A big challenge for cancer research is to find drugs and treatments that kill cancer cells without harming the other cells of a patient. Cancer cells contain genetic mutations that cause them to grow and divide more rapidly than healthy cells. About half a million cancer patients worldwide have tumors that feature mutations to the gene that produces a protein called STAG2, a component of a large protein ring called cohesin. These mutations are particularly common in bladder cancers and Ewing sarcoma, a childhood bone cancer.

The cohesin ring holds together duplicated chromosomes during cell division, establishing the iconic X-shape of chromosomes in dividing cells. It is not clear exactly how mutations that affect STAG2 make cancer more likely to develop. However, it is possible that these cancer-specific mutations make cancer cells vulnerable in ways that healthy cells are not.

Using a genetic screening approach, van der Lelij, Lieb et al. searched for genes whose inactivation would harm only those cells that have mutant STAG2 proteins. This search found that one such gene encodes a protein called STAG1, a close relative of STAG2. Reducing the amount of STAG1 protein in cells with mutant forms for STAG2 caused these cells to start dying, whereas healthy cells were unaffected.

Van der Lelij, Lieb et al. then conducted biochemical and cell biological experiments on bladder cancer and Ewing sarcoma cells to show that the cells need at least one of STAG1 or STAG2 to hold replicated chromosomes together. Without either protein, the X-shape of the chromosomes was lost and the cells died when they tried to divide.

Thus, human cells can survive without STAG1 or STAG2 but not without both, a concept known as synthetic lethality. More research is now needed to identify how the STAG1 protein could be prevented from working. This knowledge could ultimately be used to develop drugs that would kill off only those cancer cells that have mutations that affect STAG2.

Cohesin is a highly conserved ring-shaped protein complex that is thought to topologically embrace chromatid fibers (Peters and Nishiyama, 2012), which is essential for sister chromatid cohesion and chromosome segregation in eukaryotes. In addition, cohesin participates in DNA repair, genome organization and gene expression (Losada, 2014). The cohesin subunits SMC1, SMC3 and RAD21 (also called SCC1) comprise the core ring of the complex. A fourth universally conserved subunit, a HEAT repeat protein of the Scc3/STAG family, peripherally associates with the core cohesin ring by binding to RAD21 (Tóth et al., 1999), and is required for the dynamic association of cohesin with chromatin (Hu et al., 2011; Murayama and Uhlmann, 2014). Human somatic cells express two paralogs of this protein, called STAG1 and STAG2 (Losada et al., 2000; Sumara et al., 2000).

Recent cancer genome studies identified recurrent mutations in cohesin subunits and regulators in approximately 7.3% of all human cancers (Lawrence et al., 2014; Leiserson et al., 2015; Solomon et al., 2011). STAG2, the most frequently mutated cohesin subunit, emerges as one of only 12 genes that are significantly mutated in four or more major human malignancies (Lawrence et al., 2014). STAG2 mutations have been reported in ~6% of acute myeloid leukemias and myelodysplastic syndromes (Kon et al., 2013; Thota et al., 2014; Walter et al., 2012), 15–22% of Ewing’s sarcomas (Brohl et al., 2014; Crompton et al., 2014; Tirode et al., 2014), and in up to 26% of bladder cancers of various stages and grades (Balbás-Martínez et al., 2013; Guo et al., 2013; Solomon et al., 2013; Taylor et al., 2014). The deleterious nature of most STAG2 mutations strongly suggests that the gene represents a new tumor suppressor (Hill et al., 2016). STAG2 mutations were initially thought to promote tumorigenesis due to defects in sister chromatid cohesin leading to genome instability (Barber et al., 2008; Solomon et al., 2011). However, the vast majority of cohesin-mutated cancers are euploid (Balbás-Martínez et al., 2013; Kon et al., 2013), indicating that cohesin mutations may promote tumorigenesis through altering different cohesin functions such as genome organization and transcriptional regulation (Galeev et al., 2016; Mazumdar et al., 2015; Mullenders et al., 2015; Viny et al., 2015). Regardless of the mechanisms driving cohesin mutant tumors, the recent success of poly(ADP-ribose) polymerase inhibitors in the treatment of BRCA-mutated ovarian and prostate cancer demonstrates that exploiting tumor suppressor loss by applying the concept of synthetic lethality in defined patient populations can impact clinical cancer care (Castro et al., 2016; Kim et al., 2015; Mirza et al., 2016; Oza et al., 2015). The estimated half a million individuals with STAG2-mutant malignancies would greatly profit from exploring specific dependencies of these cancers.

