5 research outputs found
Development of a mouse model for spontaneous oral squamous cell carcinoma in Fanconi anemia
Altres ajuts: European Regional Development Fund (FEDER); the European Union; the Spanish Fundacion Anemia de Fanconi and Fanconi Anemia Research Fund USA; Comunidad de Madrid (ref PEJ-2019-TL_BMD-12905).Fanconi anemia (FA) patients frequently develop oral squamous cell carcinoma (OSCC). This cancer in FA patients is diagnosed within the first 3-4 decades of life, very often preceded by lesions that suffer a malignant transformation. In addition, they respond poorly to current treatments due to toxicity or multiple recurrences. Translational research on new chemopreventive agents and therapeutic strategies has been unsuccessful partly due to scarcity of disease models or failure to fully reproduce the disease. Here we report that Fanca gene knockout mice (Fanca ) frequently display pre-malignant lesions in the oral cavity. Moreover, when these animals were crossed with animals having conditional deletion of Trp53 gene in oral mucosa (K14cre;Trp53), they spontaneously developed OSCC with high penetrance and a median latency of less than ten months. Tumors were well differentiated and expressed markers of squamous differentiation, such as keratins K5 and K10. In conclusion, Fanca and Trp53 genes cooperate to suppress oral cancer in mice, and Fanca;K14cre;Trp53 mice constitute the first animal model of spontaneous OSCC in FA
Detectable clonal mosaicism in blood as a biomarker of cancer risk in Fanconi anemia
Detectable clonal mosaicism for large chromosomal events has
been associated with aging and an 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
(4.4-159 Mb in size) in 16 out of 130 patients (12.3%), of which
9 had multiple CMEs. The 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 locus (P = 7.3 x
10(-9)). Compared with 15 743 age-matched population controls,
FA patients had a 126 to 140 times higher risk of detectable
CMEs in blood (P < 2.2 x 10(-16)). Prevalent and incident
hematologic and solid cancers were more common in CME carriers
(odds ratio [OR] = 11.6, 95% confidence interval [CI] =
3.4-39.3, P = 2.8 x 10(-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, 95% CI = 2.0-7.9, P = 5.7
x 10(-5)). Therefore, our data suggest 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
Chromosome fragility in Fanconi anemia patients: diagnostic implications and clinical impact
International audienceFanconi anemia (FA) is a rare syndrome characterized by bone marrow failure, malformations, and cancer predisposition. Chromosome fragility induced by DNA interstrand crosslink (ICL)-inducing agents such as DEB or MMC is the gold standard test for the diagnosis of FA. In this study we present data from 198 DEB-induced chromosome fragility tests in non-FA and in FA patients where information on genetic subtype, cell sensitivity to MMC and clinical data were available. This large series allowed us to quantify the variability and the level of overlap in ICL-sensitivity among FA patients and normal population. In this article we propose a new chromosome fragility index that provides a cut-off diagnostic level to unambiguously distinguish FA patients, including mosaics, from non-FA individuals. Spontaneous chromosome fragility and its correlation with DEB-induced fragility was also analyzed, indicating that, while both variables are correlated, 54% of FA patients do not have spontaneous fragility. Our data reveal a correlation between malformations and sensitivity to ICLs, This correlation is also statistically significant when the analysis is restricted to the patients from the FA-A complementation group and suggests that genome instability during embryo development may be related to malformations in FA. Finally, chromosome fragility does not correlate with the age of onset of hematological disease, indicating that DEB-induced chromosome breaks in T-cells has no prognostic value in FA
Detectable clonal mosaicism in blood as a biomarker of cancer risk in Fanconi anemia
Detectable clonal mosaicism for large chromosomal events has
been associated with aging and an 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
(4.4-159 Mb in size) in 16 out of 130 patients (12.3%), of which
9 had multiple CMEs. The 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 locus (P = 7.3 x
10(-9)). Compared with 15 743 age-matched population controls,
FA patients had a 126 to 140 times higher risk of detectable
CMEs in blood (P < 2.2 x 10(-16)). Prevalent and incident
hematologic and solid cancers were more common in CME carriers
(odds ratio [OR] = 11.6, 95% confidence interval [CI] =
3.4-39.3, P = 2.8 x 10(-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, 95% CI = 2.0-7.9, P = 5.7
x 10(-5)). Therefore, our data suggest 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
Risk factors and outcomes according to age at transplantation with an HLA-identical sibling for sickle cell disease.
Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapy for sickle cell disease (SCD).41 Several barriers prevent its widespread application, including the lack of a suitable donor, risk of early and late onset of regimen-related toxicities, rejection and mortality. Despite these limitations, the number of transplants for hemoglobinopathies has been increasing in the last decade. The overall probability of survival (OS) for patients with SCD transplanted with a human lymphocyte antigen (HLA)- identical sibling graft ranges between 91 and 100% with an event-free survival (EFS) of 73-100%.3 A controversial issue is the ideal age to perform HSCT in SCD patients. In fact, whilst early age HSCT could prevent SCD-related organ damage, resulting in better patient outcomes, the emergence of new available SCD supportive care, promising curative therapies could justify not proceeding with HSCT in certain cases [...