Hereditary and Genetic Aspects Familial Patterns and Associations

Although there are several case reports of more than one case of leukemia occurring in the same family, these associations could either reflect similar environmental influences, or shared genetic factors.73,149,150 As with childhood leukemia, however, these familial associations only account for a very small proportion of cases. In contrast to twin studies in children, studies in adults do not show any concordance for the development of leukemia.151 Interestingly, one report found an increased risk of leukemia among parents of children with Down syndrome.152

Finally, a recent report suggested that although the risk of leukemia in individuals with Down syndrome is highest in childhood, there is an elevated risk throughout life.153

Chromosomal Abnormalities

As in children, somatic genetic abnormalities are commonly found in adult leukemias. About 50 percent of adult AML cases demonstrate an abnormal karyotype using standard methods.89'154 With the addition of molecular techniques—including reverse transcriptase polymerase chain reaction (RT-PCR)—the percentage is likely higher. Chromosomal abnormalities that are frequently found in adult AML include loss or deletion of chromosomes 5 and/or 7, addition of chromosome 8, t(9;22), and translocations involving the MLL gene at 11q23. Specific chromosomal abnormalities and translocations are also associated with certain FAB groups including t(15;17)(q22;q11) in AML-M3, t(8;21)(q22;q22) in AML-M2, and inversion 16 in AML-M4.154 Interestingly, several of these abnormalities are associated with prognosis: monosomy 7, found in about 3 percent of AML is typically associated with a poor prognosis, whereas t(15;17) is associated with a better response to therapy.155 Using cytogenetics and fluorescent in situ hybridization (FISH), somatic chromosomal abnormalities are found in about 70 percent of ALL patients. About 10 percent of adults have high hyperdiploidy, with t(9;22) being the most common chromosomal rearrangement found. Other chromosomal abnormalities found in adult ALL include translocations involving 11q23 (3 to 10 percent of patients), deletion of 6q, and addition of chromosome 12. FAB-associated karyotypes include t(9;22) observed in approximately 20 to 30 percent of pre-B-cell ALL (L1 and L2), t(14q11) in T-cell ALL, and t(1;19) in pre-B-cell ALL.

It is important to note that losses of chromosomes 5 and 7 are often found in treatment-related leukemias.156 Thus, it is possible that de novo patients could be subclassified based on their karyotype and exposures (e.g., occupational exposure to benzene). Three recent studies have found that exposures to pesticides, smoking, and/or solvents may be more often associated with AML demonstrating chromosomal loss of 5 and/or 7, whereas one study did not.157-160

More recent genetic abnormalities that have been explored with respect to adult leukemia include mutations in the ras family of protooncogenes, including N ras, K ras, and H ras. Ras gene products are important in cell signaling and trans-duction.161 Mutations in specific areas of these ras genes (particularly N- or K-ras at codons 12, 13, or 61) have been found in about 30 percent of patients with AML and myelodysplas-tic syndrome.162-164 Interestingly, in animal studies, these ras mutations appear more frequently in chemically induced tumors.165 In one small study of 62 patients with AML, ras mutations were found significantly more often among patients who reported employment that involved exposure to chemicals compared to patients who reported no such occupational exposures.166

Genetic Susceptibility Genes

As with childhood leukemia, genetic susceptibility genes have been recently explored in adult leukemia. In a study of 557 adults with leukemia and 952 age-, sex-, and geographically matched controls, Rollinson et al.167 reported a higher frequency of the GST-T1 null genotype among cases (19 percent) than among controls 14 percent (OR = 1.45, 95 percent CI = 1.09 to 1.93); this association was most striking for ALL (OR = 3.28, 95 percent CI = 1.31 to 8.26). The authors found no statistically significant associations between overall leukemia (or subtypes) with the GSTM1 null genotype nor the GSTPi valine variant. Lemos et al.168 found an increase in the proportion of the NAT2 fast acetylator genotype among adults with leukemia (n = 64) compared with controls (n = 128). Upon further analyses, however, the highest proportion of fast acetylators was among adults with CLL. Finally, in a recent study by Skibola et al.169 of 308 adults with acute leukemia and 491 age- and sex-matched controls, there was a decreased proportion of one of the 5'-methylenetetrahydrofolate reductase (MTHFR) genotypes among cases with ALL, but not AML. The MTHFR gene is important in folate metabolism and the authors speculate that folate inadequacy may play a key role in ALL development.

Other Associations

Few studies have explored associations between diet and adult leukemia. An ecological study of international data demonstrated some positive correlations between energy intake and leukemia incidence, particularly with lymphoid leukemia. A case-control study of 119 patients in Poland suggested an increased risk of leukemia associated with consumption of poultry and milk, and a decreased risk with vegetable intake.170,171 In a study from China, no association was found with antioxidant supplements and leukemia risk.172 Finally, in contrast to childhood leukemia, there is little evidence that alcohol consumption is a risk factor for adult leukemia.173

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