We hypothesized that STAG2 loss could alter the properties and function of the cohesin complex leading to unique vulnerabilities of STAG2 mutated cells. To identify factors whose inactivation would be synthetic lethal with loss of STAG2 function, we first used CRISPR/Cas9 to inactivate STAG2 in near-diploid, chromosomally stable HCT 116 colon carcinoma cells (Figure 1A). Two clones, STAG2- 505c1 and 502c4, harboring deleterious mutations in STAG2 and lacking detectable STAG2 protein expression were selected for analyses (Figure 1—figure supplement 1 and Supplementary file 1). The isogenic parental and STAG2- HCT 116 cells were transfected with short-interfering RNA (siRNA) duplexes targeting 25 known cohesin subunits and regulators. After normalization to the non-target control siRNA (NTC), the effects of siRNA duplexes targeting individual genes were compared in parental and STAG2- cells. Depletion of the known essential cohesin regulator SGOL1 had a detrimental impact on viability of both parental and STAG2- cells. Remarkably, depletion of STAG1 strongly decreased cell viability in STAG2- cells, while being tolerated by the isogenic parental cells (Figure 1B). The pronounced selective effect of STAG1 depletion on STAG2- cells was confirmed in individual transfection experiments and colony formation assays (Figure 1C,D,E). Expression of an siRNA-resistant STAG1 transgene alleviated the anti-proliferative effect of STAG1 but not of SGOL1 siRNA duplexes in STAG2- HCT 116 cells demonstrating the specificity of the siRNA treatment (Figure 1—figure supplement 2). Double depletion of STAG1 and STAG2 by siRNA in parental cells confirmed their synthetic lethal interaction (Figure 1—figure supplement 3). Co-depletion of p53 and STAG1 indicated that the dependency of STAG2- cells on STAG1 was independent of p53 (Figure 1—figure supplement 4). In contrast to the loss of essential cohesin subunits or regulators, depletion of STAG1 had no effect on cell viability in non-transformed telomerase-immortalized human retinal pigment epithelial cells (hTERT RPE-1) (Figure 1—figure supplement 5). This result is supported by a large-scale genetic loss-of-function study that found that neither STAG1 nor STAG2 is essential for the proliferation of hTERT-RPE1 cells (Hart et al., 2015). To corroborate our genetic interaction findings using an independent strategy, we introduced Cas9 into parental and STAG2- HCT 116 cells as well as KBM-7 leukemia cells for competition assays (Figure 1F and Figure 1—figure supplement 1). Transduction of lentiviruses co-expressing mCherry and single guide RNAs (sgRNAs) targeting essential cohesin subunit genes, such as RAD21 and SMC3, resulted in the rapid loss of the infected and mCherry-positive cells from the population irrespective of STAG2 genotype (Figure 1F). In striking contrast, transduction with sgRNAs targeting STAG1 caused the depletion of STAG2- HCT 116 and KBM-7 cells but not of their parental STAG2 proficient counterparts (Figure 1F). Collectively, these experiments identify STAG1 as a vulnerability of STAG2 mutated cells in engineered solid cancer and leukemia models. STAG1 inactivation has little if any impact on the viability and proliferation of STAG2 wild-type cancer cells and non-transformed cells, but is essential for survival in the absence of STAG2.

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To elucidate the mechanistic basis for this synthetic lethal interaction, we hypothesized that the combined loss of STAG1 and STAG2, in contrast to loss of either component alone, could severely impair cell division. Chromosome alignment and segregation during mitosis rely on sister chromatid cohesion, the central function of the cohesin complex (Peters and Nishiyama, 2012). Depletion of STAG1 resulted in an increase in the mitotic index and a prolongation of the duration of mitosis in STAG2- but not wild-type cells (Figure 2A and Figure 2—figure supplement 1). Immunofluorescence microscopy revealed a failure to align chromosomes at the metaphase plate upon STAG1 loss in STAG2- cells (Figure 2B). In mitotic chromosome spread analysis STAG2 inactivation caused a partial loss of centromeric cohesion in HCT 116 cells as previously reported (Canudas and Smith, 2009; Kim et al., 2016; Remeseiro et al., 2012; Solomon et al., 2011) (Figure 2C). Depletion of the essential centromeric cohesin protection factor SGOL1 resulted in a complete loss of sister chromatid cohesion in most chromosome spreads irrespective of STAG2 genotype. In striking contrast, STAG1 depletion selectively abrogated sister chromatid cohesion in STAG2- but not parental cells (Figure 2C, single chromatids). The severe mitotic defects observed upon loss of STAG1 in STAG2- cells were accompanied by the emergence of aberrantly sized and shaped interphase nuclei (Figure 2—figure supplement 2) and by a progressive increase in apoptosis (Figure 2D). These results provide a mechanistic basis for the synthetic lethal interaction between STAG1 and STAG2. STAG1 inactivation abrogates sister chromatid cohesion exclusively in STAG2- cells resulting in catastrophic mitotic failure, abnormal cell division and apoptosis. To hold sister chromatids together, cohesin can tolerate the loss of either STAG1 or STAG2 alone but not the loss of both.

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We next expanded our analysis to patient-derived STAG2 mutations and STAG2-mutant cancer cell lines in order to investigate the disease relevance of the observed synthetic lethality (Figure 3). STAG1 depletion by siRNA abrogated both cell viability and sister chromatid cohesion in HCT 116 cell clones, in which three patient-derived deleterious mutations had been engineered into the STAG2 locus (Kim et al., 2016), but not in parental HCT 116 cells (Figure 3—figure supplement 1). Among solid human cancers, STAG2 mutational inactivation is most prevalent in urothelial bladder cancer and Ewing sarcoma. Therefore, we assembled a panel of 16 bladder cancer cell lines: 11 STAG2-positive, three with deleterious STAG2 mutations (UM-UC-3, UM-UC-6 and VM-CUB-3), one in which STAG2 was inactivated by CRISPR/Cas9 (UM-UC-5 STAG2- 505c6) (Figure 3—figure supplement 2), and two with no detectable STAG2 expression (LGWO1 and MGH-U3) (Supplementary file 2) (Balbás-Martínez et al., 2013; Solomon et al., 2013). The STAG2 protein expression status in the panel of bladder cancer cell lines was confirmed using immunoblotting (Figure 3A). siRNA experiments revealed that STAG2 status represented a predictive marker for the sensitivity to STAG1 depletion across the bladder cancer cell line panel. Whereas all cell lines were highly sensitive to depletion of the key mitotic kinase PLK1, STAG1 siRNA reduced cell viability in STAG2-negative bladder cancer cells but had little or no effect on STAG2-positive bladder cancer cell lines (Figure 3B). STAG1 depletion prevented colony formation and abolished sister chromatid cohesion selectively in STAG2 mutated UM-UC-3 (F983fs) but not in STAG2 wild-type UM-UC-5 bladder cancer cells (Figure 3C,D). In contrast, SGOL1 depletion abrogated cell growth and cohesion in both cell lines. Consistent with the results obtained in bladder cancer cells, STAG2 mutation status was also linked to STAG1 dependency in a panel of four Ewing sarcoma cell lines (Figure 3E,F and Supplementary file 2) (Solomon et al., 2011; Tirode et al., 2014). Lentiviral transduction of a FLAG-STAG2 transgene into STAG2 mutated UM-UC-3 bladder cancer cells resulted in the restoration of STAG2 expression, nuclear localization of the transgenic protein and its incorporation into the cohesin complex (Figure 3—figure supplement 3). Crucially, restoration of STAG2 expression alleviated the STAG1 dependency of UM-UC-3 cells providing a causal link between STAG2 loss and STAG1 dependency (Figure 3G). These results demonstrate that the synthetic lethal interaction between STAG1 and STAG2 that we discovered in isogenic cell pairs is recapitulated in disease-relevant bladder cancer and Ewing sarcoma cell models.

