Mitotic Checkpoints and Chromosome Instability Are Strong Predictors of Clinical Outcome in Gastrointestinal Stromal Tumors

Lagarde, Pauline; Pérot, Gaëlle; Kauffmann, Audrey; Brulard, Céline; Dapremont, Valérie; Hostein, Isabelle; Neuville, Agnès; Woźniak, Agnieszka; Sciot, Raf; Schöffski, Patrick; Aurias, Alain; Coindre, Jean Michél; Dębiec‐Rychter, Maria; Chibon, Fréderic

doi:10.1158/1078-0432.ccr-11-1610

Cited by 124 publications

(142 citation statements)

References 45 publications

(55 reference statements)

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“…4,[10][11][12][13] Several tumor cell-intrinsic molecular prognosticators have been suggested, mainly based on proteins [47][48][49][50][51] or gene signatures 52,53 related to cell proliferation. Potential immune prognostic/predictive parameters have been more recently reported.…”

Section: Discussionmentioning

confidence: 99%

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PDL1 expression is an independent prognostic factor in localized GIST

et al. 2015

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Gastrointestinal stromal tumors (GIST) are the most frequently occurring digestive sarcomas. The prognosis of localized GIST is heterogeneous, notably for patients with an Armed Forces Institute of Pathology (AFIP) intermediate or high risk of relapse. Despite imatinib effectiveness, it is crucial to develop therapies able to overcome the resistance mechanisms. The immune system represents an attractive prognostic and therapeutic target. The Programmed cell Death 1 (PD1)/programmed cell death ligand 1 (PDL1) pathway is a key inhibitor of the immune response; recently, anti-PD1 and anti-PDL1 drugs showed very promising results in patients with solid tumors. However, PDL1 expression has never been studied in GIST. Our objective was to analyze PDL1 expression in a large series of clinical samples. We analyzed mRNA expression data of 139 operated imatinib-untreated localized GIST profiled using DNA microarrays and searched for correlations with histoclinical features including postoperative metastatic relapse. PDL1 expression was heterogeneous across tumors and was higher in AFIP low-risk than in high-risk samples, and in samples without than with metastatic relapse. PDL1 expression was associated with immunity-related parameters such as T-cell-specific and CD8C T-cell-specific gene expression signatures and probabilities of activation of interferon a (IFNa), IFNg, and tumor necrosis factor a (TNFa) pathways, suggesting positive correlation with a cytotoxic T-cell response. In multivariate analysis, the PDL1-low group was associated with a higher metastatic risk independently of the AFIP classification and the KIT mutational status. In conclusion, PDL1 expression refines the prediction of metastatic relapse in localized GIST and might improve our ability to better tailor adjuvant imatinib. In the metastatic setting, PDL1 expression might guide the use of PDL1 inhibitors, alone or associated with tyrosine kinase inhibitors.

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Section: Discussionmentioning

confidence: 99%

“…We collected histoclinical and gene expression data of clinical GIST samples from our 2 databases 57,58 and 3 public data sets 53,59,60 from the National Center for Biotechnology Information (NCBI)/Genbank GEO and ArrayExpress databases. The 5 datasets are described in Table S5.…”

Section: Tumor Samplesmentioning

confidence: 99%

PDL1 expression is an independent prognostic factor in localized GIST

et al. 2015

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“…12 The array comparative genomic hybridization (aCGH) data from 54 GIST included in this study were published before by our group. 14,15 Mutational analysis of the entire coding sequence of PTEN (ENST00000371953-exons 1-9) was performed as described. 12 The primer sequences are listed in Table 2.…”

