Average annual percentage change (AAPC) in the incidence of ALL by gender, United States SEER registry, 1975-2000

into categories based on the degree of certainty of the association, and include demographic, environmental, genetic, and exposure-related factors (Table 6.2). Age, gender, race/ethnicity, socioeconomic status, genetic syndromes, and radiation exposure (in utero and/or therapeutic) are known risk factors for leukemias in younger age groups [8].

Genetic syndromes have been reported in an estimated 2.6% of British children diagnosed with leukemia; 90% of these attributable to Down syndrome (DS, constitutional trisomy 21) [9]. Whereas the pathogenic basis for the 10- to 20-fold increased risk of ALL in individuals with DS has not been elucidated, somatic mutations of the GATA1 gene are seen in virtually all cases of DS-associated AML and may be implicated in the development of megakaryoblastic AML seen in these patients [10, 11]. Such mutations may also confer enhanced leukemic sensitivity to cytarabine via dysreg-ulation of cytidine deaminase gene expression [12].

Among individuals with neurofibromatosis type 1, homozygous mutations in the neurofibromin tumor-suppressor gene are associated with myeloid leukemias [13]. Characteristic to the chromosome breakage syndromes is DNA instability resulting in aberrant pathways of DNA repair. Mutations associated with leuke-mic and lymphomatous malignancy have been identified in genes associated with ataxia-telangiecta-

sia, Fanconi anemia (FANC family), and Bloom syndrome [14, 15]. Causative factors in the development of leukemias in those with congenital neutropenia (Kostmann agranulocytosis, Shwachman syndrome) have not been identified. The autosomal dominant form of severe congenital neutropenia is associated with heterozygous mutations in the neutrophil elastase gene (ELA2) and consequent alterations in the serine protease neutrophil elastase. Proteolytic regulation of hematopoiesis may be affected [16].

In 1988, Greaves attempted to correlate patterns of infection during infancy with the development of B-precursor ALL in early childhood [17]. Specifically, he hypothesized that exposure to infection during the first year of life purportedly results in immunologic naiveté, a biologically abnormal response to later infection and, rarely, leukemic transformation of a susceptible clone [18, 19]. Support for the hypothesis has been derived mainly from proxy measures of delayed infectious exposure during infancy, including higher socioeconomic status (improved hygiene), social isolation (avoidance of daycare), breast feeding (passive immunity), and birth order (higher rank equated with reduced exposure) [20, 21]. Studies assessing the history of infections during infancy have drawn conflicting conclusions [21, 22].

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