Clonal Expansion and Aging Fuel the Development of Neoplasms, Say Experts at ASH

At a joint symposium between the American Society of Hematology and the European Hematology Association, 2 hematologists shared their own research findings, and others from the field, on somatic mutations in hematopoietic cells and clonal expansion, which is acquired and correlated with aging. This clonally restricted hematopoiesis is associated with an increased risk of myeloid or lymphoid neoplasms as well as increased cardiovascular and all-cause mortality.

Benjamin L. Ebert, MD, PhD, of the Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts, was the first to present. He explained that full-grown malignancies result from somatic mutations and the expansion of mutated hematopoietic stem cells, a condition described as myelodysplastic syndrome.¹ Ebert pointed out that an important question to answer is, ‘What is the percent of individuals who accumulate the mutations but do not develop a malignancy?’

Ebert noted that X chromosome inactivation is central to our understanding of the pathogenesis of hematological malignancies and evidence from several research groups has shown skewed X-inactivation patterns in multiple lineages and the stem cell origin for these diseases.² Additionally, evidence presented by other labs have indicated the presence of recurrent somatic mutations in TET2 with X-inactivation skewing—these mutations were specific for individuals who had clonal hematopoiesis and were non-malignant.³

The existing trend, Ebert said, it to look for specific somatic mutations in myeloid malignancy by analyzing the peripheral blood cells (PBCs) of individuals. This has been described in a paper published by his research group in 2014,⁴ wherein PBCs of over 17,000 individuals were analyzed for single-nucleotide variants that are commonly mutated in hematologic cancers. An age-related phenomenon was observed in the samples—detectable somatic mutations were rare in those younger than 40 years and were more frequently observed in those over 70 years of age. A majority of these variants were in epigenetic regulators like TP53, TET2, and ASXL1.

“This clonally-restricted hematopoiesis increases an individual’s risk of developing a hematologic malignancy,” Ebert said.

A review published by Ebert’s group in 2015 described the phenomenon of clonal hematopoiesis of indeterminate potential (CHIP)⁵. The authors noted that while age-related increase in mutations is a normal occurrence, mutations associated with myelodysplatic syndrome (MDS) in a cytopenic patient, when there are no other signs of MDS, can lead to diagnostic uncertainty. He explained that 4 types of clonal hematopoiesis have been noted:

• Unknown drivers
• Stem cell attrition
• Clonal drift
• Rare mutations

There is a significant amount of unknown, Ebert explained, adding that the field is evolving rapidly as researchers try to define whether clonal hematopoiesis, in the absence of cytopenias can convey health risks, and whether prophylactic interventions can be developed.

A recent study by his group does point to an association between CHIP and the development of myeloid malignancies.⁶ Of the 401 patients who received autologous stem-cell transplants for their lymphoma treatment, patients with CHIP had significantly lower 10-year overall survival (30.4%) compared with patients without CHIP (60.9%, P <.001).

Several studies have also noted an increased risk of therapy-related myeloid neoplasms, Ebert noted. “Patients with CHIP have reduced survival, partially due to therapy-related malignancies as well as the development of cardiovascular [CV] disease.” Ebert’s group, in their recent paper in The New England Journal of Medicine,⁷ showed that CHIP can cause a significant increase in patient risk of both coronary artery disease (HR, 2.0; 95% CI, 1.2-3.4; P = .018) and stroke (HR 2.6; 95% CI, 1.4-4.8; P = .003). Additionally, in 2 early-onset myocardial infarction cohorts, the presence of CHIP was associated with a high odds ratio for CV disease. The group also identified a few causative mutations—in the DNMT3A, TET2, ASXL1, and JAK2&mdash;that could lead to coronary artery disease.

“CHIP is associated with increased overall mortality,” Ebert concluded.

Representing the European perspective was George S. Vassiliou, MD, PhD, Wellcome Trust Sanger Institute; Department of Haematology, Wellcome Trust-MRC Cambridge Stem Cell Institute, United Kingdom.

“Myeloid neoplams can shift grades to lead to acute myeloid leukemia [AML],” Vassiliou said, adding that 50 genes of varying frequencies have been identified that have known association with clinical symptoms. “The number of coding mutations, however, are small: there are 10 known mutations in adult MDS and 13 in adult AML,” which are numbers comparable to mutations in normal hematopoietic stem cells in an older individual.

Vassiliou explained that while some cancers such as breast cancer, have a large number of mutagens, acute myeloid neoplasms have just 2 known signatures. Accumulation of mutations in 1 of 6 genes leads to clonal hematopoiesis; accumulation of additional mutations following exposure to various insults results in additional mutations that can lead to the development of myeloid syndromes in these individuals and can eventually lead to AML. “However, not all mutations lead to neoplasms,” Vassilou said.

Age-related clonal hematopoiesis is known to be associated with hotspot mutations. About 10% of individuals have mutations in specific hotspots, to which are added age-related changes in driver mutations.⁸ In individuals above 70, mutations in the spliceosome genes are more common, which are associated with MDS. Vassilou explained that these spliceosome gene mutations drive clonal expansion under selection pressures to the aging hemopoietic system and can explain the high incidence of clonal disorders associated with these mutations in advanced old age.

“Can we predict who will develop a myeloid malignancy?” Vassilou asked.

He then described an ongoing study that he’s actively involved in, the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which is designed to investigate the relationships between diet, nutritional status, lifestyle, and environmental factors, and the incidence of cancer and other chronic diseases. The study, which has more than half a million participants across 10 European countries, has a 15-year follow-up period.

The discovery cohort of the study includes 95 individuals with AML and the validation cohort has 29 with AML. Across age-groups, the prevalence of clonal hematopoiesis in the pre-AML population was 73%, compared with 33% in the control population (P <001). “The study has also discovered that splicing gene mutations accumulate at a younger age in the pre-AML population and could be predictive of malignancy,” Vassilou said.

References

1. Sperling AS, Gibson CJ, Ebert BL. The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nat Rev Cancer. 2017;17(1):5-19. doi: 10.1038/nrc.2016.112.
2. Champion KM, Gilbert JG, Asimakopoulos FA, Hinshelwood S, Green AR. Clonal haemopoiesis in normal elderly women: implications for the myeloproliferative disorders and myelodysplastic syndromes. Br J Haematol. 1997;97(4):920-926.
3. Busque L, Patel JP, Figueroa ME, et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet. 2012;44(11):1179-1181. doi: 10.1038/ng.2413.
4. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488-2498. doi: 10.1056/NEJMoa1408617.
5. 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. doi: 10.1182/blood-2015-03-631747.
6. Gibson CJ, Lindsley RC, Tchekmedyian V, et al. Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell transplantation for lymphoma. J Clin Oncol. 2017;35(14):1598-1605. doi: 10.1200/JCO.2016.71.6712.
7. Jaiswal S, Natarajan P, Silver AJ, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017;377(2):111-121. doi: 10.1056/NEJMoa1701719.
8. McKerrell T, Park N, Moreno T, et al. Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep. 2015;10(8):1239-1245. doi: 10.1016/j.celrep.2015.02.005.