Loss of Chromosome 8p Governs Tumor Progression and Drug Response by Altering Lipid Metabolism

Cai, Yanyan; Crowther, Jonathan; Pastor, Tibor J.; Asbagh, Layka Abbasi; Baietti, Maria Francesca; Troyer, Magdalena De; Vázquez, Iria; Talebi, Ali; Renzi, Fabrizio; Dehairs, Jonas; Swinnen, Johannes V.; Sablina, Anna

doi:10.1016/j.ccell.2016.04.003

Cited by 165 publications

(157 citation statements)

References 41 publications

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“…It has been recently shown that large-scale loss of chromosome material in cancer cells can disturb multiple signaling pathways and produce phenotypes distinct from those arising through loss of a single gene (46). We performed gene ontology (GO) analyses of the differentially expressed mRNAs and of the mRNA targets of the differentially expressed miRs to test whether genes involved in specific biologic processes are enriched in signatures associated with loss of the entire chromosome 7.…”

Section: Resultsmentioning

confidence: 99%

Mutational Landscape and Gene Expression Patterns in Adult Acute Myeloid Leukemias with Monosomy 7 as a Sole Abnormality

et al. 2017

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Monosomy of chromosome 7 is the most frequent autosomal monosomy in acute myeloid leukemia (AML), where it associates with poor clinical outcomes. However, molecular features associated with this sole monosomy subtype (-7 AML) which may give insights into the basis for its poor prognosis have not been characterized. In this study, we analyzed 36 cases of -7 AML for mutations in 81 leukemia/cancer-associated genes using a customized targeted next-generation sequencing panel (Miseq). Global gene and microRNA expression profiles were also determined using paired RNA and small RNA sequencing data. Notably, gene mutations were detected in all the major AML-associated functional groups, which include activated signaling, chromatin remodeling, cohesin complex, methylation, NPM1, spliceosome, transcription factors and tumor suppressors. Gene mutations in the activated signaling and chromatin remodeling groups were relatively more frequent in patients <60 years of age, who also had more mutations in the methylation and spliceosome groups compared to patients {greater than or equal to} 60 years of age. Novel recurrent mutational events in AML were identified in the SMARCA2 gene. In patients {greater than or equal to} 60 years of age, the presence of spliceosome mutations associated with a lower complete remission rate (p=0.03). RNA sequencing revealed distinct gene and microRNA expression patterns between the sole -7 and non-7 AML cases, with reduced expression as expected of many genes and microRNAs mapped to chromosome 7, and overexpression of ID1, MECOM, and PTPRM, among others. Overall, our findings illuminate a number of molecular features of the underlying aggressive pathobiology in -7 AML patients.

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Section: Resultsmentioning

confidence: 99%

Mutational Landscape and Gene Expression Patterns in Adult Acute Myeloid Leukemias with Monosomy 7 as a Sole Abnormality

et al. 2017

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“…Further studies to establish the consequences of these alterations on HLA class I antigen processing and presentation are ongoing. One hypothesis is that while none of these events alone are sufficient to down-modulate antigen presentation, multiple hits together in the same pathway could have this effect similar to how hemizygous loss of multiple contiguous tumor suppressor genes can affect tumorigenesis (41,42). Further supporting the potential for a role of defective antigen processing and presentation defects in mediating resistance to ICIs, we found that three out of five PDXs generated from ICI-resistant tumors exhibited B2M downregulation and two of these also had either loss or barely detectable levels of cell surface HLA class I expression.…”

Section: Discussionmentioning

confidence: 99%

Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer

et al. 2017

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Mechanisms of acquired resistance to immune checkpoint inhibitors (ICIs) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell surface HLA class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knock-out of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer.

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“…Cai et al (2016) created isogenic derivatives of MCF 10A, a human mammary epithelial cell line, with a defined hemizygous deletion in chromosome 8p by TALEN-mediated engineering. Surprisingly, although this SCNA has been implicated as an early event during breast tumorigenesis, it had little impact on transformation capacity alone or with established driver genes.…”

mentioning

confidence: 99%

Coordinated Tumor Suppression by Chromosome 8p

2016

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Loss of Chromosome 8p Governs Tumor Progression and Drug Response by Altering Lipid Metabolism

Cited by 165 publications

References 41 publications

Mutational Landscape and Gene Expression Patterns in Adult Acute Myeloid Leukemias with Monosomy 7 as a Sole Abnormality

Mutational Landscape and Gene Expression Patterns in Adult Acute Myeloid Leukemias with Monosomy 7 as a Sole Abnormality

Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer

Coordinated Tumor Suppression by Chromosome 8p

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