Nature Medicine9, 568 - 574 (2003)
Published online: 7 April 2003; | doi:10.1038/nm852
Disruption of the Fanconi anemia−BRCA pathway in cisplatin-sensitive ovarian tumors
Toshiyasu Taniguchi1, Marc Tischkowitz2, Najim Ameziane3, Shirley V. Hodgson2, Christopher G. Mathew2, Hans Joenje3, Samuel C. Mok4
& Alan D. D'Andrea1
1
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Guy's King's and St. Thomas' School of Medicine, London, UK
2
Division of Genetics and Development, Guy's King's and St. Thomas' School of Medicine, London, UK
3
Department of Clinical Genetics and Human Genetics, VU University Medical Center, Amsterdam, The Netherlands
4
Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Ovarian tumor cells are often genomically unstable and hypersensitive to cisplatin. To understand the molecular basis for this phenotype, we examined the integrity of the Fanconi anemia−BRCA (FANC-BRCA) pathway in those cells. This pathway regulates cisplatin sensitivity and is governed by the coordinate activity of six genes associated with Fanconi anemia (FANCA, FANCC, FANCD2, FANCE, FANCF and FANCG) as well as BRCA1 and BRCA2 (FANCD1). Here we show that the FANC-BRCA pathway is disrupted in a subset of ovarian tumor lines. Mono-ubiquitination of FANCD2, a measure of the function of this pathway, and cisplatin resistance were restored by functional complementation with FANCF, a gene that is upstream in this pathway. FANCF inactivation in ovarian tumors resulted from methylation of its CpG island, and acquired cisplatin resistance correlated with demethylation of FANCF. We propose a model for ovarian tumor progression in which the initial methylation of FANCF is followed by FANCF demethylation and ultimately results in cisplatin resistance.
