No increased late-life mortality related to certain mutations in bone marrow DNA

Tech Science 13. jan 2020 3 min Professor and chief physician Kirsten Grønbæk Written by Kristian Sjøgren

New Danish research shows that certain mutations in bone marrow DNA do not show familial aggregation or lead to increased mortality among the elderly. Elderly people with these mutations can relax, says a researcher.

Clonal haematopoiesis is mutations in bone marrow cells. In the United States and elsewhere, population-based studies have been conducted of healthy older people with these mutations, which have been associated with increased risk of developing leukaemia and cardiovascular diseases and early death.

However, the new Danish research found no association with late-life mortality in a population of 299 twin pairs 73–94 years old followed for more than 20 years.

“We conclude that there is no reason for otherwise healthy older people with clonal haematopoiesis to worry about developing leukaemia and dying early,” explains Kirsten Grønbæk, Professor and Chief Consultant, Department of Haematology, Rigshospitalet, Copenhagen.

The results recently published in Blood are based on the internationally renowned Danish Twin Registry. The research was conducted in close collaboration between the research group of the Twin Registry’s research leader, Kaare Christensen, University of Southern Denmark and Kirsten Grønbæk’s research group, with Jakob Werner Hansen, Postdoctoral Fellow, Department of Haematology, Rigshospitalet as the first author.

Clinics in the United States to monitor people with clonal haematopoiesis

Interest in clonal haematopoiesis skyrocketed in 2015 when research showed that these mutations might be associated with an increased risk of developing leukaemia and early death.

The mutations are in the same genes as the mutations known to cause leukaemia but were not previously detected in otherwise healthy people and were not associated with the development of myeloid leukaemia or myelodysplastic syndrome (another type of blood cancer).

The Memorial Sloan Kettering Cancer Center in the United States and others therefore established special departments to monitor people with clonal haematopoiesis.

However, the Danish research group wanted to investigate this more closely in a very well-characterized Danish cohort of elderly twins. One reason is that other studies also suggested the possibility of genetic predisposition to clonal haematopoiesis.

“One benefit of twin studies is that they identify the optimal control person: the other twin. Comparing a twin with clonal haematopoiesis and his or her twin without clonal haematopoiesis controls for shared rearing environment as well as genetic factors – all for identical twins and half for fraternal twins,” says Kirsten Grønbæk.

Older people with clonal haematopoiesis live as long as those without

The research group examined blood samples from a population-based study of 594 healthy older twins. The blood tests had been taken from 299 twin pairs 73–94 years old, and the researchers had followed all of them for more than 20 years until they died.

The researchers could thereby determine whether the participants had clonal haematopoiesis 20 years ago and how this was associated with their health and subsequent mortality.

The results show that 214 twins (36%) had clonal haematopoiesis at baseline, but there was no difference in longevity in 127 twin pairs in which one twin had clonal haematopoiesis and the other did not.

Overall, the researchers did not find that the twins with clonal haematopoiesis died earlier or had an increased risk of developing leukaemia compared with people without clonal haematopoiesis.

Other studies have shown that people with clonal haematopoiesis have an increased risk of developing cardiovascular diseases, but this risk was not reflected in increased mortality in this group of older Danish twins.

“We found no difference and based on our data there is no reason to treat one third of the elderly as being sick simply because they have clonal haematopoiesis. Regular genetic testing will clearly remind them that they are at risk of developing leukaemia and dying earlier, and we imagine that this could unnecessarily create considerable anxiety,” says Kirsten Grønbæk.

No evidence that clonal haematopoiesis is heritable

The Danish research group also investigated whether there is hereditary predisposition to develop clonal haematopoiesis. They did this by examining whether an identical twin whose co-twin (with identical DNA) had developed clonal haematopoiesis was more likely to develop it compared with fraternal twins in the same situation.

The data showed no evidence of genetic predisposition. This led the research team to conclude that clonal haematopoiesis has environmental rather than genetic causes.

“Otherwise, relatively more identical twins would have developed clonal haematopoiesis if their co-twin had it. This is a negative result but nevertheless positive. The best news is that our study found no evidence that clonal haematopoiesis in the elderly is hereditary or increase mortality – and only strong data such as those in the Danish Twin Registry can demonstrate this,” says Kirsten Grønbæk.

However, the findings only apply for now to clonal haematopoiesis among people older than 73 years.

Important to decide who to monitor

Kirsten Grønbæk says that the researchers have previously shown that people with both anaemia and clonal haematopoiesis have a substantially increased risk of developing myelodysplastic syndrome and leukaemia over 1–10 years.

“They should be monitored closely. We therefore have several research projects underway focusing on whether the development of myelodysplastic syndrome and leukaemia can be delayed or completely prevented in this group,” says Kirsten Grønbæk.

“But few older people with clonal haematopoiesis have anaemia. It is therefore important to decide which older people should be monitored and thus become patients and which ones should remain healthy older people without unnecessary worries,” adds Kirsten Grønbæk.

Clonal hematopoiesis in elderly twins: concordance, discordance and mortality” has been published in Blood. The study was supported by Odense University Hospital AgeCare (Academy of Geriatric Cancer Research) and the Danish Cancer Society. The Novo Nordisk Foundation awarded a 5-year clinical research grant in 2013 to Kirsten Grønbæk for the project Translational Epigenetics in Haematological Cancer, and in 2017 she joined the Foundation-funded Program for Translational Hematology, which is part of the Novo Nordisk Foundation Center for Stem Cell Biology, DanStem.

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