Frequent truncating mutations of STAG2 in bladder cancer

Solomon, David A.; Kim, Jung-Sik; Bondaruk, Jolanta; Shariat, Shahrokh F.; Wang, Zeng Feng; Elkahloun, Abdel G.; Ozawa, Tomoko; Gerard, Julia; Zhuang, Dazhong; Zhang, Shizhen; Navai, Neema; Siefker-Radtke, Arlene; Phillips, Joanna J.; Robinson, Brian D.; Rubin, Mark A.; Volkmer, Björn; Hautmann, Richard E.; Küfer, R.; Hogendoorn, Pancras C.W.; Netto, George J.; Theodorescu, Dan; James, C. David; Czerniak, Bogdan; Miettinen, Markku; Waldman, Todd

doi:10.1038/ng.2800

Cited by 175 publications

(156 citation statements)

References 13 publications

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“…Such trends will undoubtedly continue in the years to come. It will also be important to determine to what extent mutations or misregulation of cohesin and condensin subunits might contribute to human cancers (Ham et al 2007;Balbás-Martínez et al 2013;Guo et al 2013;Kon et al 2013;Solomon et al 2013). Third, and, finally, all issues described above need to be addressed, also, from an evolutionary point of view.…”

Section: Resultsmentioning

confidence: 99%

Chromosome Dynamics during Mitosis

Hirano

2015

Cold Spring Harb Perspect Biol

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The primary goal of mitosis is to partition duplicated chromosomes into daughter cells. Eukaryotic chromosomes are equipped with two distinct classes of intrinsic machineries, cohesin and condensins, that ensure their faithful segregation during mitosis. Cohesin holds sister chromatids together immediately after their synthesis during S phase until the establishment of bipolar attachments to the mitotic spindle in metaphase. Condensins, on the other hand, attempt to "resolve" sister chromatids by counteracting cohesin. The products of the balancing acts of cohesin and condensins are metaphase chromosomes, in which two rod-shaped chromatids are connected primarily at the centromere. In anaphase, this connection is released by the action of separase that proteolytically cleaves the remaining population of cohesin. Recent studies uncover how this series of events might be mechanistically coupled with each other and intricately regulated by a number of regulatory factors.

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Section: Resultsmentioning

confidence: 99%

Chromosome Dynamics during Mitosis

Hirano

2015

Cold Spring Harb Perspect Biol

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“…Mutations in cohesion genes could therefore lead to CIN by different mechanisms: mis-segregation of chromosomes followed by aneuploidy due to partial or total loss of cohesion or as a consequence of impaired DNA repair as well as altered gene expression. Recently, in several studies, alterations in sister chromatid cohesion genes were identified in a variety of cancers (27,(43)(44)(45)(46). In particular, inactivating alterations in STAG2 have been frequently found.…”

Section: Discussionmentioning

confidence: 99%

Defects in the Fanconi Anemia Pathway and Chromatid Cohesion in Head and Neck Cancer

et al. 2015

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Failure to repair DNA damage or defective sister chromatid cohesion, a process essential for correct chromosome segregation, can be causative of chromosomal instability (CIN), which is a hallmark of many types of cancers. We investigated how frequent this occurs in head and neck squamous cell carcinoma (HNSCC) and whether specific mechanisms or genes could be linked to these phenotypes. The genomic instability syndrome Fanconi anemia is caused by mutations in any of at least 16 genes regulating DNA interstrand crosslink (ICL) repair. Since patients with Fanconi anemia have a high risk to develop HNSCC, we investigated whether and to which extent Fanconi anemia pathway inactivation underlies CIN in HNSCC of non-Fanconi anemia individuals. We observed ICL-induced chromosomal breakage in 9 of 17 (53%) HNSCC cell lines derived from patients without Fanconi anemia. In addition, defective sister chromatid cohesion was observed in five HNSCC cell lines. Inactivation of FANCM was responsible for chromosomal breakage in one cell line, whereas in two other cell lines, somatic mutations in PDS5A or STAG2 resulted in inadequate sister chromatid cohesion. In addition, FANCF methylation was found in one cell line by screening an additional panel of 39 HNSCC cell lines. Our data demonstrate that CIN in terms of ICL-induced chromosomal breakage and defective chromatid cohesion is frequently observed in HNSCC. Inactivation of known Fanconi anemia and chromatid cohesion genes does explain CIN in the minority of cases. These findings point to phenotypes that may be highly relevant in treatment response of HNSCC. Cancer Res; 75(17); 3543-53. Ó2015 AACR.

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“…Notably recurrent mutations have been observed in acute myeloid leukemia (AML) cases de novo AML and AML with myelodysplasia-related changes (10-20%), down syndrome-associated acute megakaryoblastic leukemia (50% DS-AMKL), myelodysplastic syndromes (5-15%), and myeloproliferative neoplasms (MPNs; up to 10%), as classified according to the 2008 WHO classification for hematopoietic and lymphoid tissue (Ding et al, 2012;Cancer Genome Atlas Research Network, 2013;Kon et al, 2013;Nikolaev et al, 2013;Yoshida et al, 2013;Thol et al, 2014;Thota et al, 2014;Lindsley et al, 2015). In addition, somatic mutations have been found in a wide range of solid cancers like bladder cancer (20%) and Ewing's sarcoma (20%; Balbás-Martínez et al, 2013;Guo et al, 2013;Solomon et al, 2013;Crompton et al, 2014;Tirode et al, 2014). Besides the aforementioned somatic mutations, germline mutations of cohesin have been described in patients with developmental syndromes, particularly Cornelia de Lange syndrome (CdLS; Mannini et al, 2013).…”

Section: Cohesin Silencing Leads To Increased Replating Capacity In Vmentioning

confidence: 99%

Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms

Mullenders¹,

Aranda-Orgillés²,

Lhoumaud³

et al. 2015

J Cell Biol

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The cohesin complex (consisting of Rad21, Smc1a, Smc3, and Stag2 proteins) is critically important for proper sister chromatid separation during mitosis. Mutations in the cohesin complex were recently identified in a variety of human malignancies including acute myeloid leukemia (AML). To address the potential tumor-suppressive function of cohesin in vivo, we generated a series of shRNA mouse models in which endogenous cohesin can be silenced inducibly. Notably, silencing of cohesin complex members did not have a deleterious effect on cell viability. Furthermore, knockdown of cohesin led to gain of replating capacity of mouse hematopoietic progenitor cells. However, cohesin silencing in vivo rapidly altered stem cells homeostasis and myelopoiesis. Likewise, we found widespread changes in chromatin accessibility and expression of genes involved in myelomonocytic maturation and differentiation. Finally, aged cohesin knockdown mice developed a clinical picture closely resembling myeloproliferative disorders/neoplasms (MPNs), including varying degrees of extramedullary hematopoiesis (myeloid metaplasia) and splenomegaly. Our results represent the first successful demonstration of a tumor suppressor function for the cohesin complex, while also confirming that cohesin mutations occur as an early event in leukemogenesis, facilitating the potential development of a myeloid malignancy.

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Frequent truncating mutations of STAG2 in bladder cancer

Cited by 175 publications

References 13 publications

Chromosome Dynamics during Mitosis

Chromosome Dynamics during Mitosis

Defects in the Fanconi Anemia Pathway and Chromatid Cohesion in Head and Neck Cancer

Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms

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