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Here we identify STAG1 as a strong genetic vulnerability of cells lacking the major emerging tumor suppressor STAG2 (Figure 4). The paralog dependency between STAG1 and STAG2 has recently also been reported in an independent study (Benedetti et al., 2017). We show that the synthetic lethal interaction between STAG1 and STAG2 is observed in isogenic HCT 116 and KBM-7 cells as well as in bladder cancer and Ewing sarcoma cell lines. Thus, the genetic interaction between STAG paralogs is conserved in three major human malignancies: carcinoma, leukemia and sarcoma. Importantly, the finding that cancer cells harboring deleterious STAG2 mutations remain exquisitely dependent on STAG1 demonstrates that this genetic vulnerability is maintained throughout the process of carcinogenesis and not bypassed by adaptive processes, such as the transcriptional activation of the germline-specific paralog STAG3 (Pezzi et al., 2000; Prieto et al., 2001). Furthermore, expression analysis did not reveal upregulation of STAG1 protein or mRNA as a major compensatory mechanism for the loss of STAG2 function in cancer cell lines or patient tumors (Figure 4—figure supplement 1).

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Our experiments strongly suggest that the loss of sister chromatid cohesion followed by aberrant cell division and cell death is the mechanistic basis underlying the synthetic lethality between STAG1 and STAG2 (Figure 4). Both paralogs associate with the cohesin complex in a mutually exclusive manner (Losada et al., 2000; Sumara et al., 2000). Although STAG1 and STAG2 may confer distinct functionalities to the cohesin complex (Canudas and Smith, 2009; Remeseiro et al., 2012), STAG1 and STAG2 containing complexes act redundantly to ensure sufficient sister chromatid cohesion to support cell division in human somatic cells. While the loss of one paralog is compatible with cell viability and proliferation, the loss of both paralogs abrogates cohesin’s ability to hold sister chromatids together, which results in lethality. These mechanistic findings are consistent with previous studies that employed double siRNA depletion experiments to indicate functional redundancy between STAG1 and STAG2 in maintaining sister chromatid cohesion (Canudas and Smith, 2009; Hara et al., 2014; Remeseiro et al., 2012).

Since STAG1 inactivation has little or no effect on the proliferation of STAG2 proficient cells, selective targeting of STAG1 could offer a large therapeutic window. The fact that STAG2 mRNA is expressed in all normal human tissues analyzed (Figure 4—figure supplement 2) supports the hypothesis that selective inhibition of STAG1 function would indeed spare most non-cancerous tissues. Potential approaches for therapeutic targeting of STAG1 include the inhibition of the interaction between STAG1 and the cohesin ring subunit RAD21 (Hara et al., 2014) and the selective degradation of STAG1 using proteolysis-targeting chimera (PROTAC) technology (Deshaies, 2015). The high degree of homology between the STAG1 and its paralog STAG2 will be a key challenge to overcome. The mechanisms by which mutations in STAG2 and other cohesin subunits drive tumorigenesis in solid and hematological tissues are not yet firmly established. Our work highlights the fact that such knowledge is not a prerequisite for the identification of selective vulnerabilities.

Both deleterious STAG2 mutations and the loss of STAG2 expression are strong predictive biomarkers for STAG1 dependence in cell models and could be utilized for patient stratification in the future. Our work demonstrates that unique genetic dependencies of cohesin mutated cancer cells exist. Such vulnerabilities hold the promise for the development of selective treatments for patients suffering from STAG2 mutated cancer.

1. 1. Cerami E
   2. Gao J
   3. Dogrusoz U
   4. Gross BE
   5. Sumer SO
   6. Aksoy BA
   7. Jacobsen A
   8. Byrne CJ
   9. Heuer ML
   10. Larsson E
   11. Antipin Y
   12. Reva B
   13. Goldberg AP
   14. Sander C
   15. Schultz N

   (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data

   Publicly available via the cBioPortal GitHub (https://github.com/cBioPortal).

   https://github.com/cBioPortal/datahub/tree/master/public
2. 1. Vivian J
   2. Rao AA
   3. Nothaft FA
   4. Ketchum C
   5. Armstrong J
   6. Novak A
   7. Pfeil J
   8. Narkizian J
   9. Deran AD
   10. Musselman-Brown A
   11. Schmidt H
   12. Amstutz P
   13. Craft B
   14. Goldman M
   15. Rosenbloom K
   16. Cline M
   17. O'Connor B
   18. Hanna M
   19. Birger C
   20. Kent WJ
   21. Patterson DA
   22. Joseph AD
   23. Zhu J
   24. Zaranek S
   25. Getz G
   26. Haussler D
   27. Paten B

   (2017) Toil enables reproducible, open source, big biomedical data analyses

   Publicly available via the UCSC Xena data hub (http://xena.ucsc.edu/).

   https://xenabrowser.net/datapages/?dataset=TcgaTargetGtex_rsem_gene_tpm&host=https://toil.xenahubs.net

