The Clinical Importance of BRCAness in a Danish Cohort of Epithelial Ovarian Carcinoma.
Germline BRCA1 and BRCA2 mutations are responsible for 5-15% of epithelial ovarian carcinomas (EOC). These patients have recently been observed to be sensitive to targeted therapy with Poly (Adenosine Diphosphate Ribose) Polymerase (PARP) inhibitors (PARPi). The BRCAness phenomenon describes EOC tumors that lack a germline BRCA1/2 mutation, but express the BRCA1/2 mutation phenotype characterized by defect homologous recombination (HR). BRCAness may be caused by somatic mutations, promotor hypermethylation, and other epigenetic changes in the BRCA1, BRCA2, or other HR-genes.
We aim to investigate the BRCAness phenomenon in a national Danish population-based cohort of epithelial ovarian cancer patients with a follow-up of more than a decade and correlate these findings with progression free survival and overall survival. We hypothesize that up to 50% of a population-based cohort of EOC patients will show BRCAness phenotype with detectable defects in the HR pathway and increased overall survival as compared to the BRCA wild type population of EOC patients.
In 2005, 512 patients were diagnosed with epithelial ovarian, fallopian tube or primary peritoneal cancer and registered in DGCD (The Danish Database on Gynecological Cancer). We have collected formalin fixed, paraffin-embedded (FFPE) tumor tissue from all 512 patients and DNA derived from FFPE-tumor tissue was sequenced by next generation sequencing to detect pathogenic and likely pathogenic variants in BRCA1, BRCA2 and 20 other “HR-genes”. BRCA1 silencing by other means was investigated by BRCA1 methylation analyses of tumor derived DNA and BRCA1 immunohistochemical staining of FFPE-tumor specimens and subsequent semi-quantitative analyses of percentage of stained nuclei.
For validation of variants potentially germline in origin, paired normal tissue DNA from mutation positive samples was sequenced for variants of the genes in question, and suspected somatic mutations (negative in normal tissue DNA) were validated by pyrosequencing. Statistical analyses for correlation with survival and clinico pathological data is ongoing.
1. oktober 2014 - 1. oktober 2018
Karina Dahl Steffensen, overlæge, ph.d., lektor, Onkologisk Afdeling, Vejle Sygehus.
Marianne Waldstrøm, ledende overlæge, lektor, Patologisk Afdeling, Vejle Sygehus.
Mads Jørgensen, cand. Scient., ph.d. Klinisk Genetisk Afdeling, Vejle Sygehus.
Erik Søgaard-Andersen, overlæge, dr. med. Gynækologisk-Obstetrisk Afdeling, Aalborg Universitetshospital.
Anders Jakobsen, overlæge, professor, Onkologisk Afdeling, Vejle Sygehus.
Publikationer og aktiviteter
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