Project description:Detectable clonal mosaicism for large chromosomal events has been associated with aging and increased risk of hematological and some solid cancers. We hypothesized that genetic cancer predisposition disorders such as Fanconi anemia (FA) could manifest a high rate of chromosomal mosaic events (CMEs) in peripheral blood, which could be used as early biomarkers of cancer risk. We studied the prevalence of CMEs by Single-Nucleotide Polymorphism (SNP) array in 130 FA patients’ blood DNA and their impact on cancer risk. We detected 51 CMEs (4.4-159Mb in size) in 16/130 patients (12.3%), 9 of them with multiple CMEs. Most frequent events were gains at 3q (n=6) and 1q (n=5), both previously associated with leukemia, as well as rearrangements with breakpoint clustering within the Major Histocompatibility Complex (MHC) locus (p=7.3x10-9). Compared to 15743 age-matched population controls, FA patients had 126-140 higher risk of detectable CMEs in blood (p<2.2x10-16). Prevalent and incident hematologic and solid cancers were more common in CME carriers (OR=11.6, CI95%=3.4-39.3, p=2.8x10-5), leading to poorer prognosis. The age-adjusted hazard risk (HR) of having cancer was almost 5 times higher in FA individuals with CMEs than in those without CMEs. Regarding survival, the HR of dying was 4 times higher in FA individuals having CMEs (HR=4.0, CI95%=2.0-7.9, p=5.7x10-5). Therefore, our data suggests that molecular karyotyping with SNP arrays in easy-to-obtain blood samples could be used for better monitoring of bone marrow clonal events, cancer risk and overall survival of FA patients.
Project description:Fanconi anemia (FA) is a rare inherited disease complicated by aplastic anemia. There is evidence that hematopoietic stem cells have lost self replicative capacity and undergo apoptosis when exposed to inhibitory cytokines including interferon gamma and tumor necrosis factor-alpha. We used gene expression microarrays to identify transcriptomal differences between bone marrow cells from normal volunteers and from children and adults with Fanconi anemia Experiment Overall Design: Fanconi anemia patients were identified using mitomycin C and/or diepoxybutane chromosomal breakage analysis. Eleven normal volunteers and 21 FA patients were studied. All FA patients with cytogenetic evidence of clonal evolution were excluded. All FA patients with acute leukemia were excluded. RNA was prepared from freshly obtained low density mononuclear cell fractions.
Project description:Fanconi anemia is a rare inherited hematological disorder which commonly presents with bone marrow failure, developmental abnormalities and susceptibility to cancer with high rates of prevalence in ethnic populations. The objective of this study was to identify potential genes that aid in the progression of the disease or produce its principal symptoms and to hypothesize enabling roles for certain genes that are not part of the central molecular machinery causing the disease. A total of 2 Fanconi anemia samples were collected from patients who displayed characteristic FA features. All of them gave positive results for the DNA breakage test after mitomycin C treatment. Samples were referred by Dr. Sheila Mohan of REFAIN (Registry for Fanconi anemia in India). Whole genome microarray analysis of peripheral blood from 2 patient samples and one normal individual. Sequential analysis of microarray data was carried out using gene ontology and pathway analysis to identify candidate genes.
Project description:Fanconi anemia (FA) is a rare inherited disease complicated by aplastic anemia. There is evidence that hematopoietic stem cells have lost self replicative capacity and undergo apoptosis when exposed to inhibitory cytokines including interferon gamma and tumor necrosis factor-alpha. We used gene expression microarrays to identify transcriptomal differences between bone marrow cells from normal volunteers and from children and adults with Fanconi anemia
