Richardson, Michaela

Background With the exception of therapy related MDS due to treatment with alkylating agents and/or radiation or with a topoisomerase II inhibitor, little is known about the etiology of myelodysplastic syndromes (MDS). A few studies have evaluated pre-existing medical conditions as risk factors for MDS, with evidence suggesting that autoimmune disease is associated with an increased risk of MDS. Here, we evaluated associations between history of autoimmune disease, overall and by individual disease subtype, and risk of MDS in a population-based case control study. Methods MDS cases were identified by rapid case ascertainment through the population-based Minnesota Cancer Surveillance System (MCSS). Participants were recruited if they were diagnosed with MDS between April 1, 2010 and October 31, 2014. Eligibility criteria included residence in Minnesota, age at diagnosis between 20 and 85 years, and ability to understand English or Spanish. Centralized pathology and cytogenetics review were conducted to confirm diagnosis and classify by subtypes. Controls were identified through the Minnesota State driver's license/identification card list. History of autoimmune disease was reported using a self-administered questionnaire; proxy interviews were not conducted. Unconditional logistic regression with adjustment for age, sex and confounders (education, NSAID use, benzene exposure, BMI) was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CI) for autoimmune disease and MDS. Results A total of 399 cases with a confirmed diagnosis of MDS and 1399 controls were included. Cases were significantly more likely to report a diagnosis of any autoimmune disease when compared with controls (OR=1.49, 95% CI 1.13-1.97). As illustrated in Figure 1, specific associations were observed for hypothyroidism (OR=2.07, 95% CI 1.39-3.08), ulcerative colitis (OR=2.26, 95% CI 1.09-4.69), Crohn's disease (OR=3.88, 95% CI 1.23-12.2), and systemic lupus erythematosus (SLE; OR=7.52, 95% CI 1.98-28.6). Autoimmune conditions were more commonly reported in both female cases and female controls when compared with males; however, associations for hypothyroidism and ulcerative colitis were significantly associated with MDS in males in an analysis stratified by sex. Associations between autoimmune disease and MDS remained statistically significant after exclusion of therapy-related MDS cases. Discussion Our results validate previous findings of an association between autoimmune disease and MDS risk from population-based registry studies and case-control studies. In addition, our results provide additional evidence to suggest that this association is largely driven by hypothyroidism, inflammatory bowel disease, and SLE. This increased MDS risk following a diagnosis for an autoimmune condition is hypothesized to be due to shared genetic or environmental risk factors, treatment for autoimmune diseases, altered immune surveillance or damage to the bone marrow caused by the autoimmune condition. Further studies are required to confirm which of these is the most plausible explanation. Disclosures No relevant conflicts of interest to declare.

Abstract Myelodysplastic syndromes (MDS) are a heterogeneous collection of clonal disorders of hematopoietic stem cells characterized by ineffective hematopoiesis, dysplasia, and risk of progression to secondary acute myeloid leukemia (AML). Despite the development of numerous prognostic scoring systems (MDS Comorbidity Index (MDS-CI),International Prognostic Scoring System (IPSS) and IPSS-R, updated WHO classifications, and WHO prognostic scoring system (WPSS)), little prospective data regarding the influence of these and other factors on patient outcomes is available. To better elucidate the features of early mortality in MDS we compare characteristics of patients dying within one year of MDS diagnosis with those surviving longer in our Adults in Minnesota with MDS (AIMMS) population based case-control study. The AIMMS study is a statewide prospective population-based case-control study (R01 CA142714) conducted by the University of Minnesota (UMN), Mayo Clinic, and the Minnesota Department of Health. Adults (age 20-85 years) with a