Author:
|
Reina Castillon, Judith; Pujol, Roser; López Sánchez, Marcos; Rodriguez Santiago, Benjamín; Aza-Carmona, Miriam; González, Juan Ramón; Casado, José Antonio; Bueren, Juan Antonio; Sevilla, Julián; Badel, Isabel; Català, Albert; Belendez, Cristina; Dasi, María Ángeles; Díaz de Heredia, Cristina; Soulier, Jean; Schindler, Detlev; Perez-Jurado, Luis Alberto; Surralles, Jordi
|
Abstract:
|
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. |