Langer, Erica

Background Maintenance of telomere length has long been established to play a role in the biology of cancer, and several lines of evidence suggest that it may be especially important in myeloid malignancy. Measuring leukocyte telomere length (LTL) directly in case control studies is problematic because telomere length is likely to be influenced by the disease process. Recent studies have led to the identification of a robust genetic predictor of LTL, which we have used to compare differences in predicted telomere length in case control studies of myeloid leukemia and myelodysplastic syndromes (MDS) using Mendelian randomization (MR). MR is a method used to measure the association between a trait (e.g. telomere length) and an outcome (e.g. myeloid malignancy) that can't be measured directly by utilizing genetic variants known to be associated with the trait as instrumental variables. The use of genetic predictors of telomere length reduces the possibility that the association is explained by reverse causation and confounding likely to be relevant in case-control studies where telomere length is measured directly because genotypes in the general population should be randomly distributed. Additionally, predicted telomere length has the added advantage of representing telomere length over the lifetime of the individual while measuring LTL directly will represent only one time point in an individual's life. Methods Myeloid leukemia (AML and CML) 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. We used the Sequenom platform to genotype seven SNPs that were validated predictors of LTL in a recently published meta-analysis. We estimated associations between individual SNPs and myeloid malignancy using multivariable logistic regression. Mendelian randomization was used to evaluate the association between predicted LTL and risk of myeloid malignancy. Results We included 253 AML cases, 353 MDS cases, 145 CML cases, and 1,042 controls. We observed a significant association between longer predicted telomere length and AML in analyses adjusted for sex and age (OR 4.82 per additional kilobase of average telomere length, 95% CI 1.32-17.63). The individual SNP analyses suggest that the association is largely driven by rs10936599, located in TERC (OR 1.47 per allele, 95% CI 1.14-1.90; Figure). We did not observe statistically significant associations between predicted LTL and MDS or CML. Discussion In this analysis of predicted telomere length and myeloid malignancy, we identified a significant association between longer predicted leukocyte telomere length and AML. In contrast, no significant association was observed for MDS or CML although we did observe an elevated OR for longer predicted telomere length and MDS that did not reach statistical significance. Figure 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.

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.