ATRX loss is an independent predictor of poor survival in pancreatic neuroendocrine tumors

Chou, Angela; Itchins, Malinda; Reuver, Philip R. de; Arena, Jennifer; Clarkson, Adele; Sheen, Amy; Sioson, Loretta; Cheung, Veronica; Perren, Aurel; Nahm, Christopher B.; Mittal, Anubhav; Samra, Jaswinder S.; Pajic, Marina; Gill, Anthony J.

doi:10.1016/j.humpath.2018.07.032

Cited by 48 publications

(51 citation statements)

References 23 publications

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“…Immunohistochemical loss of ATRX and DAXX can be used as a surrogate marker of inactivating mutations of ATRX or DAXX, respectively [18,19]. The presence of either of these alterations is associated with recurrence and liver metastases [20][21][22][23][24][25]. In addition to ATRX or DAXX mutations and ALT, loss of ARID1A, loss of H3K36 trimethylation (H3K36me3) by SETD2 dysfunction, and CDKN2A deletions were also reported to be of prognostic value for non-functional PanNET [26].…”

Section: Introductionmentioning

confidence: 99%

Alternative Lengthening of Telomeres and Differential Expression of Endocrine Transcription Factors Distinguish Metastatic and Non-metastatic Insulinomas

et al. 2020

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Insulin-producing pancreatic neuroendocrine tumors (PanNETs)/insulinomas are generally considered to be indolent tumors with an excellent prognosis after complete resection. However, some insulinomas have a poor prognosis due to relapses and metastatic disease. Recently, studies in non-functional PanNETs indicated that behavior can be stratified according to alpha-and beta-cell differentiation, as defined by expression of the transcription factors ARX and PDX1, respectively. It is unknown whether similar mechanisms play a role in insulinomas. Therefore, we determined ARX and PDX1 expression in a cohort of 35 sporadic primary insulinomas and two liver metastases of inoperable primary insulinomas. In addition, WHO grade and loss of ATRX or DAXX were determined by immunohistochemistry, and alternative lengthening of telomeres (ALT) and CDKN2A status by fluorescence in situ hybridization. These findings were correlated with tumor characteristics and clinical follow-up data. In total, five out of 37 insulinoma patients developed metastatic disease. Metastatic insulinomas were all larger than 3 cm, whereas the indolent insulinomas were smaller (p value < 0.05). All three primary insulinomas that metastasized showed ARX expression, 2/3 showed ALT, and 1/3 had a homozygous deletion of CDKN2A as opposed to absence of ARX expression, ALT, or CDKN2A deletions in the 32 non-metastatic cases. The two liver metastases also showed ARX expression and ALT (2/2). The presence of ARX expression, which is usually absent in beta-cells, and genetic alterations not seen in indolent insulinomas strongly suggest a distinct tumorigenic mechanism in malignant insulinomas, with similarities to non-functional PanNETs. These observations may inform future follow-up strategies after insulinoma surgery.

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Section: Introductionmentioning

confidence: 99%

Alternative Lengthening of Telomeres and Differential Expression of Endocrine Transcription Factors Distinguish Metastatic and Non-metastatic Insulinomas

et al. 2020

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“…In prostate cancer, strong DAXX expression was associated strongly with a high Gleason grade, advanced pT stage, increased cell proliferation index, and early prostate-specific antigen recurrence (Tsourlakis et al, 2013). Chou et al (2018) also found that DAXX and ATRX losses were mutually exclusive and associated with other adverse clinicopathological variables and poor survival in patients with pNETs. Furthermore, 4-Hydroxy nonene aldehyde can promote DAXX localization to the cytoplasm and inhibition of apoptosis by blocking the apoptosis signal–regulating kinase 1 pathway (Sharma et al, 2008), associated with the progression of cervical cancer (Tang et al, 2014).…”

Section: Discussionmentioning

confidence: 96%

Association of Mental Health-Related Proteins DAXX, DRD3, and DISC1 With the Progression and Prognosis of Chondrosarcoma

Shi

Chen

et al. 2019

Front. Mol. Biosci.

