Monosomy of Chromosome 10 Associated With Dysregulation of Epidermal Growth Factor Signaling in Glioblastomas

Yadav, Ajay; Renfrow, Jaclyn J.; Scholtens, Denise M.; Xie, Hehuang; Durán, George E.; Bredel, Claudia; Vogel, Hannes; Chandler, James P.; Chakravarti, Arnab; Robe, Pierre A.; Das, Sunit; Scheck, Adrienne C.; Kessler, John A.; Soares, Marcelo B.; Šikić, Branimir I.; Harsh, Griffith R.; Bredel, Markus

doi:10.1001/jama.2009.1022

Cited by 63 publications

(52 citation statements)

References 40 publications

(55 reference statements)

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“…Of note, miR-124 expression levels were also lower and PTBP1 expression levels higher in NPCs and GPCs compared with those in normal brain. This further supports the idea that a common miR-124/PTBP1/ ANXA7 splicing axis is inherited by glioblastoma cells from a potential ancestral precursor cell and that this axis is further exploited and constitutively activated during glioblastoma progression through the selection of additional genetic alterations, including PTBP1 amplification and, as we have shown before, heterozygous ANXA7 losses and EGFR aberrations (2,8).…”

Section: Figuresupporting

confidence: 88%

“…These findings and our previous observation associating ANXA7 with deregulation of EGFR signaling in glioblastoma (2,8) prompted further investigation of the differential functional roles of the 2 ANXA7 splice variants in EGFR regulation. SNB19 glioblastoma…”

Section: Lineage-specific Splicing Of a Brain-enriched Exon In Anxa7 mentioning

confidence: 59%

“…This suggests that the EGFR pathway-activating splicing trait peculiar to glioblastoma cells might be inherited from these progenitor lineages, which may represent the potential cell of origin of glioblastoma (48). Therefore, it is likely that the miR-124/PTBP1/ANXA7 splicing axis is not a tumor-specific, but rather a lineage-specific, characteristic that is further exploited to promote tumor progression through the accumulation and selection of additional genetic alterations, including PTBP1 amplification, heterozygous ANXA7 deletion, and EGFR aberrations (2,8). Altogether, these genetic alterations cumulatively contribute to the establishment of a permissive environment by enhancing EGFR pathway activation.…”

Section: Discussionmentioning

confidence: 99%

“…Almost all glioblastomas exhibit excessive activation of the EGFR pathway, often elicited by amplification or activating mutations of the EGFR oncogene (5) or by additional or alternative genetic mechanisms, leading to deregulation of EGFR signaling (6)(7)(8). We have previously shown that loss of the tumor suppressor annexin A7 (ANXA7), a membrane-binding protein with diverse properties, is associated with deregulation of EGFR signaling and glioblastoma patient prognosis (2,8).…”

Section: Introductionmentioning

confidence: 99%

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Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

et al. 2014

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Tissue-specific alternative splicing is critical for the emergence of tissue identity during development, yet the role of this process in malignant transformation is undefined. Tissue-specific splicing involves evolutionarily conserved, alternative exons that represent only a minority of the total alternative exons identified. Many of these conserved exons have functional features that influence signaling pathways to profound biological effect. Here, we determined that lineage-specific splicing of a brain-enriched cassette exon in the membrane-binding tumor suppressor annexin A7 (ANXA7) diminishes endosomal targeting of the EGFR oncoprotein, consequently enhancing EGFR signaling during brain tumor progression. ANXA7 exon splicing was mediated by the ribonucleoprotein PTBP1, which is normally repressed during neuronal development. PTBP1 was highly expressed in glioblastomas due to loss of a brain-enriched microRNA (miR-124) and to PTBP1 amplification. The alternative ANXA7 splicing trait was present in precursor cells, suggesting that glioblastoma cells inherit the trait from a potential tumor-initiating ancestor and that these cells exploit this trait through accumulation of mutations that enhance EGFR signaling. Our data illustrate that lineage-specific splicing of a tissue-regulated alternative exon in a constituent of an oncogenic pathway eliminates tumor suppressor functions and promotes glioblastoma progression. This paradigm may offer a general model as to how tissue-specific regulatory mechanisms can reprogram normal developmental processes into oncogenic ones.

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Section: Figuresupporting

confidence: 88%

Section: Lineage-specific Splicing Of a Brain-enriched Exon In Anxa7 mentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

et al. 2014

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“…Different regions are frequently lost at chromosome 10, including the regions containing PTEN, MGMT [28,58], and ANXA7, an EGFR inhibitor [59]. PTEN directly antagonizes PI3K signaling and is one of the most frequently altered genes in cancer.…”

Section: Deletionsmentioning

confidence: 99%

Genetic Profiling: Searching for Novel Genetic Aberrations in Glioblastoma

Jamshidi¹,

Chen²

2013

Oncogenomics and Cancer Proteomics - Novel Approaches in Biomarkers Discovery and Therapeutic Targets in Cancer

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One Step Forward Toward Identification of the Genetic Signature of Glioblastomas

Pasche¹

2009

JAMA

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Monosomy of Chromosome 10 Associated With Dysregulation of Epidermal Growth Factor Signaling in Glioblastomas

Cited by 63 publications

References 40 publications

Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

Genetic Profiling: Searching for Novel Genetic Aberrations in Glioblastoma

One Step Forward Toward Identification of the Genetic Signature of Glioblastomas

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