1. 1. Balbás-Martínez C
   2. Sagrera A
   3. Carrillo-de-Santa-Pau E
   4. Earl J
   5. Márquez M
   6. Vazquez M
   7. Lapi E
   8. Castro-Giner F
   9. Beltran S
   10. Bayés M
   11. Carrato A
   12. Cigudosa JC
   13. Domínguez O
   14. Gut M
   15. Herranz J
   16. Juanpere N
   17. Kogevinas M
   18. Langa X
   19. López-Knowles E
   20. Lorente JA
   21. Lloreta J
   22. Pisano DG
   23. Richart L
   24. Rico D
   25. Salgado RN
   26. Tardón A
   27. Chanock S
   28. Heath S
   29. Valencia A
   30. Losada A
   31. Gut I
   32. Malats N
   33. Real FX

   (2013) Recurrent inactivation of STAG2 in bladder Cancer is not associated with aneuploidy

   Nature Genetics 45:1464–1469.

   https://doi.org/10.1038/ng.2799

   • PubMed
   • Google Scholar
2. 1. Ban J
   2. Aryee DN
   3. Fourtouna A
   4. van der Ent W
   5. Kauer M
   6. Niedan S
   7. Machado I
   8. Rodriguez-Galindo C
   9. Tirado OM
   10. Schwentner R
   11. Picci P
   12. Flanagan AM
   13. Berg V
   14. Strauss SJ
   15. Scotlandi K
   16. Lawlor ER
   17. Snaar-Jagalska E
   18. Llombart-Bosch A
   19. Kovar H

   (2014) Suppression of deacetylase SIRT1 mediates tumor-suppressive NOTCH response and offers a novel treatment option in metastatic Ewing sarcoma

   Cancer Research 74:6578–6588.

   https://doi.org/10.1158/0008-5472.CAN-14-1736

   • PubMed
   • Google Scholar
3. 1. Barber TD
   2. McManus K
   3. Yuen KW
   4. Reis M
   5. Parmigiani G
   6. Shen D
   7. Barrett I
   8. Nouhi Y
   9. Spencer F
   10. Markowitz S
   11. Velculescu VE
   12. Kinzler KW
   13. Vogelstein B
   14. Lengauer C
   15. Hieter P

   (2008) Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers

   PNAS 105:3443–3448.

   https://doi.org/10.1073/pnas.0712384105

   • PubMed
   • Google Scholar
4. 1. Benedetti L
   2. Cereda M
   3. Monteverde L
   4. Desai N
   5. Ciccarelli FD

   (2017) Synthetic lethal interaction between the tumour suppressor STAG2 and its paralog STAG1

   Oncotarget 8:37619–37632.

   https://doi.org/10.18632/oncotarget.16838

   • PubMed
   • Google Scholar
5. 1. Brohl AS
   2. Solomon DA
   3. Chang W
   4. Wang J
   5. Song Y
   6. Sindiri S
   7. Patidar R
   8. Hurd L
   9. Chen L
   10. Shern JF
   11. Liao H
   12. Wen X
   13. Gerard J
   14. Kim JS
   15. Lopez Guerrero JA
   16. Machado I
   17. Wai DH
   18. Picci P
   19. Triche T
   20. Horvai AE
   21. Miettinen M
   22. Wei JS
   23. Catchpool D
   24. Llombart-Bosch A
   25. Waldman T
   26. Khan J

   (2014) The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation

   PLoS Genetics 10:e1004475.

   https://doi.org/10.1371/journal.pgen.1004475

   • PubMed
   • Google Scholar
6. 1. Brummelkamp TR
   2. Bernards R
   3. Agami R

   (2002) A system for stable expression of short interfering RNAs in mammalian cells

   Science 296:550–553.

   https://doi.org/10.1126/science.1068999

   • PubMed
   • Google Scholar
7. 1. Canudas S
   2. Smith S

   (2009) Differential regulation of telomere and centromere cohesion by the Scc3 homologues SA1 and SA2, Respectively, in human cells

   The Journal of Cell Biology 187:165–173.

   https://doi.org/10.1083/jcb.200903096

   • PubMed
   • Google Scholar
8. 1. Castro E
   2. Mateo J
   3. Olmos D
   4. de Bono JS

   (2016) Targeting DNA repair: the role of PARP inhibition in the treatment of Castration-Resistant prostate Cancer

   Cancer Journal 22:353–356.

   https://doi.org/10.1097/PPO.0000000000000219

   • PubMed
   • Google Scholar
9. 1. Cerami E
   2. Gao J
   3. Dogrusoz U
   4. Gross BE
   5. Sumer SO
   6. Aksoy BA
   7. Jacobsen A
   8. Byrne CJ
   9. Heuer ML
   10. Larsson E
   11. Antipin Y
   12. Reva B
   13. Goldberg AP
   14. Sander C
   15. Schultz N

   (2012) The cBio Cancer genomics portal: an open platform for exploring multidimensional Cancer genomics data

   Cancer Discovery 2:401–404.

   https://doi.org/10.1158/2159-8290.CD-12-0095

   • PubMed
   • Google Scholar
10. 1. Crompton BD
    2. Stewart C
    3. Taylor-Weiner A
    4. Alexe G
    5. Kurek KC
    6. Calicchio ML
    7. Kiezun A
    8. Carter SL
    9. Shukla SA
    10. Mehta SS
    11. Thorner AR
    12. de Torres C
    13. Lavarino C
    14. Suñol M
    15. McKenna A
    16. Sivachenko A
    17. Cibulskis K
    18. Lawrence MS
    19. Stojanov P
    20. Rosenberg M
    21. Ambrogio L
    22. Auclair D
    23. Seepo S
    24. Blumenstiel B
    25. DeFelice M
    26. Imaz-Rosshandler I
    27. Schwarz-Cruz Y Celis A
    28. Rivera MN
    29. Rodriguez-Galindo C
    30. Fleming MD
    31. Golub TR
    32. Getz G
    33. Mora J
    34. Stegmaier K

    (2014) The genomic landscape of pediatric Ewing sarcoma

    Cancer Discovery 4:1326–1341.

    https://doi.org/10.1158/2159-8290.CD-13-1037

    • PubMed
    • Google Scholar
11. 1. Deshaies RJ

    (2015) Protein degradation: prime time for PROTACs

    Nature Chemical Biology 11:634–635.

