title: Fancf-deficient mice are prone to develop ovarian tumours.
abstract: Fanconi anaemia (FA) is a rare recessive disorder marked by developmental abnormalities, bone marrow failure, and a high risk for the development of leukaemia and solid tumours. The inactivation of FA genes, in particular FANCF, has also been documented in sporadic tumours in non-FA patients. To study whether there is a causal relationship between FA pathway defects and tumour development, we have generated a mouse model with a targeted disruption of the FA core complex gene Fancf. Fancf-deficient mouse embryonic fibroblasts displayed a phenotype typical for FA cells: they showed an aberrant response to DNA cross-linking agents as manifested by G(2) arrest, chromosomal aberrations, reduced survival, and an inability to monoubiquitinate FANCD2. Fancf homozygous mice were viable, born following a normal Mendelian distribution, and showed no growth retardation or developmental abnormalities. The gonads of Fancf mutant mice functioned abnormally, showing compromised follicle development and spermatogenesis as has been observed in other FA mouse models and in FA patients. In a cohort of Fancf-deficient mice, we observed decreased overall survival and increased tumour incidence. Notably, in seven female mice, six ovarian tumours developed: five granulosa cell tumours and one luteoma. One mouse had developed tumours in both ovaries. High-resolution array comparative genomic hybridization (aCGH) on these tumours suggests that the increased incidence of ovarian tumours correlates with the infertility in Fancf-deficient mice and the genomic instability characteristic of FA pathway deficiency.
authors.affiliation: Division of Molecular Biology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Sietske T
authors.initials: ST
authors.lastname: Bakker
authors.forename: Henri J
authors.initials: HJ
authors.lastname: van de Vrugt
authors.forename: Jenny A
authors.initials: JA
authors.lastname: Visser
authors.forename: Elly
authors.initials: E
authors.lastname: Delzenne-Goette
authors.forename: Anja
authors.initials: A
authors.lastname: van der Wal
authors.forename: Mariska A D
authors.initials: MA
authors.lastname: Berns
authors.forename: Marieke
authors.initials: M
authors.lastname: van de Ven
authors.forename: Anneke B
authors.initials: AB
authors.lastname: Oostra
authors.forename: Sandra
authors.initials: S
authors.lastname: de Vries
authors.forename: Piet
authors.initials: P
authors.lastname: Kramer
authors.forename: Fré
authors.initials: F
authors.lastname: Arwert
authors.forename: Martin
authors.initials: M
authors.lastname: van der Valk
authors.forename: Johan P
authors.initials: JP
authors.lastname: de Winter
authors.forename: Hein
authors.initials: H
authors.lastname: te Riele
mesh_terms: D000818:Animals; D055028:Comparative Genomic Hybridization; D004195:Disease Models, Animal; D052219:Fanconi Anemia Complementation Group F Protein / Q000172:deficiency / Q000235:genetics*; D005260:Female; D006106:Granulosa Cell Tumor / Q000235:genetics*; D006801:Humans; D018311:Luteoma / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010051:Ovarian Neoplasms / Q000235:genetics*
chemical_list: D052219:Fanconi Anemia Complementation Group F Protein