistance in the context of tumor heterogeneity. Understanding the mechanisms of resistance is clinically crucial since these molecular interlayers in cancer-resistance mechanisms may help to devise novel and individualized anticancer therapeutic approaches.

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Phasing analysis of lung cancer genomes using a long read sequencer

Cited by 17 publications

References 85 publications

Pan-cancer analysis of chromothripsis-related gene expression patterns indicates an association with tumor immune and therapeutic agent responses

Pan-cancer analysis of chromothripsis-related gene expression patterns indicates an association with tumor immune and therapeutic agent responses

High-resolution Nanopore methylome-maps reveal random hyper-methylation at CpG-poor regions as driver of chemoresistance in leukemias

Unraveling the Impact of Intratumoral Heterogeneity on EGFR Tyrosine Kinase Inhibitor Resistance in EGFR-Mutated NSCLC

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