The chromosome 22q11.2 region is susceptible to rearrangements, mediated by low copy repeats (LCR22s). Deletions and duplications are mediated by homologous recombination events between LCR22s. The recurrent balanced constitutional translocation t(11;22)(q23;q11) breakpoint occurs in an LCR22 and is mediated by double strand breaks in AT-rich palindromes on both chromosomes 11 and 22. Recently, two cases of a t(17;22)(q11;q11) were reported, mediated by a similar mechanism (21). Except for these constitutional translocations, the molecular basis for non-recurrent, reciprocal 22q11.2 translocations is not known. To determine whether there are specific mechanisms that could mediate translocations, we analyzed cell lines derived from 14 different individuals by genotyping and FISH mapping. Somatic cell hybrid analysis was carried out for four cell lines. In five cell lines, the translocation breakpoints occurred in the same LCR22 as for the t(11;22) translocation, suggesting that similar molecular mechanisms are responsible. An additional three occurred in other LCR22s, and six were in non-LCR22 regions, mostly in the proximal half of the 22q11.2 region. The translocation breakpoints on the partner chromosomes were all located in the telomeric bands, proximal to the most telomeric unique sequence probe, in eight cell lines and distal to those loci in six. Therefore, several of the breakpoints were found to occur in the vicinity of highly dynamic regions of the genome, 22q11.2 and telomeric bands. We hypothesize that these regions are more susceptible to breakage and repair, resulting in translocations.
Background
Malignant mesothelioma (MM) is a diagnostically challenging entity in cytology specimens due to the lack of architectural context and a cytomorphologic overlap between malignant and reactive mesothelial cells (RMCs). A diagnostic marker with excellent specificity is not currently available in clinical practice. The newly appreciated BRCA1‐associated protein 1 (BAP1) antibody may help distinguish MM from RMC based on its immunohistochemical (IHC) staining pattern but its role in cytopathology is controversial.
Methods
Immunohistochemistry with BAP1 antibody was performed on cell blocks from 39 cytology specimens including 13 cases of RMC and 26 cases of effusion and fine‐needle aspiration specimens (FNAC) with tissue‐specimen‐proven MM. Cases were dichotomised into positive and negative cohorts. Positivity was defined as >50% loss of nuclear BAP1 IHC staining.
Results
Of the 26 MM cases, a slight majority (14/26, 54%) showed loss of BAP1 nuclear IHC staining, while all 13 RMC controls showed strong nuclear BAP1 IHC staining. MM was more likely to show loss of BAP1 than RMC (P < .001); and peritoneal MM was more likely to demonstrate loss of BAP1 than pleural MM (P = .04). There was perfect specificity at 1.0 and positive predictive value of 1.0 for loss of nuclear BAP1 IHC staining. However, only modest sensitivity at 0.52 and negative predictive value of 0.50 was seen.
Conclusion
These data confirm that absence of BAP1 nuclear staining identifies malignant mesothelial cells. On the other hand, positive BAP1 nuclear staining can occur in both benign and malignant pleural effusions.
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