Clinical significance of immunohistochemistry for detection of BAP1 mutations in uveal melanoma

Anna Koopmans, Rob Verdijk, Rutger Brouwer, Thierry van den Bosch, MMP van den Berg, Jolanda Vaarwater, Christel Kockx, D Paridaens, Nicole Naus, Mark Nellist, Wilfred van Ijcken, Emine Kiliç, Annelies de Klein

Research output: Contribution to journalArticleAcademicpeer-review

169 Citations (Scopus)


Uveal melanoma is a lethal cancer with a strong propensity to metastasize. Limited therapeutic options are available once the disease has disseminated. A strong predictor for metastasis is the loss of chromosome 3. Inactivating mutations in BAP1 encoding the BRCA1-associated protein 1 and located on chromosome 3p21.1, have been described in uveal melanoma and other types of cancer. In this study, we determined the prevalence of somatic BAP1 mutations and examined whether these mutations correlate with the functional expression of BAP1 in uveal melanoma tissue and with other clinical, histopathological and chromosomal parameters. We screened a cohort of 74 uveal melanomas for BAP1 mutations, using different deep sequencing methods. The frequency of BAP1 mutations in our study group was 47%. The expression of BAP1 protein was studied using immunohistochemistry. BAP1 staining was absent in 43% of the cases. BAP1 mutation status was strongly associated with BAP1 protein expression (P<0.001), loss of chromosome 3 (P<0.001), and other aggressive prognostic factors. Patients with a BAP1 mutation and absent BAP1 expression had an almost eightfold higher chance of developing metastases compared with those without these changes (P=0.002). We found a strong correlation between the immunohistochemical and sequencing data and therefore propose that, immunohistochemical screening for BAP1 should become routine in the histopathological work-up of uveal melanoma. Furthermore, our analysis indicates that loss of BAP1 may be particularly involved in the progression of uveal melanoma to an aggressive, metastatic phenotype.
Original languageUndefined/Unknown
Pages (from-to)1321-1330
Number of pages10
JournalModern Pathology
Issue number10
Publication statusPublished - 2014

Research programs

  • EMC MGC-02-13-02
  • EMC MGC-02-96-01
  • EMC MM-03-24-01
  • EMC OR-01-60-01

Cite this