Xiaomei Ma

Myelodysplastic syndromes: incidence and survival in the United States.

Myelodysplastic syndromes (MDS) became reportable to the Surveillance, Epidemiology, and End Results (SEER) Program (the United States cancer surveillance program) in 2001. This provided the first opportunity to examine the incidence and survival of patients with MDS in the United States using a large, population‐based database.

Epidemiology of Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem cell malignancies with significant morbidity and high mortality. The incidence of MDS increases markedly with age, and the disease is most prevalent in individuals who are white and male. It is conservatively estimated that >10,000 new cases of MDS occur in the United States annually, and that ≥ 60,000 individuals with MDS currently reside in the country. With an aging population and an improving awareness of the disease, the documented disease burden is expected to escalate in the near future. Recent studies have identified new or inconsistent etiologic factors that warrant further research. Given the poor survival of individuals with MDS, it is important to identify prognostic factors to better risk-stratify patients for more effective treatment. The relevance of different comorbidities to MDS prognosis and the potential interaction between various comorbidities represents an interesting area of research.

Site-specific translocation and evidence of postnatal origin of the t(1;19) E2A-PBX1 fusion in childhood acute lymphoblastic leukemia

The t(1;19) translocation yields a fusion between E2A and PBX1 genes and occurs in 5% of acute lymphoblastic leukemia in children and adults. We used chromosomal translocations and Ig heavy chain (IGH)/T cell antigen receptor (TCR) rearrangements to develop an understanding of the etiology and natural history of this subtype of leukemia. We sequenced the genomic fusion between E2A and PBX1 in 22 preB acute lymphoblastic leukemias and two cell lines. The prenatal origin of the leukemia was assessed in 15 pediatric patients by screening for the clonotypic E2A-PBX1 translocation in neonatal blood spots, or Guthrie cards, obtained from the children at the time of birth. Two patients were determined to be weakly positive for the fusion at the time of birth, in contrast to previously studied childhood leukemia fusions, t(12;21), t(8;21), and t(4;11), which were predominantly prenatal. The presence of extensive N-nucleotides at the point of fusion in the E2A-PBX1 translocation as well as specific characteristics of the IGH/TCR rearrangements provided additional evidence for a postnatal, preB cell origin. Intriguingly, 16 of 24 breakpoints on the 3.2-kb E2A intron 14 were located within 5 bp, providing evidence for a site-specific recombination mechanism. Breakpoints on the 232-kb PBX1 intron 1 were more dispersed but highly clustered proximal to exon 2. In sum, the translocation breakpoints displayed evidence of unique temporal, ontological, and mechanistic formation than the previously analyzed pediatric leukemia translocation breakpoints and emphasize the need to differentiate cytogenetic and molecular subgroups for studies of leukemia causality.

Maternal Dietary Risk Factors in Childhood Acute Lymphoblastic Leukemia (United States)

AbstractObjective: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and the second most common cause of mortality in children aged 1–14 years. Recent research has established that the disease can originate in utero, and thus maternal diet may be an important risk factor for ALL. Methods: The Northern California Childhood Leukemia Study is a population-based case–control study of risk factors for childhood leukemia, including maternal diet. Cases (n = 138) and controls (n = 138) were matched on sex, date of birth, mothers race, Hispanicity, and county of residence at birth. Maternal dietary intake in the 12months prior to pregnancy was obtained by a 76-item food frequency questionnaire. Results: Consumption of the vegetables (OR = 0.53; 95% CI, 0.33–0.85; p= 0.008), protein sources (OR = 0.40; 95% CI, 0.18–0.90, p= 0.03), and fruits (OR = 0.71; 95% CI, 0.49–1.04; p= 0.08) food groups were inversely associated with ALL. Among nutrients, consumption of provitamin A carotenoids (OR = 0.65, 95% CI, 0.42–1.01; p= 0.05), and the antioxidant glutathione (OR = 0.42; 95% CI, 0.16–1.10; p= 0.08) were inversely associated with ALL. Conclusion: Maternal dietary factors, specifically the consumption of vegetables, fruits, protein sources and related nutrients, may play a role in the etiology of ALL. Dietary carotenoids and glutathione appear to be important contributors to this effect.

