Credit: Lara Crow/NPG

Sister chromatid cohesion, which is regulated by the cohesin complex, is crucial for the appropriate segregation of chromosomes, and disruption of this process can lead to aneuploidy. Stromal antigen 2 (STAG2) is a cohesin component, and inactivating mutations in STAG2 have been reported in several cancer types. However, whether STAG2 loss results in aneuploidy is the subject of some debate. Using different approaches, three papers have now shown that recurring deleterious mutations in STAG2, as well as in other components of sister chromatid cohesion and segregation, occur in urothelial bladder cancer (UBC), but whether STAG2 loss causes aneuploidy is still unclear.

whether STAG2 loss causes aneuploidy is still unclear

Balbás-Martínez et al. carried out whole-exome sequencing (n = 17) and further mutation prevalence screening (n = 60) of UBCs of non-aggressive stage Ta and higher, and Guo et al. carried out whole-exome sequencing of 99 UBCs of predominantly stage T1 and higher. Both groups identified frequent inactivating mutations in STAG2. Solomon et al. also discovered STAG2 mutations using a different method: they analysed STAG2 expression in 2,214 different tumour types by immunohistochemistry and found that 52 of 295 UBCs did not express STAG2. Subsequent sequencing of STAG2 in 111 UBCs of various stages revealed a high prevalence of truncating mutations. Balbás-Martínez et al. and Guo et al. also identified frequent mutations and additional alterations in several other genes involved in cohesion and segregation.

Does STAG2 loss affect aneuploidy? Guo et al. found that the UBCs that had alterations in cohesion and segregation genes (including STAG2) in their data set had significantly higher aneuploidy than tumours without these alterations, as estimated using a chromosome instability score that was derived from copy number alterations. Similarly, using molecular cytogenetic analyses, Solomon et al. found that nine of 12 STAG2-mutant UBCs of various stages were aneuploid, although 10 of 12 UBCs with wild-type STAG2 were also aneuploid. Such findings indicate that the alterations of other genes and pathways are probably involved in aneuploidy, although this group did not analyse this further. Furthermore, the knockdown of STAG2 in RT4 UBC cells altered the modal chromosome number. However, Balbás-Martínez et al. reported data that somewhat conflicted with those of the other two papers. They observed that STAG2 loss was significantly associated with tumours of lower stage and lower grade. Using single nucleotide polymorphism and bacterial artificial chromosome arrays, they analysed chromosome numbers in 11 Ta-stage tumours that lacked STAG2 expression and found that nine were not aneuploid and that two had a loss of one chromosome; similar data were observed in 12 tumours that expressed STAG2. Furthermore, when these authors knocked down STAG2 in three different UBC cell lines (639V, RT112 and UM-UC-11 cells), they observed no effect on chromosome numbers.

Do STAG2 mutations correlate with prognosis in UBC? Guo et al. found that patients in their data set with STAG2-mutant UBC had a worse prognosis than patients whose tumours contained wild-type STAG2. Solomon et al. also found a similar association between the loss of STAG2 expression and indicators of poor prognosis in muscle-invasive UBCs, but they did not find this in non-muscle-invasive tumours — in these tumours, STAG2 loss was associated with increased disease-free survival. Similarly, Balbás-Martínez et al. found that the loss of STAG2 expression was associated with better prognosis in non-muscle-invasive UBCs, but in their data set, loss of STAG2 expression also indicated a better prognosis for patients with muscle-invasive UBCs. Differences in the patient populations that were analysed might account for the difference in these findings.

Although these data suggest that mutations in STAG2 and in other genes that are involved in cohesion and segregation are selected for in UBC, much remains to be determined about the biological effects of these mutations at different tumour stages and their links to patient prognosis.