Section: Pten Copy Number Loss Mutational Analysis and Methylation mentioning

confidence: 99%

Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors

et al. 2014

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Insufficiency of phosphatase and tensin homolog (PTEN) occurs in numerous tumor types and has been implicated as a resistance mechanism to receptor tyrosine kinase-targeted therapies in human cancer. In this study, we have performed a comprehensive molecular and immunohistochemical characterization of PTEN in 58 imatinib-naı¨ve and 54 imatinib-treated gastrointestinal stromal tumors (GISTs). The findings were correlated with clinicopathological data. At the genomic level, PTEN was affected mainly by mono-allelic loss, which was significantly less frequent in imatinib-naı¨ve vs imatinib-resistant tumors (9% vs 39%, Po0.001). Neither PTEN mutations nor PTEN promoter hyper-methylation were found. By immunohistochemistry, PTEN depletion was clearly related to GIST progression. Low PTEN protein expression was common (50%) and often paralleled with total immunonegativity in imatinib-resistant tumors. The abnormal PTEN protein expression correlated with PTEN loss at the genomic level (P ¼ 0.001). In addition, the effect of small interfering RNA (siRNA) PTEN knockdown on KIT signaling was examined in GIST-T1 and GIST430 cell lines, in the absence or presence of a dual PI3K/mTOR inhibitor NVP-BEZ235, alone or in combination with imatinib. In both cell lines, siRNA silencing of PTEN resulted in the substantial upregulation of PI3K-AKT and MAPK pathways. The MAPK hyperactivation was further potentiated by NVP-BEZ235 in the imatinib-sensitive GIST-T1 cells; yet, this effect was counteracted efficiently by combined treatment. In the imatinib-resistant GIST430 cells, neither NVP-BEZ235 alone or in combination with imatinib yielded sufficient inhibition of hyper-phosphorylated MAPK and downstream intermediate S6 protein. In conclusion, depleted PTEN expression associated with mono-allelic PTEN loss occurs frequently in imatinib-resistant GIST and might serve as a biomarker for stratifying patients for optimal treatment. In vitro, the PTEN insufficiency leads to hyperactivation of AKT and MAPK pathways in tumor cells. Novel therapies targeting multiple components of the integrated KIT receptor signaling pathways in imatinibresistant GIST warrant further studies.

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“…The genomic signature (genomic index) is a powerful predictor of metastatic relapse, as is the CINSARC signature. 17 Further, this array-CGH technique is adapted to formalin-fixed paraffin-embedded tumor material and its efficacy has been demonstrated on tumor samples that have been archived for over 15 years.…”

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confidence: 99%

Uterine smooth muscle tumor analysis by comparative genomic hybridization: a useful diagnostic tool in challenging lesions

et al. 2015

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The diagnosis and management of uterine smooth muscle tumors with uncertain malignant potential (STUMP) is often challenging, and genomic data on these lesions as well as on uterine smooth muscle lesions are limited. We tested the hypothesis that genomic profile determination by array-CGH could split STUMP into a benign group with scarce chromosomal alterations akin to leiomyoma and a malignant group with high chromosomal instability akin to leiomyosarcoma. Array-CGH genomic profile analysis was conducted for a series of 29 cases of uterine STUMP. A group of ten uterine leiomyomas and ten uterine leiomyosarcomas served as controls. The mean age was 50 years (range, 24-85) and the follow-up ranged from 12 to 156 months (average 70 months). Since STUMP is a heterogenous group of tumors with genomic profiles that can harbor few to many chromosomal alterations, we compared genomic indices in leiomyomas and leiomyosarcomas and set a genomic index ¼ 10 threshold. Tumors with a genomic index o10 were classified as nonrecurring STUMPs and those with a genomic index 410 represented STUMPs with recurrences and unfavorable outcomes. Hence, the genomic index threshold splits the STUMP category into two groups of tumors with different outcomes: a group comparable to leiomyomas and another similar to leiomyosarcomas, but more indolent. In our STUMP series, genomic analysis by array-CGH is an innovative diagnostic tool for problematic smooth muscle uterine lesions, complementary to the morphological evaluation approach. We provide an improved classification method for distinguishing truly malignant tumors from benign lesions within the category of STUMP, especially those with equivocal morphological features.

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Mitotic Checkpoints and Chromosome Instability Are Strong Predictors of Clinical Outcome in Gastrointestinal Stromal Tumors

Cited by 124 publications

References 45 publications

PDL1 expression is an independent prognostic factor in localized GIST

PDL1 expression is an independent prognostic factor in localized GIST

Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors

Uterine smooth muscle tumor analysis by comparative genomic hybridization: a useful diagnostic tool in challenging lesions

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