Comorbidities and survival in a large cohort of patients with newly diagnosed myelodysplastic syndromes

Comorbid conditions have rarely been systematically studied among patients with myelodysplastic syndromes (MDS). We conducted a large population-based study to assess the role of comorbidity in the survival of newly diagnosed MDS patients. This study included 1708 MDS patients (age > or =66 years) diagnosed in the US during 2001-2002, with follow-up through the end of 2004. Hazard ratios (HRs) were estimated using multivariate Cox proportional hazard models. The median survival time was approximately 18 months. Fifty one percent of MDS patients had comorbid conditions. Patients with comorbid conditions had significantly greater risk of death than those without comorbidities. The HR was 1.19 (95% confidence interval (CI): 1.05-1.36) and 1.77 (95% CI: 1.50-2.08) for those with a Charlson index of 1-2 and > or = 3, respectively. The risk of death increases with Charlson index. MDS patients who have congestive heart failure or chronic obstructive pulmonary disease had significantly shorter survival than patients without those conditions, whereas diabetes did not appear to have an impact on survival. This study confirms comorbidity as a significant and independent determinant of MDS survival, and the findings underscore the importance to take comorbid conditions into account when assessing the prognosis of MDS.

Heterocyclic aromatic amine pesticide use and human cancer risk: Results from the U.S. Agricultural Health Study†

Imazethapyr, a heterocyclic aromatic amine, is a widely used crop herbicide first registered for use in the United States in 1989. We evaluated cancer incidence among imazethapyr‐exposed pesticide applicators enrolled in the Agricultural Health Study (AHS). The AHS is a prospective cohort of 57,311 licensed pesticide applicators in the U.S., enrolled from 1993–1997. Among the 49,398 licensed pesticide applicators eligible for analysis, 20,646 applicators reported use of imazethapyr and 2,907 incident cancers developed through 2004. Imazethapyr exposure was classified by intensity‐weighted lifetime exposure days calculated as [years of use × days per year × intensity level]. Poisson regression analysis was used to evaluate the relationship between imazethapyr exposure and cancer incidence. We found significant trends in risk with increasing lifetime exposure for bladder cancer (p for trend 0.01) and colon cancer (p for trend 0.02). Rate ratios (RRs) were increased by 137% for bladder cancer and 78% for colon cancer when the highest exposed were compared to the nonexposed. The excess risk for colon cancer was limited to proximal cancers, (RR = 2.73, 95% confidence intervals 1.42, 5.25, p for trend 0.001). No association was observed for prostate, lung, rectum, kidney, oral, pancreas, lymphohematopoietic cancers or melanoma. These findings provide new evidence that exposure to aromatic amine pesticides may be an overlooked exposure in the etiology of bladder and colon cancer. The use of imazethapyr and other imidazolinone compounds should continue to be evaluated for potential risk to humans. Published 2008 Wiley‐Liss, Inc.

Meat and Meat Mutagens and Risk of Prostate Cancer in the Agricultural Health Study

Meats cooked at high temperatures, such as pan-frying or grilling, are a source of carcinogenic heterocyclic amines and polycyclic aromatic hydrocarbons. We prospectively examined the association between meat types, meat cooking methods, meat doneness, and meat mutagens and the risk for prostate cancer in the Agricultural Health Study. We estimated relative risks and 95% confidence intervals (95% CI) for prostate cancer using Cox proportional hazards regression using age as the underlying time metric and adjusting for state of residence, race, smoking status, and family history of prostate cancer. During 197,017 person-years of follow-up, we observed 668 incident prostate cancer cases (613 of these were diagnosed after the first year of follow-up and 140 were advanced cases) among 23,080 men with complete dietary data. We found no association between meat type or specific cooking method and prostate cancer risk. However, intake of well or very well done total meat was associated with a 1.26-fold increased risk of incident prostate cancer (95% CI, 1.02-1.54) and a 1.97-fold increased risk of advanced disease (95% CI, 1.26-3.08) when the highest tertile was compared with the lowest. Risks for the two heterocyclic amines 2-amino-3,4,8-trimethylimidazo-[4,5-f]quinoxaline and 2-amino-3,8-dimethylimidazo-[4,5-b]quinoxaline were of borderline significance for incident disease [1.24 (95% CI, 0.96-1.59) and 1.20 (95% CI, 0.93-1.55), respectively] when the highest quintile was compared with the lowest. In conclusion, well and very well done meat was associated with an increased risk for prostate cancer in this cohort. (Cancer Epidemiol Biomarkers Prev 2008;17(1):80–7)