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Chondrosarcoma is the second most common malignant bone tumor. Current therapies remain ineffective, resulting in poor prognoses. Biomarkers for chondrosarcoma and predictors of its prognosis have not been established. Mental health–related proteins have been associated with the pathogenesis, progression, and prognosis of many cancers, but their association with chondrosarcoma has not been reported. In this study, the expression and clinicopathological significance of the mental health–related proteins DAXX, DRD3, and DISC1 in chondrosarcoma tissue samples were examined, over an 84-months follow-up period. In immunohistochemical analysis, the rates of positive DAXX, DRD3, and DISC1 expression were significantly higher in chondrosarcoma than in osteochondroma tissue (P < 0.01). The percentages of positive DAXX, DRD3, and DISC1 expression were significantly lower in tissues with good differentiation (P < 0.01), AJCC stage I/ II (P < 0.01), Enneking stage I (P < 0.01), and non-metastasis (P < 0.05), respectively. In Kaplan–Meier survival analysis, significantly shorter mean survival times were associated with moderate and poor differentiation (P = 0.000), AJCC stage III/IV (P = 0.000), Enneking stage II/III (P = 0.000), metastasis (P = 0.019), invasion (P = 0.013), and positive DAXX (P = 0.012), and/or DRD3 (P = 0.018) expression. In Cox regression analysis, moderate and poor differentiation (P = 0.006), AJCC stage III/IV (P = 0.013), Enneking stage II/III (P = 0.016), metastasis (P = 0.033), invasion (P = 0.011), and positive DAXX (P = 0.033), and/or DRD3 (P = 0.025) staining correlated negatively with the postoperative survival rate and positively with mortality. In competing-risks regression analysis, differentiation (P = 0.005), metastasis (P = 0.014), invasion (P = 0.028), AJCC stage (P = 0.003), Enneking stage (P = 0.036), and DAXX (P = 0.039), and DRD3(P = 0.019) expression were independent predictors of death from chondrosarcoma. The areas under receiver operating characteristic curves for DAXX, DRD3, and DISC1 expression were 0.673 (95% CI, 0.557–0.788; P = 0.010), 0.670 (95% CI, 0.556–0.784; P = 0.011), and 0.688 (95% CI, 0.573–0.802; P = 0.005), respectively. These results suggest that DAXX, DRD3, and DISC1 could serve as biomarkers of chondrosarcoma progression and predictors of its prognosis.

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“…Several markers have the potential to identify high and low risk subgroups. PanNET tumorigenesis is commonly driven by mutations in the tumor suppressor genes MEN1 , ATRX , or DAXX , of which the latter two are associated with the alternative lengthening of telomeres phenotype (ALT) and correlate with worse prognosis and liver metastases . Protein loss, detected by immunohistochemistry (IHC), can be used as a surrogate for somatic inactivating mutations in ATRX and DAXX .…”

Section: Introductionmentioning

confidence: 99%

“…PanNET tumorigenesis is commonly driven by mutations in the tumor suppressor genes MEN1, ATRX, or DAXX, of which the latter two are associated with the alternative lengthening of telomeres phenotype (ALT) and correlate with worse prognosis and liver metastases. [4][5][6][7][8][9] Protein loss, detected by immunohistochemistry (IHC), can be used as a surrogate for somatic inactivating mutations in ATRX and DAXX. 9,10 Recently, promising results in determining these markers in preoperative cytologic specimens have been published.…”

Section: Introductionmentioning

confidence: 99%

Assessment of ARX expression, a novel biomarker for metastatic risk in pancreatic neuroendocrine tumors, in endoscopic ultrasound fine‐needle aspiration

Hackeng

Morsink

Moons

et al. 2019

Diagnostic Cytopathology

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Background The transcription factors ARX and PDX1, and alternative lengthening of telomeres (ALT) were recently described as prognostic markers for resected non‐functional pancreatic neuroendocrine tumors (PanNETs). ALT positive tumors with ARX expression relapse most often. Currently, tumor size is the only preoperative marker used to decide whether or not to operate, thus additional preoperative prognostic markers are needed. Therefore, it is critical to assess the performance of these biomarkers on preoperative cytologic specimens. Methods Endoscopic fine‐needle aspiration cellblock material and corresponding surgical specimens of 13 patients with PanNETs were assessed for histology, immunohistochemical staining of ARX, PDX1, Synaptophysin, Ki67, and telomere‐specific fluorescence in situ hybridization to detect ALT, and then associated with clinicopathological features. Scoring for ARX and PDX1 was performed blinded by two independent observers. Results Of the 13 surgical specimens, 8 were ARX+/PDX1−, 2 ARX−/PDX1+, and 3 ARX+/PDX1+. Concordance between cytologic and surgical specimens for ARX protein expression was 100%, whereas concordance for PDX1, ALT, and WHO tumor grade was 85%, 91%, and 73%, respectively. There was a perfect inter‐observer agreement in ARX and PDX1 scoring. Conclusion ARX can reliably be determined in cytologic specimens and has low inter‐observer variability. For cytology, false‐positive PDX1 expression was observed, possibly due to contamination or sampling, while ALT had a false‐negative case due to incomplete sampling. As previously observed, tumor grade is underestimated in cytologic specimens. Thus, ARX and ALT are the most promising markers to predict metastatic behavior in PanNETs, thereby warranting further validation in larger studies.

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ATRX loss is an independent predictor of poor survival in pancreatic neuroendocrine tumors

Cited by 48 publications

References 23 publications

Alternative Lengthening of Telomeres and Differential Expression of Endocrine Transcription Factors Distinguish Metastatic and Non-metastatic Insulinomas

Alternative Lengthening of Telomeres and Differential Expression of Endocrine Transcription Factors Distinguish Metastatic and Non-metastatic Insulinomas

Association of Mental Health-Related Proteins DAXX, DRD3, and DISC1 With the Progression and Prognosis of Chondrosarcoma

Assessment of ARX expression, a novel biomarker for metastatic risk in pancreatic neuroendocrine tumors, in endoscopic ultrasound fine‐needle aspiration

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