RESUMO
PURPOSE: The most common childhood malignancy, acute lymphoblastic leukemia (ALL), remains the leading cause of cancer-related death in children because of resistant cases in which underlying predisposing factors are poorly understood. The interindividual variation in the activity of xenobiotic metabolizing enzymes that modify individual somatic mutation burden in the context of environmental exposure was shown to modify susceptibility to childhood ALL. Variable DNA repair capacity may further modulate induced DNA lesions. Similarly, differential capacity of ALL patients to process carcinogens and chemotherapeutic drugs could both modify an individual's risk of recurrent malignancy and response to therapy. EXPERIMENTAL DESIGN: We investigated the relationship between the risk of relapse in ALL patients and functional polymorphisms in genes encoding carcinogen-metabolizing enzymes, including CYP1A1, CYP2D6, CYP2E1, MPO, GSTM1, GSTT1, GSTP1, NAT1, NAT2, NQO1, as well as DNA-repair enzymes hMLH1, hMSH3, XRCC1, XPF, and APE. Our study included 320 children with ALL, of which 68 relapsed or died because of this disease within 5 years of follow-up. RESULTS: Among children of the latter group, we found that carriers of CYP1A1*2A and NQO1*2 variants had worse disease prognosis according to Kaplan-Meier (P = 0.003) and Cox regression (P Assuntos
Acetiltransferases/genética
, Sistema Enzimático do Citocromo P-450/genética
, Reparo do DNA/genética
, Glutationa Transferase/genética
, NAD(P)H Desidrogenase (Quinona)/genética
, Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico
, Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia
, Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
, Criança
, Pré-Escolar
, Suscetibilidade a Doenças
, Genótipo
, Humanos
, Lactente
, Polimorfismo Genético
, Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade
, Prognóstico
, Taxa de Sobrevida
, Resultado do Tratamento
, Xenobióticos/metabolismo
RESUMO
Founder effects are largely responsible for changes in frequency profiles of genetic variants in local populations or isolates. They are often recognized by elevated incidence of certain hereditary disorders as observed in regions of Charlevoix and Saguenay-Lac-Saint-Jean (SLSJ) in Northeastern Quebec. Dominantly transmitted myotonic dystrophy (DM1) is highly prevalent in SLSJ where its carrier rate reaches 1/550, compared with 1/5,000 to 1/50,000 elsewhere. To shed light on the origin of DM1 in this region, we have screened 50 nuclear DM1 families from SLSJ and studied the genetic variation in a 2.05 Mb (2.9 cM) segment spanning the site of the expansion mutation. The markers analyzed included 22 biallelic SNPs and two microsatellites. Among 50 independent DM1 chromosomes, we distinguished ten DM1-associated haplotypes and grouped them into three haplotype families, A, B and C, based on the relevant extent of allele sharing between them. To test whether the data were consistent with a single entry of the mutation into SLSJ, we evaluated the age of the founder effect from the proportion of recombinant haplotypes. Taking the prevalent haplotype A1_21 (58%) as ancestral to all the disease-associated haplotypes in this study, the estimated age of the founder effect was 19 generations, long predating the colonization of Nouvelle-France. In contrast, considering A1_21 as ancestral to the haplotype family A only, yielded the estimated founder age of nine generations, consistent with the settlement of Charlevoix at the turn of 17th century and subsequent colonization of SLSJ. We conclude that it was the carrier of haplotype A (present day carrier rate of 1/730) that was a "driver" of the founder effect, while minor haplotypes B and C, with corresponding carrier rates of 1/3,000 and 1/10,000, respectively, contribute DM1 to the incidence level known in other populations. Other studies confirm that this might be a general scenario in which a major "driver" mutation/haplotype issued from a founder effect is found accompanied by distinct minor mutations/haplotypes occurring at background population frequencies.