Germline mutations in Dok1 do not predispose to chronic lymphocytic leukemia

Sellick, Gabrielle S.; Coleman, R. J.; Talaban, R; Fleischmann, Christina M.; Rudd, Matthew; Allinson, Ruth; Catovsky, Daniel; Houlston, Richard S.

doi:10.1016/j.leukres.2004.05.022

Cited by 5 publications

(5 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have reported that, consistent with its potential role as a tumour suppressor, DOK1 expression is altered in a series of Burkitt lymphoma cell lines and in chronic lymphocytic leukaemia (CLL) 11, 12. Moreover, we reported a frameshift mutation of the DOK1 gene in CLL,12 although DOK1 does not seem to play a major role in familial CLL cases 13. The suppressive effects of DOK1 appear to correlate with its subcellular localisation.…”

mentioning

confidence: 70%

“…DOK1 is also constitutively tyrosine phosphorylated in a number of other transformed cells,5–7 suggesting that this event may regulate its tumour suppression functions. DOK1 inhibits MAP kinase activity, and displays anti‐proliferative activities 8–14. Genetic disruption of DOK1 and its related member DOK2 in mice increases their susceptibility to leukaemia development 8, 9.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Inactivation of the putative suppressor gene DOK1 by promoter hypermethylation in primary human cancers

Saulnier¹,

Vaissière²,

Yue³

et al. 2011

Intl Journal of Cancer

View full text Add to dashboard Cite

The DOK1 gene is a putative tumour suppressor gene located on the human chromosome 2p13 which is frequently rearranged in leukemia and other human tumours. We previously reported that the DOK1 gene can be mutated and its expression down-regulated in human malignancies. However, the mechanism underlying DOK1 silencing remains largely unknown. We show here that unscheduled silencing of DOK1 expression through aberrant hypermethylation is a frequent event in a variety of human malignancies. DOK1 was found to be silenced in nine head and neck cancer (HNC) cell lines studied and DOK1 CpG hypermethylation correlated with loss of gene expression in these cells. DOK1 expression could be restored via demethylating treatment using 5-aza-2′deoxycytidine. In addition, transduction of cancer cell lines with DOK1 impaired their proliferation, consistent with the critical role of epigenetic silencing of DOK1 in the development and maintenance of malignant cells. We further observed that DOK1 hypermethylation occurs frequently in a variety of primary human neoplasm including solid tumours (93% in HNC, 81% in lung cancer) and hematopoietic malignancy (64% in Burkitt’s lymphoma). Control blood samples and exfoliated mouth epithelial cells from healthy individuals showed a low level of DOK1 methylation, suggesting that DOK1 hypermethylation is a tumour specific event. Finally, an inverse correlation was observed between the level of DOK1 gene methylation and its expression in tumour and adjacent non tumour tissues. Thus, hypermethylation of DOK1 is a potentially critical event in human carcinogenesis, and may be a potential cancer biomarker and an attractive target for epigenetic-based therapy.

show abstract

mentioning

confidence: 70%

mentioning

confidence: 99%

Inactivation of the putative suppressor gene DOK1 by promoter hypermethylation in primary human cancers

Saulnier¹,

Vaissière²,

Yue³

et al. 2011

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…For second chronic lymphoid leukaemia after prostate cancer, it is difficult to explain the increased risks for a concordant parental cancer history, as no germline mutation has been identified so far (Sellick et al , 2005). Another new finding was the increased risks for skin squamous cell carcinoma after prostate cancer, when the offspring had a parental history of prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Prostate cancer as a first and second cancer: effect of family history

et al. 2009

View full text Add to dashboard Cite

Background:Diagnosis with prostate cancer has been reported to increase the risk of subsequent tumours. However, specific data on individuals with a parental history are not available so far.Methods:On the basis of the nationwide Swedish Family-Cancer Database including 18,207 primary invasive prostate cancers, standardised incidence ratios (SIRs) were used to estimate the relative risks of subsequent tumours after prostate cancer in the general population and among individuals with a parental history of cancer.Results:A significantly increased SIR of colorectal cancer was found among prostate cancer patients with a parental history of colorectal cancer (2.26, 11 cases). The SIRs of parental concordant (same site) tumours after prostate cancer were also increased for urinary bladder cancer (4.42, 4 cases) and chronic lymphoid leukaemia (38.0, 2 cases).Conclusion:A higher than additive and multiplicative interaction was observed between the individual history of prostate cancer and parental history of colorectal and urinary bladder cancers, although the number of cases did not permit the rejection of any interaction model. The results suggest that the occurrence of second tumours, for example bladder after prostate or prostate after bladder tumours, is mostly related to shared genetic and non-genetic risk factors rather than treatment of first cancer.

show abstract

“…Although most changes were not concordant among family members, some were, or were present in multiple families; these included losses of Xp11.2–p21, 2p12–14 and 4q11–q21 [89]. Dok1 , a candidate gene at 2p13, is a suppressor of cell proliferation and B-cell signaling that has not been found to have pathogenic mutations in a follow-up study of 140 familial CLL patients [90]. The significance of these chromosomal loci, therefore, still remains to be determined.…”

Section: Genomic Alterations In Cllmentioning

confidence: 99%

Inherited predisposition to chronic lymphocytic leukemia

Brown¹

2008

Expert Review of Hematology

View full text Add to dashboard Cite

Inherited susceptibility to chronic lymphocytic leukemia (CLL) has been recognized for decades. Approximately 10% of individuals with CLL report a family history of CLL or a related lymphoproliferative disorder, and genetic predisposition is the best understood risk factor for CLL. Studies of familial CLL have suggested that the disease features are largely similar to sporadic CLL, although recent data suggest that familial CLL may more commonly show somatic hypermutation of the immunoglobulin heavy-chain variable region, suggesting a more indolent disease course. Monoclonal B-cell lymphocytosis (MBL) has been identified recently as a likely precursor to CLL; it is found in the general population with increasing age and enriched in unaffected relatives of individuals with familial CLL. Studies of MBL as well as mouse models of CLL may lead to better understanding of early CLL pathogenesis that is relevant to familial predisposition. To date, the identification of genes that predispose to familial CLL has been slow, primarily due to the relatively few families available for study, the small size of those families and disease causation most likely by multiple genes that each confer smaller risks. In the coming years, the application of systematic genomics approaches to familial CLL should, hopefully, lead to the identification of novel loci involved in the disease.

show abstract

Germline mutations in Dok1 do not predispose to chronic lymphocytic leukemia

Cited by 5 publications

References 7 publications

Inactivation of the putative suppressor gene DOK1 by promoter hypermethylation in primary human cancers

Inactivation of the putative suppressor gene DOK1 by promoter hypermethylation in primary human cancers

Prostate cancer as a first and second cancer: effect of family history

Inherited predisposition to chronic lymphocytic leukemia

Contact Info

Product

Resources

About