    https://doi.org/10.1038/nchembio.1887

    • PubMed
    • Google Scholar
12. 1. GTEx Consortium

    (2013) The Genotype-Tissue Expression (GTEx) project

    Nature Genetics 45:580–585.

    https://doi.org/10.1038/ng.2653

    • PubMed
    • Google Scholar
13. 1. Galeev R
    2. Baudet A
    3. Kumar P
    4. Rundberg Nilsson A
    5. Nilsson B
    6. Soneji S
    7. Törngren T
    8. Borg Å
    9. Kvist A
    10. Larsson J

    (2016) Genome-wide RNAi Screen identifies Cohesin genes as modifiers of renewal and differentiation in human HSCs

    Cell Reports 14:2988–3000.

    https://doi.org/10.1016/j.celrep.2016.02.082

    • PubMed
    • Google Scholar
14. 1. Gao J
    2. Aksoy BA
    3. Dogrusoz U
    4. Dresdner G
    5. Gross B
    6. Sumer SO
    7. Sun Y
    8. Jacobsen A
    9. Sinha R
    10. Larsson E
    11. Cerami E
    12. Sander C
    13. Schultz N

    (2013) Integrative analysis of complex Cancer genomics and clinical profiles using the cBioPortal

    Science Signaling 6:pl1.

    https://doi.org/10.1126/scisignal.2004088

    • PubMed
    • Google Scholar
15. 1. Guo G
    2. Sun X
    3. Chen C
    4. Wu S
    5. Huang P
    6. Li Z
    7. Dean M
    8. Huang Y
    9. Jia W
    10. Zhou Q
    11. Tang A
    12. Yang Z
    13. Li X
    14. Song P
    15. Zhao X
    16. Ye R
    17. Zhang S
    18. Lin Z
    19. Qi M
    20. Wan S
    21. Xie L
    22. Fan F
    23. Nickerson ML
    24. Zou X
    25. Hu X
    26. Xing L
    27. Lv Z
    28. Mei H
    29. Gao S
    30. Liang C
    31. Gao Z
    32. Lu J
    33. Yu Y
    34. Liu C
    35. Li L
    36. Fang X
    37. Jiang Z
    38. Yang J
    39. Li C
    40. Zhao X
    41. Chen J
    42. Zhang F
    43. Lai Y
    44. Lin Z
    45. Zhou F
    46. Chen H
    47. Chan HC
    48. Tsang S
    49. Theodorescu D
    50. Li Y
    51. Zhang X
    52. Wang J
    53. Yang H
    54. Gui Y
    55. Wang J
    56. Cai Z

    (2013) Whole-genome and whole-exome sequencing of bladder Cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation

    Nature Genetics 45:1459–1463.

    https://doi.org/10.1038/ng.2798

    • PubMed
    • Google Scholar
16. 1. Hara K
    2. Zheng G
    3. Qu Q
    4. Liu H
    5. Ouyang Z
    6. Chen Z
    7. Tomchick DR
    8. Yu H

    (2014) Structure of cohesin subcomplex pinpoints direct shugoshin-Wapl antagonism in centromeric cohesion

    Nature Structural & Molecular Biology 21:864–870.

    https://doi.org/10.1038/nsmb.2880

    • PubMed
    • Google Scholar
17. 1. Hart T
    2. Chandrashekhar M
    3. Aregger M
    4. Steinhart Z
    5. Brown KR
    6. MacLeod G
    7. Mis M
    8. Zimmermann M
    9. Fradet-Turcotte A
    10. Sun S
    11. Mero P
    12. Dirks P
    13. Sidhu S
    14. Roth FP
    15. Rissland OS
    16. Durocher D
    17. Angers S
    18. Moffat J

    (2015) High-Resolution CRISPR Screens Reveal Fitness genes and Genotype-Specific Cancer liabilities

    Cell 163:1515–1526.

    https://doi.org/10.1016/j.cell.2015.11.015

    • PubMed
    • Google Scholar
18. 1. Hill VK
    2. Kim JS
    3. Waldman T

    (2016) Cohesin mutations in human Cancer

    Biochimica Et Biophysica Acta (BBA) - Reviews on Cancer 1866:1–11.

    https://doi.org/10.1016/j.bbcan.2016.05.002

    • PubMed
    • Google Scholar
19. 1. Hu B
    2. Itoh T
    3. Mishra A
    4. Katoh Y
    5. Chan KL
    6. Upcher W
    7. Godlee C
    8. Roig MB
    9. Shirahige K
    10. Nasmyth K

    (2011) ATP hydrolysis is required for relocating cohesin from sites occupied by its Scc2/4 loading complex

    Current Biology 21:12–24.

    https://doi.org/10.1016/j.cub.2010.12.004

    • PubMed
    • Google Scholar
20. 1. Kim G
    2. Ison G
    3. McKee AE
    4. Zhang H
    5. Tang S
    6. Gwise T
    7. Sridhara R
    8. Lee E
    9. Tzou A
    10. Philip R
    11. Chiu HJ
    12. Ricks TK
    13. Palmby T
    14. Russell AM
    15. Ladouceur G
    16. Pfuma E
    17. Li H
    18. Zhao L
    19. Liu Q
    20. Venugopal R
    21. Ibrahim A
    22. Pazdur R

    (2015) FDA Approval Summary: olaparib Monotherapy in patients with deleterious germline BRCA-Mutated Advanced ovarian Cancer treated with three or more lines of Chemotherapy

    Clinical Cancer Research 21:4257–4261.

    https://doi.org/10.1158/1078-0432.CCR-15-0887

    • PubMed
    • Google Scholar
21. 1. Kim JS
    2. He X
    3. Orr B
    4. Wutz G
    5. Hill V
    6. Peters JM
    7. Compton DA
    8. Waldman T

    (2016) Intact cohesion, Anaphase, and chromosome segregation in human cells harboring Tumor-Derived mutations in STAG2

