Saturday, May 05, 2007


HIG1: Nature. 2007 Apr 12;446(7137):758-64. Links
Comment in:
Nature. 2007 Apr 12;446(7137):739-40.
Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia.Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, Girtman K, Mathew S, Ma J, Pounds SB, Su X, Pui CH, Relling MV, Evans WE, Shurtleff SA, Downing JR.
Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Chromosomal aberrations are a hallmark of acute lymphoblastic leukaemia (ALL) but alone fail to induce leukaemia. To identify cooperating oncogenic lesions, we performed a genome-wide analysis of leukaemic cells from 242 paediatric ALL patients using high-resolution, single-nucleotide polymorphism arrays and genomic DNA sequencing. Our analyses revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases. The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in reduced levels of PAX5 protein or the generation of hypomorphic alleles. Deletions were also detected in TCF3 (also known as E2A), EBF1, LEF1, IKZF1 (IKAROS) and IKZF3 (AIOLOS). These findings suggest that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis. Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer.

Multivariable analyses showed a positive association between high paternal age (> or =35 years) and acute lymphoblastic leukaemia (relative risk=1.49; 95% confidence interval (CI)=0.96--2.31) but no association with maternal age

1: Br J Cancer. 2002 Feb 1;86(3):356-61. Links
Association of early life factors and acute lymphoblastic leukaemia in childhood: historical cohort study.Murray L, McCarron P, Bailie K, Middleton R, Davey Smith G, Dempsey S, McCarthy A, Gavin A.
Northern Ireland Cancer Registry, Department of Epidemiology and Public Health, The Queens University, Belfast, Riddel Hall, Stranmillis Road, Belfast BT9 5EE, UK.

In a historical cohort study of all singleton live births in Northern Ireland from 1971-86 (n=434,933) associations between early life factors and childhood acute lymphoblastic leukaemia were investigated. Multivariable analyses showed a positive association between high paternal age (> or =35 years) and acute lymphoblastic leukaemia (relative risk=1.49; 95% confidence interval (CI)=0.96--2.31) but no association with maternal age. High birth weight (> or =3500 g) was positively associated with acute lymphoblastic leukaemia (relative risk=1.66; 95% CI=1.18--2.33). Children of mothers with a previous miscarriage or increased gestation (> or =40 weeks) had reduced risks of ALL (respective relative risks=0.49; 95% CI=0.29--0.80, and 0.67; 95% CI=0.48--0.94). Children born into more crowded households (> or =1 person per room) had substantially lower risks than children born into less crowded homes with also some evidence of a lower risk for children born into homes with three adults (relative risks=0.56; 95% CI=0.35-0.91 and 0.58; 95% CI=0.21-1.61 respectively). These findings indicate that several early life factors, including living conditions in childhood and maternal miscarriage history, influence risk of acute lymphoblastic leukaemia in childhood. Copyright 2002 The Cancer Research Campaign

PMID: 11875699 [PubMed - indexed for MEDLINE]

Cancer Causes Control. 2002 Feb;13(1):15-25. Links
Birth characteristics, maternal reproductive history, hormone use during pregnancy, and risk of childhood acute lymphocytic leukemia by immunophenotype (United States).Ou SX, Han D, Severson RK, Chen Z, Neglia JP, Reaman GH, Buckley JD, Robison LL.
Department of Pediatrics, University of Minnesota, Minneapolis, USA.

OBJECTIVE: To investigate the associations of birth characteristics and maternal reproductive factors with risk of childhood acute lymphoblastic leukemia (ALL) by immunophenotypic subtypes. METHODS: Data collected from a case-control study including 1842 ALL cases (age < 15 years) and 1986 individually matched controls were analyzed. Exposure information was obtained through telephone interviews of parents. RESULTS: Factors associated with risk of ALL from all subgroups combined included high birth weight (OR = 1.4, 95% CI = 1.1-1.8), high birth order (OR = 2.0, 95% CI = 1.3-3.0 for fourth-born child compared to first-born child). young maternal age (<20 compared to 25-29, OR = 1.4, 95% CI = 1.1-1.9), advanced paternal age (>39 compared to 25-29, OR = 1.4, 95% CI = 1.0-1.9), induced abortion prior to the index pregnancy (OR = 1.2, 95% CI = 1.0-1.4), and oral contraceptive use during the index pregnancy (OR = 1.5, 95% CI = 1.0-2.2) with children under the age of 2 (OR = 5.1, 95% CI = 1.0-24.7) being the predominantly affected group. Risk of early pre-B-cell ALL increased with advanced paternal age (OR = 1.7, 95% CI = 1.1-2.7) and high birth order (OR = 2.0, 95% CI = 1.1-3.6), while risk of pre-B-cell ALL increased with both younger (OR = 3.4, 95% CI = 1.4-8.4) and advanced maternal age (OR = 2.6, 95% CI = 1.1-5.9). T-cell ALL was associated with high birth weight (OR = 2.4, 95% CI = 1.1-5.5) and history of induced abortion (OR = 2.4, 95% CI = 1.3-4.5). CONCLUSION: This study suggests that the association of ALL with birth characteristics and maternal reproductive factors varies with the immunophenotype of the ALL. Future studies are needed to better understand the effect of maternal hormone in the development of subtype of childhood ALL.

PMID: 11899114 [PubMed - indexed for MEDLINE]

1: Int J Epidemiol. 2006 Dec;35(6):1495-503. Epub 2006 Sep 28. Links
Parental age and risk of childhood cancers: a population-based cohort study from Sweden.Yip BH, Pawitan Y, Czene K.
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 171 77 Stockholm, Sweden.

BACKGROUND: Frequent germ line cells mutations were previously demonstrated to be associated with aging. This suggests a higher incidence of childhood cancer among children of older parents. A population-based cohort study of parental ages and other prenatal risk factors for five main childhood cancers was performed with the use of a linkage between several national-based registries. METHODS: In total, about 4.3 million children with their parents, born between 1961 and 2000, were included in the study. Multivariate Poisson regression was used to obtain the incidence rate ratios (IRR) and 95% confidence interval (CI). Children <5 years of age and children 5-14 years of age were analysed independently. RESULTS: There was no significant result for children 5-14 years of age. For children <5 years of age, maternal age were associated with elevated risk of retinoblastoma (oldest age group's IRR = 2.39, 95%CI = 1.17-4.85) and leukaemia (oldest age group's IRR = 1.44, 95%CI = 1.01-2.05). Paternal age was significantly associated with leukaemia (oldest age group's IRR = 1.31, 95%CI = 1.04-1.66). For central nervous system cancer, the effect of paternal age was found to be significant (oldest age group's IRR = 1.69, 95%CI = 1.21-2.35) when maternal age was included in the analysis. CONCLUSION: Our findings indicate that advanced parental age might be associated with an increased risk of early childhood cancers.



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