new diagnosis of MDS between April 2010 and October 2014 were recruited through the Minnesota Cancer Surveillance System. Patients completed a comprehensive questionnaire to capture retrospective epidemiologic data. All cases went through central medical review including pathology review by two independent hematopathologists, cytogenetic analyses, and oncologist medical record review with assignment of IPSS, IPSS-R, WPSS 1.2 noting past medical history, exposures, and treatment history and response. Annual clinical review of all patient cases for four years after initial enrollment is ongoing in a batched, non-real time manner. Three hundred and ninety-nine patients with a confirmed diagnosis of MDS based on central review and one year of clinical follow-up review were included in the analysis. For the entire group, we observed early mortality in those with abnormal cytogenetics, three or greater cytogenetic abnormalities, treatment at a community medical center only (versus academic), and with 2-3 concurrent medical comorbidities (Table 1). Treatment with hypomethylating agents also correlated with early mortality but when adjusted for WPSS and IPSS-R, this association was no longer significant. To investigate varied impact of disease and patient characteristics within different groups of MDS patients, we did multivariable regression analysis within the following categories: High/Very High Risk IPSS-R; Very low/Low/Intermediate Risk IPSS-R; Treated Patients; Supportive Care Only Patients. In patients with high or very high risk IPSS-R, the presence of 3 or more cytogenetic abnormalities was the only significant predictor early mortality in a multivariable adjusted model (OR: 3.66, 95% CI: 1.57-8.53). Similarly, in those with very low, low, or intermediate IPSS-R, abnormal cytogenetics was the only significant predictor of early mortality in an adjusted model (OR: 3.71, 95% CI 1.49-9.26). In patients receiving supportive care only, early mortality was seen in those who had diabetes (OR: 3.06, 95% CI 1.11-8.42), had complex cytogenetics (OR for ≥ 3 abnormalities: 4.94, 95% CI 1.25-19.46), and had very high or high IPSS-R (OR: 4.20, 95% CI 1.43-12.34). Likewise, complex cytogenetics remained the sole significant predictor of early mortality in treated patients (OR: 4.84, 95% CI 1.43-16.37). Complex cytogenetics and prognostic risk category (either by WPSS or IPSS-R) have previously been associated with higher risk disease and early mortality without intervention. Our data confirm this association in a large prospectively followed MDS cohort and highlight the significance of cytogenetic abnormalities and complexity regardless of IPSS-R risk categorization or treatment. Disclosures No relevant conflicts of interest to declare.

Abstract Background Polymorphisms in mitochondrial DNA can be used to group individuals into haplogroups that reflect human global migration. These mitochondrial variants are associated with differences in mitochondrial function and have been associated with multiple diseases, including cancer. In this analysis, we evaluated the association between mtDNA haplogroup and risk of myelodysplastic syndromes (MDS). Methods Cases were identified by rapid case ascertainment through the population-based Minnesota Cancer Surveillance System (MCSS). Participants were recruited to the MDS study if they were diagnosed with MDS between April 1, 2010 and October 31, 2014. Eligibility criteria included residence in Minnesota, age at diagnosis between 20 and 85 years, and ability to understand English or Spanish. Centralized pathology and cytogenetics review were conducted to confirm diagnosis and classify by subtypes. Controls were identified through the Minnesota State driver's license/identification card list. Genomic DNA from cases and controls was collected using Oragene DNA collection kits (DNA Genotek, Ontario, Canada) and extracted via Autopure LS Instrument according to manufacturer's instructions (Qiagen). We genotyped 15 mtSNPs that capture common European mitochondrial haplogroup variation (Mitchell et al Hum Genet 2014; Raby et al J Allergy Clin Immunol 2007) on the Sequenom iPLEX Gold MassArray platform (Sequenom, Inc., San Diego, CA) in