Intake of meat, meat mutagens, and iron and the risk of breast cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Background:Epidemiological evidence on meat intake and breast cancer is inconsistent, with little research on potentially carcinogenic meat-related exposures. We investigated meat subtypes, cooking practices, meat mutagens, iron, and subsequent breast cancer risk.Methods:Among 52 158 women (aged 55–74 years) in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, who completed a food frequency questionnaire, 1205 invasive breast cancer cases were identified. We estimated meat mutagen and haem iron intake with databases accounting for cooking practices. Using Cox proportional hazards regression, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) within quintiles of intake.Results:Comparing the fifth to the first quintile, red meat (HR=1.23; 95% CI=1.00–1.51, P trend=0.22), the heterocyclic amine (HCA), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), (HR=1.26; 95% CI=1.03–1.55; P trend=0.12), and dietary iron (HR=1.25; 95% CI=1.02–1.52; P trend=0.03) were positively associated with breast cancer. We observed elevated, though not statistically significant, risks with processed meat, the HCA 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), mutagenic activity, iron from meat, and haem iron from meat.Conclusion:In this prospective study, red meat, MeIQx, and dietary iron elevated the risk of invasive breast cancer, but there was no linear trend in the association except for dietary iron.

Cytogenetics of Hispanic and White Children with Acute Lymphoblastic Leukemia in California

Epidemiologic studies of childhood leukemia have made limited use of tumor genetic characteristics, which may be related to disease etiology. We characterized the cytogenetics of 543 childhood leukemia patients (0-14 years of age) enrolled in the Northern California Childhood Leukemia Study, an approximately population-based study comprised primarily of Hispanics (42%) and non-Hispanic Whites (41%), and compared the cytogenetic profiles between these two ethnic groups. Subjects were classified by immunophenotype, conventional cytogenetic characteristics, and fluorescence in situ hybridization findings. The ploidy levels most frequently observed among acute lymphoblastic leukemia patients were high hyperdiploidy (51-67 chromosomes) and pseudodiploidy (34% and 27%, respectively). No ethnic differences in the frequency of 11q23/MLL rearrangements were observed between Hispanics and non-Hispanic Whites. Among B-lineage acute lymphoblastic leukemia patients, the percentage of TEL-AML1 translocations was significantly lower in Hispanics (13%) than in non-Hispanic Whites (24%; P = 0.01). This is the first time that this ethnic variation has been observed in a large number of patients in a defined geographic region, which is consistent with findings from smaller international studies. The mechanistic basis for this 2-fold variation in frequency of TEL-AML1 may be due to ethnic-specific risk factors or genetics and should be explored further. (Cancer Epidemiol Biomarkers Prev 2006;(15)3:578–81)

Hypermethylation of the 5′ CpG Island of the FHIT Gene Is Associated with Hyperdiploid and Translocation-Negative Subtypes of Pediatric Leukemia

The human FHIT (fragile histidine triad) gene is a putative tumor suppressor gene located at chromosome region 3p14.2. Previous studies have shown that loss of heterozygosity, homozygous deletions, and abnormal expression of the FHIT gene are involved in several types of human malignancies. A CpG island is present in the 5′ promoter region of the FHIT gene, and methylation in this region correlates with loss of FHIT expression. To test whether aberrant methylation of the FHIT gene may play a role in pediatric leukemia, we assessed the FHIT methylation status of 10 leukemia cell lines and 190 incident population-based cases of childhood acute lymphocytic and myeloid leukemias using methylation-specific PCR. Conventional and fluorescence in situ hybridization cytogenetic data were also collected to examine aneuploidy, t(12, 21), and other chromosomal rearrangements. Four of 10 leukemia cell lines (40%) and 52 of 190 (27.4%) bone marrows from childhood leukemia patients demonstrated hypermethylation of the promoter region of FHIT. Gene expression analyses and 5-aza-2′-deoxycytidine treatment showed that promoter hypermethylation correlated with FHIT inactivation. Among primary leukemias, hypermethylation of FHIT was strongly correlated with acute lymphoblastic leukemia (ALL) histology (P = 0.008), high hyperdiploid (P < 0.0001), and translocation-negative (P < 0.0001) categories. Hyperdiploid B-cell ALLs were 23-fold more likely to be FHIT methylated compared with B-cell ALL harboring TEL-AML translocations. FHIT methylation was associated with high WBC counts at diagnosis, a known prognostic indicator. These results suggest that hypermethylation of the promoter region CpG island of the FHIT gene is a common event and may play an important role in the etiology and pathophysiology of specific cytogenetic subtypes of childhood ALL.