    PLOS Genetics 12:e1005865.

    https://doi.org/10.1371/journal.pgen.1005865

    • PubMed
    • Google Scholar
22. 1. Kon A
    2. Shih LY
    3. Minamino M
    4. Sanada M
    5. Shiraishi Y
    6. Nagata Y
    7. Yoshida K
    8. Okuno Y
    9. Bando M
    10. Nakato R
    11. Ishikawa S
    12. Sato-Otsubo A
    13. Nagae G
    14. Nishimoto A
    15. Haferlach C
    16. Nowak D
    17. Sato Y
    18. Alpermann T
    19. Nagasaki M
    20. Shimamura T
    21. Tanaka H
    22. Chiba K
    23. Yamamoto R
    24. Yamaguchi T
    25. Otsu M
    26. Obara N
    27. Sakata-Yanagimoto M
    28. Nakamaki T
    29. Ishiyama K
    30. Nolte F
    31. Hofmann WK
    32. Miyawaki S
    33. Chiba S
    34. Mori H
    35. Nakauchi H
    36. Koeffler HP
    37. Aburatani H
    38. Haferlach T
    39. Shirahige K
    40. Miyano S
    41. Ogawa S

    (2013) Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms

    Nature Genetics 45:1232–1237.

    https://doi.org/10.1038/ng.2731

    • PubMed
    • Google Scholar
23. 1. Lawrence MS
    2. Stojanov P
    3. Mermel CH
    4. Robinson JT
    5. Garraway LA
    6. Golub TR
    7. Meyerson M
    8. Gabriel SB
    9. Lander ES
    10. Getz G

    (2014) Discovery and saturation analysis of Cancer genes across 21 tumour types

    Nature 505:495–501.

    https://doi.org/10.1038/nature12912

    • PubMed
    • Google Scholar
24. 1. Leiserson MD
    2. Vandin F
    3. Wu HT
    4. Dobson JR
    5. Eldridge JV
    6. Thomas JL
    7. Papoutsaki A
    8. Kim Y
    9. Niu B
    10. McLellan M
    11. Lawrence MS
    12. Gonzalez-Perez A
    13. Tamborero D
    14. Cheng Y
    15. Ryslik GA
    16. Lopez-Bigas N
    17. Getz G
    18. Ding L
    19. Raphael BJ

    (2015) Pan-cancer network analysis identifies combinations of rare somatic mutations across pathways and protein complexes

    Nature Genetics 47:106–114.

    https://doi.org/10.1038/ng.3168

    • PubMed
    • Google Scholar
25. 1. Losada A
    2. Yokochi T
    3. Kobayashi R
    4. Hirano T

    (2000) Identification and characterization of SA/Scc3p subunits in the xenopus and human cohesin complexes

    The Journal of Cell Biology 150:405–416.

    https://doi.org/10.1083/jcb.150.3.405

    • PubMed
    • Google Scholar
26. 1. Losada A

    (2014) Cohesin in Cancer: chromosome segregation and beyond

    Nature Reviews Cancer 14:389–393.

    https://doi.org/10.1038/nrc3743

    • PubMed
    • Google Scholar
27. 1. Mazumdar C
    2. Shen Y
    3. Xavy S
    4. Zhao F
    5. Reinisch A
    6. Li R
    7. Corces MR
    8. Flynn RA
    9. Buenrostro JD
    10. Chan SM
    11. Thomas D
    12. Koenig JL
    13. Hong WJ
    14. Chang HY
    15. Majeti R

    (2015) Leukemia-Associated Cohesin Mutants dominantly enforce stem cell programs and impair human hematopoietic progenitor differentiation

    Cell Stem Cell 17:675–688.

    https://doi.org/10.1016/j.stem.2015.09.017

    • PubMed
    • Google Scholar
28. 1. Mirza MR
    2. Monk BJ
    3. Herrstedt J
    4. Oza AM
    5. Mahner S
    6. Redondo A
    7. Fabbro M
    8. Ledermann JA
    9. Lorusso D
    10. Vergote I
    11. Ben-Baruch NE
    12. Marth C
    13. Mądry R
    14. Christensen RD
    15. Berek JS
    16. Dørum A
    17. Tinker AV
    18. du Bois A
    19. González-Martín A
    20. Follana P
    21. Benigno B
    22. Rosenberg P
    23. Gilbert L
    24. Rimel BJ
    25. Buscema J
    26. Balser JP
    27. Agarwal S
    28. Matulonis UA
    29. ENGOT-OV16/NOVA Investigators

    (2016) Niraparib Maintenance therapy in Platinum-Sensitive, recurrent ovarian Cancer

    New England Journal of Medicine 375:2154–2164.

    https://doi.org/10.1056/NEJMoa1611310

    • PubMed
    • Google Scholar
29. 1. Mullenders J
    2. Aranda-Orgilles B
    3. Lhoumaud P
    4. Keller M
    5. Pae J
    6. Wang K
    7. Kayembe C
    8. Rocha PP
    9. Raviram R
    10. Gong Y
    11. Premsrirut PK
    12. Tsirigos A
    13. Bonneau R
    14. Skok JA
    15. Cimmino L
    16. Hoehn D
    17. Aifantis I

    (2015) Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms

    The Journal of Experimental Medicine 212:1833–1850.

    https://doi.org/10.1084/jem.20151323

    • PubMed
    • Google Scholar
30. 1. Murayama Y
    2. Uhlmann F

    (2014) Biochemical reconstitution of topological DNA binding by the cohesin ring

    Nature 505:367–371.

    https://doi.org/10.1038/nature12867

    • PubMed
    • Google Scholar
31. 1. Oza AM
    2. Cibula D
    3. Benzaquen AO
    4. Poole C
    5. Mathijssen RH
    6. Sonke GS
    7. Colombo N
    8. Špaček J
    9. Vuylsteke P
    10. Hirte H
    11. Mahner S
    12. Plante M
    13. Schmalfeldt B
    14. Mackay H
    15. Rowbottom J
    16. Lowe ES
    17. Dougherty B
    18. Barrett JC
    19. Friedlander M