the University of Minnesota Genomics Core. Because haplogroup frequencies vary by race and ethnicity, we restricted analyses to non-Hispanic white cases and controls. All statistical analyses were conducted using SAS v.9.3 (SAS Institute, Cary, NC). Odds ratios (OR) and 95% confidence intervals (CI) were calculated. We also evaluated associations by MDS subtype and IPSS-R risk category. Results We were able to classify 215 cases with confirmed MDS and 522 controls into one of the 11 common European haplogroups. The distribution of haplogroups in our control sample was similar to the distribution reported in a previous sample of non-Hispanic white individuals from the United States (Mitchell et al Hum Genet 2014), with the highest number in the H haplogroup (42%). Due to small sample sizes in some subgroups, we combined mt haplogroups into larger bins based on the haplogroup evolutionary tree, including HV (H+V), JT (J+T), IWX (I+W+X), UK (U+K), and Z (van Oven & Kayser Hum Mut 2009) for comparisons of cases and controls. Using haplogroup HV as the reference group, we found a statistically significant association between haplogroup JT and MDS (OR=0.57, 95% CI 0.36, 0.90, p=0.02). No other significant associations were observed in a comparison of cases and controls (Figure). In the analysis stratified by MDS subtype, the association with haplogroup JT reached statistical significance only in MDS cases with the RCMD subtype (OR=0.42, 95% CI 0.18, 0.97), although the association was similar in magnitude for RARS and the p-value for heterogeneity was non-significant (0.76). Similarly, the associations between haplogroup JT and MDS were similar in the analysis stratified by IPSS-R risk category (p-value for heterogeneity = 0.71). Conclusions In this population-based study of MDS, we observed an association between mtDNA haplogroup JT and risk of MDS. Previous studies using cybrid cells have reported functional differences by mtDNA haplogroup and provide biological plausibility for the observed association, including higher capacity to cope with oxidative stress in haplogroup T (Meuller et al PLoS One 2012) and lower levels of ATP and reactive oxygen species production in haplogroup J (Kenney et al PLoS One 2013). Further studies of the relationship between mtDNA variation and MDS are warranted in larger sample sizes. Figure 1. Association between mtDNA haplogroup and MDS Figure 1. Association between mtDNA haplogroup and MDS Disclosures No relevant conflicts of interest to declare.

Benzene exposure is one of the few well‐established risk factors for myeloid malignancy. Exposure to other chemicals has been inconsistently associated with hematologic malignancies. We evaluated occupational and residential chemical exposures as risk factors for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) using population‐based data. AML and MDS cases were identified by the Minnesota Cancer Surveillance System. Controls were identified through the Minnesota driver's license/identification card list. Chemical exposures were measured by self‐report. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CI). We included 265 MDS cases, 420 AML cases and 1388 controls. We observed significant associations between both MDS and AML and benzene (OR = 1.77, 95% CI 1.19, 2.63 and OR = 2.10, 95% CI 1.35, 3.28, respectively) and vinyl chlorides (OR = 2.05, 95% CI 1.15, 3.63 and OR = 2.81, 95% CI 1.14, 6.92). Exposure to soot, creosote, inks, dyes and tanning solutions and coal dust were associated with AML (range ORs = 2.68–4.03), while no association was seen between these exposures and MDS (range ORs = 0.57–1.68). Pesticides and agricultural chemicals were not significantly associated with AML or MDS. Similar results were observed in analyses stratified by sex. In addition to providing risk estimates for benzene from a population‐based sample, we also identified a number of other occupational and residential chemicals that were significantly associated with AML; however, all exposures were reported by only a small percentage of cases (≤10%). While chemical exposures play a clear role in the etiology of myeloid malignancy, these exposures do not account for the majority of cases.

