Abstract
Abstract
Obesity is rapidly overtaking smoking as the leading preventable cause of cancer, particularly in cancers of the breast and colon. In a large cohort of individuals participating in the National Institutes of Health-AARP Diet and Health Study, a higher incidence of MDS and an increased mortality was observed in individuals with body mass index (BMI) >30 compared to those with BMI <25 (HR 2.18 (95% CI: 1.51, 3.17; P < 0.001). The biology underlying these findings in MDS patients (pts) is not established. We hypothesized that genomic patterns may distinguish obese from non-obese pts with MDS and that these genomic changes may be associated with disease characteristics.
We performed genomic analyses by using next-generation targeted deep sequencing (NGS) and whole exome sequencing (WES) of 62 significantly affected genes that play an important role in MDS pathogenesis. Mutations were considered individually and grouped into several functional pathways. Overweight (BMI 25-29) and obese (BMI >30) were combined in one group (BMI-H).
Of 205 pts with MDS treated at our institution between 1/2000 - 1/2013, 146 (71%) were BMI-H. Interestingly, only 2 patients had BMI <18.5 (underweight) and were combined with normal BMI group (BMI-N). BMI-H pts presented with lower white blood count (median 3.6 vs. 4.4, p = .03), but other clinical characteristics were similar. With median follow up of 33.6 months (mo) (range 0.4-128.5), a trend toward inferior survival was observed in BMI-H group compared to BMI-N (32.9 mo vs. 34.8 mo, p = .07). Furthermore, higher rates of progression to acute myeloid leukemia (AML) were seen in the BMI-H as compared to BMI-N pts (23% vs. 19%, p = .02).
Overall, 74% of pts had at least one of the 62 screened mutations, the most common being: SF3B1 (17%), TET2 (17%), ASXL1 (14%), STAG2 (12%), DNMT3A (9%), U2AF1/2 (8%), GPR98 (8%), and RUNX1(7%). Mutations in IDH1/2 (5% vs. 0%), DNMT3A (11% vs. 5%), TET2 (18% vs. 14%) occurred more frequently in BMI-H, where SF3B1 (25% vs. 13%), and NRAS (7% vs. 2%) mutations were more common in BMI-N. Within functional groups, mutations in splicing machinery genes were less common in BMI-H compared to BMI-N (32% vs. 41%, p = .05) and mutations in DNA methylation genes were more common in BMI-H (20% vs. 34%, p = .02). Clonal architecture analysis points to the presence of different dominant clones between the two groups. In the dominant MDS clones, mutations in TET2 and DNMT3A were observed more frequently in pts with BMI-H, whereas mutations in SF3B1 were more frequently observed in BMI-N pts.
In conclusion, overweight and obese pts with MDS have a trend for inferior survival and higher rate of progression to AML as compared to MDS pts with normal weight. Genomic differences in clonal architecture and distribution of somatic mutations were observed in the BMI-H group. Further exploration including germline mutations and previously described familial obesity genes is needed to expound on the interaction between the biology of obesity and leukemogenesis of MDS.
Citation Format: Aziz Nazha, David Seastone, Hideki Makishima, Matt Kalaycio, Hetty E. Carraway, Anjali S. Advani, Ahamd Zarzour, Jennifer Carew, Aaron T. Gerds, Sudipto Mukherjee, Jaroslaw P. Maciejewski, Mikkael A. Sekeres. Obesity and genomic changes in patients with myelodysplastic syndromes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5575. doi:10.1158/1538-7445.AM2015-5575