    (2015) Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian Cancer: a randomised phase 2 trial

    The Lancet Oncology 16:87–97.

    https://doi.org/10.1016/S1470-2045(14)71135-0

    • PubMed
    • Google Scholar
32. 1. Peters JM
    2. Nishiyama T

    (2012) Sister chromatid cohesion

    Cold Spring Harbor Perspectives in Biology 4:a011130.

    https://doi.org/10.1101/cshperspect.a011130

    • PubMed
    • Google Scholar
33. 1. Pezzi N
    2. Prieto I
    3. Kremer L
    4. Pérez Jurado LA
    5. Valero C
    6. Del Mazo J
    7. Martínez-A C
    8. Barbero JL

    (2000)

    STAG3, a novel gene encoding a protein involved in meiotic chromosome pairing and location of STAG3-related genes flanking the Williams-Beuren syndrome deletion

    FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology 14:581–592.

    • PubMed
    • Google Scholar
34. 1. Prieto I
    2. Suja JA
    3. Pezzi N
    4. Kremer L
    5. Martínez-A C
    6. Rufas JS
    7. Barbero JL

    (2001) Mammalian STAG3 is a cohesin specific to sister chromatid arms in meiosis I

    Nature Cell Biology 3:761–766.

    https://doi.org/10.1038/35087082

    • PubMed
    • Google Scholar
35. 1. Remeseiro S
    2. Cuadrado A
    3. Carretero M
    4. Martínez P
    5. Drosopoulos WC
    6. Cañamero M
    7. Schildkraut CL
    8. Blasco MA
    9. Losada A

    (2012) Cohesin-SA1 deficiency drives aneuploidy and tumourigenesis in mice due to impaired replication of telomeres

    The EMBO Journal 31:2076–2089.

    https://doi.org/10.1038/emboj.2012.11

    • PubMed
    • Google Scholar
36. 1. Solomon DA
    2. Kim T
    3. Diaz-Martinez LA
    4. Fair J
    5. Elkahloun AG
    6. Harris BT
    7. Toretsky JA
    8. Rosenberg SA
    9. Shukla N
    10. Ladanyi M
    11. Samuels Y
    12. James CD
    13. Yu H
    14. Kim JS
    15. Waldman T

    (2011) Mutational inactivation of STAG2 causes aneuploidy in human Cancer

    Science 333:1039–1043.

    https://doi.org/10.1126/science.1203619

    • PubMed
    • Google Scholar
37. 1. Solomon DA
    2. Kim JS
    3. Bondaruk J
    4. Shariat SF
    5. Wang ZF
    6. Elkahloun AG
    7. Ozawa T
    8. Gerard J
    9. Zhuang D
    10. Zhang S
    11. Navai N
    12. Siefker-Radtke A
    13. Phillips JJ
    14. Robinson BD
    15. Rubin MA
    16. Volkmer B
    17. Hautmann R
    18. Küfer R
    19. Hogendoorn PC
    20. Netto G
    21. Theodorescu D
    22. James CD
    23. Czerniak B
    24. Miettinen M
    25. Waldman T

    (2013) Frequent truncating mutations of STAG2 in bladder Cancer

    Nature Genetics 45:1428–1430.

    https://doi.org/10.1038/ng.2800

    • PubMed
    • Google Scholar
38. 1. Sumara I
    2. Vorlaufer E
    3. Gieffers C
    4. Peters BH
    5. Peters JM

    (2000) Characterization of vertebrate cohesin complexes and their regulation in prophase

    The Journal of Cell Biology 151:749–762.

    https://doi.org/10.1083/jcb.151.4.749

    • PubMed
    • Google Scholar
39. 1. Taylor CF
    2. Platt FM
    3. Hurst CD
    4. Thygesen HH
    5. Knowles MA

    (2014) Frequent inactivating mutations of STAG2 in bladder Cancer are associated with low tumour grade and stage and inversely related to chromosomal copy number changes

    Human Molecular Genetics 23:1964–1974.

    https://doi.org/10.1093/hmg/ddt589

    • PubMed
    • Google Scholar
40. 1. Thota S
    2. Viny AD
    3. Makishima H
    4. Spitzer B
    5. Radivoyevitch T
    6. Przychodzen B
    7. Sekeres MA
    8. Levine RL
    9. Maciejewski JP

    (2014) Genetic alterations of the cohesin complex genes in myeloid malignancies

    Blood 124:1790–1798.

    https://doi.org/10.1182/blood-2014-04-567057

    • PubMed
    • Google Scholar
41. 1. Tirode F
    2. Surdez D
    3. Ma X
    4. Parker M
    5. Le Deley MC
    6. Bahrami A
    7. Zhang Z
    8. Lapouble E
    9. Grossetête-Lalami S
    10. Rusch M
    11. Reynaud S
    12. Rio-Frio T
    13. Hedlund E
    14. Wu G
    15. Chen X
    16. Pierron G
    17. Oberlin O
    18. Zaidi S
    19. Lemmon G
    20. Gupta P
    21. Vadodaria B
    22. Easton J
    23. Gut M
    24. Ding L
    25. Mardis ER
    26. Wilson RK
    27. Shurtleff S
    28. Laurence V
    29. Michon J
    30. Marec-Bérard P
    31. Gut I
    32. Downing J
    33. Dyer M
    34. Zhang J
    35. Delattre O
    36. St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project and the International Cancer Genome Consortium

    (2014) Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations

    Cancer Discovery 4:1342–1353.

    https://doi.org/10.1158/2159-8290.CD-14-0622

    • PubMed
    • Google Scholar
42. 1. Tóth A
    2. Ciosk R
    3. Uhlmann F
    4. Galova M
    5. Schleiffer A
    6. Nasmyth K