Abstract Background Myelodysplastic syndromes (MDS) are a group of clonal hematologic disorders that result in ineffective hematopoiesis. Individuals with MDS have a high risk of progressing to leukemia, with approximately 30% expected to develop acute myeloid leukemia (AML). Benzene exposure is one of the few well-established risk factors for AML, and recent studies suggest it is also a risk factor for MDS. Exposure to other occupational and residential chemicals has been inconsistently associated with hematologic malignancies. In this analysis, we evaluated occupational and residential chemical exposures as risk factors for AML and MDS using population-based data. Methods AML and MDS cases were identified by rapid case ascertainment through the Minnesota Cancer Surveillance System (MCSS). Centralized pathology and cytogenetics reviews were conducted to confirm diagnosis and classify by subtypes. Controls were identified through the Minnesota State driver's license/identification card list. Chemical exposures were measured by self-report and included occupational and residential exposure to a variety of chemicals. Unconditional logistic regression with adjustment for age, sex, previous cancer treatment, income, and farm or rural residence was used to calculate crude and adjusted odds ratios (ORs) and 95% confidence intervals (CI). Smoking, obesity and physical activity were considered as potential confounders but did not change effect estimates by 10% or more. Results We included 265 MDS cases, 420 AML cases, and 1388 controls in this analysis. As expected, we observed significant associations between benzene and both MDS and AML (OR = 1.77, 95% CI 1.17, 2.67 and OR = 2.03, 95% CI 1.45, 2.83, respectively). Exposure to vinyl chlorides was associated with MDS (OR = 2.25, 95% CI 1.32, 3.81) but not with AML (OR = 1.36, 95% CI 0.83, 2.21). Exposure to fertilizers (OR = 1.70, 95% CI 1.11, 2.59), soot (OR = 2.64, 95% CI 1.59, 4.39), creosote (OR = 1.95, 95% CI 1.08, 3.51), inks, dyes and tanning solutions (OR = 1.63, 95% 1.02, 2.60), and coal dust (2.64, 95% CI 1.30, 5.39) were associated with AML, while no association was seen between any of these exposures and MDS (range ORs = 0.78-1.25). No significant associations were observed for occupational pesticide exposures in either group. Discussion These data confirm the importance of benzene as a risk factor for myeloid malignancy and provide risk estimates in a population-based sample. A number of other significant associations with occupational and residential chemicals were observed for AML; however, all exposures were reported by only a small percentage of cases (≤10%). While chemical exposures play a clear role in the etiology of myeloid malignancy, these exposures do not account for the majority of cases. Citation Format: Jenny N. Poynter, Michaela Richardson, Michelle Roesler, Cindy K. Blair, Betsy Hirsch, Phuong Nguyen, Adina Cioc, James R. Cerhan, Erica Warlick. Chemical exposures and risk of acute myeloid leukemia and myelodysplastic syndromes in a population-based study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3427.

Polymorphisms in mitochondrial DNA (mtDNA) are used to group individuals into haplogroups reflecting human global migration and are associated with multiple diseases, including cancer. Here, we evaluate the association between mtDNA haplogroup and risk of myelodysplastic syndromes (MDS). Cases were identified by the Minnesota Cancer Surveillance System. Controls were identified through the Minnesota State driver's license/identification card list. Because haplogroup frequencies vary by race and ethnicity, we restricted analyses to non‐Hispanic whites. We genotyped 15 mtSNPs that capture common European mitochondrial haplogroup variation. We used SAS v.9.3 (SAS Institute, Cary, NC) to calculate odds ratios (OR) and 95% confidence intervals (CI) overall and stratified by MDS subtype and IPSS‐R risk category. We were able to classify 215 cases with confirmed MDS and 522 controls into one of the 11 common European haplogroups. Due to small sample sizes in some subgroups, we combined mt haplogroups into larger bins based on the haplogroup evolutionary tree, including HV (H + V), JT (J + T), IWX (I + W + X), UK (U + K), and Z for comparisons of cases and controls. Using haplogroup HV as the reference group, we found a statistically significant association between haplogroup JT and MDS (OR = 0.58, 95% CI 0.36, 0.92, P = 0.02). No statistically significant heterogeneity was observed in subgroup analyses. In this population‐based study of MDS, we observed an association between mtDNA haplogroup JT and risk of MDS. While previously published studies provide biological plausibility for the observed association, further studies of the relationship between mtDNA variation and MDS are warranted in larger sample sizes. © 2016 Wiley Periodicals, Inc.