Page 103 - 2019_12-Haematologica-web

Clonal hematopoiesis and AML risk
credibility of variants detected at very low VAF.
The most notable limitations of the study relate to sam- ple size and statistical precision, as previously noted. We had insufficient statistical power for concurrent interroga- tion of multiple mutations and for more than exploratory analysis of clone size and time to AML diagnosis. Likewise, we could not control for potential confounding variables (other than matching factors), such as body mass index or history of cigarette smoking,10,12 or stratify by those variables or by follow-up time. Additionally, myelo- proliferative neoplasms and myelodysplastic syndrome were not routinely reported in the NHS and HPFS, so we were unable to identify which participants had clonal hematopoiesis attributable to one of these pre-malignant disorders. Further, we did not have access to AML diag- nostic samples for the cases in this study, making it impos- sible to determine which, if any, clonal hematopoietic mutations detected prior to diagnosis appeared in the founding AML clone. The study was limited technically by the sequencing panel, which targeted 54 genes recur- rently mutated in AML. Future studies should expand the panel to target the entire exome or at least include addi- tional genes that have been observed in CHIP, such as PPM1D,1 to more fully characterize the spectrum of muta- tions in clonal hematopoiesis. However, any increase in panel size must be balanced with the cost of sequencing, which is higher for ECS compared to conventional NGS. Lastly, ECS, while precise, cannot co-localize mutations within the same cell. Future single-cell sequencing studies would provide further insights into the evolution of pre- leukemic clones and potentially improve screening for risk
of developing AML.
In summary, we demonstrated that detection of AML-
associated variants at VAF as low as 0.01 is associated
with long-term risk of AML in concordance with other recent reports. Additionally, our study has extended by several years the period of follow up over which this increased risk applies and provided evidence that even individual variants in known driver genes may be associ- ated with AML risk, suggesting that not all clonal somatic variants have equivalent associations with AML. The col- lective data from this and previous reports underscore that, while clonal hematopoiesis is associated with a markedly increased long-term risk of AML, the vast major- ity of individuals with detectable clonal hematopoiesis will not develop AML. Likewise, further detailed investi- gation is needed to incorporate detection of clonal hematopoiesis into AML-risk assessment for healthy indi- viduals. Such studies will require considerably larger pop- ulations, ideally with serial samples and sufficient sample size to analyze multiple features of clonal hematopoiesis (including individual variants, gene-level mutational pro- files and temporal evolution of variant clones) as well as additional genetic, epigenetic and environmental factors that may influence the stepwise progression of healthy cells to leukemic clones. Future work will also need to incorporate single cell sequencing technology to identify, which rare clonal mutations occur in the same cells and tease out the sequence of mutation acquisition driving the transformation from clonal hematopoiesis to AML.
Funding
This project was supported in part by the National Institutes of Health (R01 CA211711, UM1 CA186107, P01 CA87969, R01 CA49449, UM1 CA167552 and R01 CA149445), the Children's Discovery Institute of Washington University and St Louis Children's Hospital (MC-II-2015-461), and Hyundai Hope on Wheels (2015Q3-3).
References
1. Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015; 126(1):9-16.
2. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associat- ed with adverse outcomes. N Engl J Med. 2014;371(26):2488-2498.
3. Genovese G, Kähler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014; 371(26):2477-2487.
4. Desai P, Mencia-Trinchant N, Savenkov O, et al. Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat Med. 2018;24(7):1015-1023.
5. Abelson S, Collord G, Ng SWK, et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature. 2018; 559(7714):400-404.
6. Young AL, Challen GA, Birmann BM, Druley TE. Clonal haematopoiesis har- bouring AML-associated mutations is ubiq- uitous in healthy adults. Nat Commun. 2016; 712484.
7. Wong TN, Ramsingh G, Young AL, et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature. 2015;518(7540):552- 555.
8. Hu FB, Willett WC. Diet and coronary heart disease: findings from the Nurses’ Health Study and Health Professionals’ Follow-up Study. J Nutr Health Aging. 2001;5(3):132-138.
9. Colditz GA, Hankinson SE. The Nurses’ Health Study: lifestyle and health among women. Nat Rev Cancer. 2005;5(5):388- 396.
10. Hankinson SE, Willett WC, Manson JE, et al. Alcohol, height, and adiposity in rela- tion to estrogen and prolactin levels in postmenopausal Women. JNCI J Natl Cancer Inst. 1995;87(17):1297-1302.
11. Zhang X, Tworoger SS, Eliassen AH, Hankinson SE. Postmenopausal plasma sex hormone levels and breast cancer risk over 20 years of follow-up. Breast Cancer Res Treat. 2013;137(3):883-892.
12. Poynter JN, Richardson M, Blair CK, et al. Obesity over the life course and risk of acute myeloid leukemia and myelodysplas- tic syndromes. Cancer Epidemiol. 2016; 40:134-140.
13. R Core Team (2014). R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.r-pro- ject.org/.
14. Xie M, Lu C, Wang J, et al. Age-related mutations associated with clonal hematopoietic expansion and malignan- cies. Nat Med. 2014;20(12):1472-1478.
15. Cancer Genome Research Atlas Network. Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia. N Engl J Med. 2013;368(22):2059-2074.
haematologica | 2019; 104(12)
2417