    (1999) Yeast cohesin complex requires a conserved protein, Eco1p(Ctf7), to establish cohesion between sister chromatids during DNA replication

    Genes & Development 13:320–333.

    https://doi.org/10.1101/gad.13.3.320

    • PubMed
    • Google Scholar
43. 1. Viny AD
    2. Ott CJ
    3. Spitzer B
    4. Rivas M
    5. Meydan C
    6. Papalexi E
    7. Yelin D
    8. Shank K
    9. Reyes J
    10. Chiu A
    11. Romin Y
    12. Boyko V
    13. Thota S
    14. Maciejewski JP
    15. Melnick A
    16. Bradner JE
    17. Levine RL

    (2015) Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis

    The Journal of Experimental Medicine 212:1819–1832.

    https://doi.org/10.1084/jem.20151317

    • PubMed
    • Google Scholar
44. 1. Walter MJ
    2. Shen D
    3. Ding L
    4. Shao J
    5. Koboldt DC
    6. Chen K
    7. Larson DE
    8. McLellan MD
    9. Dooling D
    10. Abbott R
    11. Fulton R
    12. Magrini V
    13. Schmidt H
    14. Kalicki-Veizer J
    15. O'Laughlin M
    16. Fan X
    17. Grillot M
    18. Witowski S
    19. Heath S
    20. Frater JL
    21. Eades W
    22. Tomasson M
    23. Westervelt P
    24. DiPersio JF
    25. Link DC
    26. Mardis ER
    27. Ley TJ
    28. Wilson RK
    29. Graubert TA

    (2012) Clonal architecture of secondary acute myeloid leukemia

    New England Journal of Medicine 366:1090–1098.

    https://doi.org/10.1056/NEJMoa1106968

    • PubMed
    • Google Scholar

Author details

1. Petra van der Lelij

   Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria

   Contribution

   PvdL, Conceptualization, Resources, Supervision, Funding acquisition, Visualization, Methodology, Writing—original draft, Project administration, Writing—review and editing

   Contributed equally with

   Simone Lieb

   Competing interests

   No competing interests declared.

2. Simone Lieb

   Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria

   Contribution

   SL, Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing

   Contributed equally with

   Petra van der Lelij

   Competing interests

   SL: Simone Lieb is a full-time employee of Boehringer Ingelheim RCV

3. Julian Jude

   Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria

   Contribution

   JJ, Formal analysis, Investigation, Visualization, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared.

   "This ORCID iD identifies the author of this article:" 0000-0002-9091-9867

4. Gordana Wutz

   Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria

   Contribution

   GW, Investigation, Methodology

   Competing interests

   No competing interests declared.

5. Catarina P Santos

   1. Spanish National Cancer Research Centre, Madrid, Spain
   2. Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain

   Contribution

   CPS, Investigation, Methodology

   Competing interests

   No competing interests declared.

6. Katrina Falkenberg

   Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria

   Contribution

   KF, Investigation, Methodology

   Competing interests

   No competing interests declared.

7. Andreas Schlattl

   Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria

   Contribution

   AS, Investigation, Methodology

   Competing interests

   AS: Andreas Schlattl is a full-time employee of Boehringer Ingelheim RCV

8. Jozef Ban

   Children’s Cancer Research Institute, Vienna, Austria

   Contribution

   JB, Formal analysis, Investigation, Visualization, Methodology

   Competing interests

   No competing interests declared.

9. Raphaela Schwentner

   Children’s Cancer Research Institute, Vienna, Austria

   Contribution

   RS, Investigation, Methodology

   Competing interests

   No competing interests declared.

   "This ORCID iD identifies the author of this article:" 0000-0001-6839-0322

10. Thomas Hoffmann

    Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria

    Contribution

    TH, Investigation, Methodology

    Competing interests

    No competing interests declared.

11. Heinrich Kovar

    1. Children’s Cancer Research Institute, Vienna, Austria
    2. Department for Pediatrics, Medical University of Vienna, Vienna, Austria

    Contribution

    HK, Conceptualization, Methodology

    Competing interests

    No competing interests declared.

12. Francisco X Real

    1. Spanish National Cancer Research Centre, Madrid, Spain
    2. Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain
    3. Department de Ciències Experimentals I de la Salut, Universitat Pompeu Fabra, Barcelona, Spain

    Contribution

    FXR, Conceptualization, Resources, Supervision, Funding acquisition, Writing—review and editing

    Competing interests

    No competing interests declared.

13. Todd Waldman

    Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington DC, United States

    Contribution

    TW, Funding acquisition, Writing—review and editing

    Competing interests

    No competing interests declared.

14. Mark A Pearson

    Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria

    Contribution

    MAP, Resources, Funding acquisition, Writing—review and editing

    Competing interests

    MAP: Mark Pearson is a full-time employee of Boehringer Ingelheim RCV

15. Norbert Kraut

    Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria

    Contribution

    NK, Conceptualization, Resources, Writing—review and editing

    Competing interests

    NK: Norbert Kraut is a full-time employee of Boehringer Ingelheim RCV

16. Jan-Michael Peters

    Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria

    Contribution

    J-MP, Resources, Writing—review and editing

    Competing interests

    No competing interests declared.

17. Johannes Zuber

    Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria

    Contribution

    JZ, Conceptualization, Resources, Supervision, Funding acquisition, Writing—review and editing

    Competing interests

    No competing interests declared.

    "This ORCID iD identifies the author of this article:" 0000-0001-8810-6835

18. Mark Petronczki

    Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria

    Contribution

    MP, Conceptualization, Resources, Supervision, Funding acquisition, Methodology, Project administration, Writing—review and editing

    For correspondence

    mark_paul.petronczki@boehringer-ingelheim.com

    Competing interests

    MP: Mark Petronczki is a full-time employee of Boehringer Ingelheim RCV

    "This ORCID iD identifies the author of this article:" 0000-0003-0139-5692

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