DYRK1A in Down syndrome: an oncogene or tumor suppressor?

Birger, Yehudit; Izraeli, Shai

doi:10.1172/jci62372

Cited by 21 publications

(20 citation statements)

References 23 publications

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“…33 Based on studies of mouse and human cells, the gene DYRK1A on chromosome 21 may possess both tumor-suppressor and leukemogenic properties. 34 The reduced risk of solid tumors and benign vascular tumors in Down syndrome 35 may be explained by endogenous antiangiogenetic regulators derived from genes on chromosome 21. Endostatin encoded by the COL18A1 gene at 21q22.3 is a potent angiogenesis inhibitor, and the serum concentration of endostatin is significantly higher in Down syndrome.…”

Section: Discussionmentioning

confidence: 99%

Low risk of solid tumors in persons with Down syndrome

Hasle

Friedman

Olsen

et al. 2016

Genetics in Medicine

150

139

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Purpose: The aim of this study was to investigate cancer incidence in a large cohort of persons with Down syndrome.Methods: Down syndrome was identified from the Danish Cytogenetic Register. Cancer occurrence was identified by linkage to the Danish Cancer Registry. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated based on observed and expected numbers from rates for all Danish residents. The cohort consisted of 3,530 persons with Down syndrome contributing 89,570 person-years at risk.Results: Acute leukemia risk was highest from 1-4 years of age and remained elevated until age 30. The overall risk of solid tumors was decreased (SIR 0.45; 95% CI 0.34-0.59), especially in persons 50 years or older (SIR 0.27; 95% CI 0.16-0.43). We found a significantly lower risk of lung cancer (SIR 0.10; 95% CI 0.00-0.56), breast cancer (SIR 0.16; 95% CI 0.03-0.47), and cervical cancer (SIR 0.0; 95% CI 0.00-0.77). Testicular cancer was the only solid tumor with an increased SIR (2.9; 95% CI 1.6-4.8). Conclusions:The risk of all major groups of solid tumors was decreased, except testicular cancer. Altered screening strategies should be considered for persons with Down syndrome. This unusual pattern of cancer occurrence may help understanding carcinogenesis in the general population.

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Section: Discussionmentioning

confidence: 99%

Low risk of solid tumors in persons with Down syndrome

Hasle

Friedman

Olsen

et al. 2016

Genetics in Medicine

150

139

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show abstract

“…The NFAT-calcineurin pathway is a major regulator of T-cell development and function and is inhibited in DS due to the increased dosage of regulator of calcineurin 1 and dual-specificity tyrosine-(Y)-phosphorylation regulated Kinase 1A1. 49,50 This is the same pathway that is targeted by the immunosuppressants cyclosporine and tacrolimus. It is also tempting to speculate that the rarity of T-ALL in DS is also possibly due to the block in the NFAT pathway.…”

Section: Treatment-related Mortalitymentioning

confidence: 99%

How I treat ALL in Down's syndrome: pathobiology and management

Izraeli

Vora

Zwaan

et al. 2014

Blood

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Children with Down syndrome are at high risk for developing B-cell precursor acute lymphoblastic leukemia (DS-ALL) associated with poor outcome due to both a high relapse rate and increased treatment-related mortality (TRM) from infections. Biologically, these heterogeneous leukemias are characterized by under-representation of the common cytogenetic subgroups of childhood ALL and overrepresentation of CRLF2-IL7R-JAK-STAT activating genetic aberrations. Although relapse is the major determinant of poor outcomes in this population, de-escalation of chemotherapy intensity might be feasible in the 10% to 15% DS-ALL patients with ETV6-RUNX1 or high hyperdipoidy in whom TRM is the major limiting event. As infection-associated TRM occurs during all treatment phases, including the maintenance period, increased surveillance and supportive care is required throughout therapy. Improvement in outcome will require better understanding of the causes of treatment failure and TRM, incorporation of new therapies targeting the unique biological properties of DS-ALL, and enhanced supportive care measures to reduce the risk of infection-related TRM. To facilitate these goals, an international collaboration plans to establish a prospective DS-ALL registry and develop specific supportive care recommendations for this at-risk population.

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“…Intriguingly, the ability of DYRK1A overexpression to inhibit another transcription factor, NFAT, is oncogenic for DS-AMKL 86 (discussed above), but is anti-angiogenic in solid tissues (discussed below). Therefore, trisomy of DYRK1A has a unique cell-context-dependent contribution to both increase the likelihood of DS-AMKL and suppress solid tumours in DS 107 . Other HSA21 genes with indirect evidence for tumour suppressive activity are shown in FIG.…”

Section: Ds Biology Predicts Cancer Pronenessmentioning

confidence: 99%

Tumorigenesis in Down's syndrome: big lessons from a small chromosome

2012

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If assessed by a number of criteria for cancer predisposition, Down's syndrome (DS) should be an overwhelmingly cancer-prone condition. Although childhood leukaemias occur more frequently in DS, paradoxically, individuals with DS have a markedly lower incidence of most solid tumours. Understanding the mechanisms that are capable of overcoming such odds could potentially open new routes for cancer prevention and therapy. In this Opinion article, we discuss recent reports that suggest unique and only partially understood mechanisms behind this paradox, including tumour repression, anti-angiogenic effects and stem cell ageing and availability.

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DYRK1A in Down syndrome: an oncogene or tumor suppressor?

Cited by 21 publications

References 23 publications

Low risk of solid tumors in persons with Down syndrome

Low risk of solid tumors in persons with Down syndrome

How I treat ALL in Down's syndrome: pathobiology and management

Tumorigenesis in Down's syndrome: big lessons from a small chromosome

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