Myelodysplastic syndromes are a malignant condition affecting the proper development of blood cells in the bone marrow. Symptoms include fatigue, anemia and immune defects and, if not properly treated, may progress towards an acute leukemia, a much worse condition. The underlying cause of a myelodysplastic syndrome is the presence of mutations, changes in the DNA, affecting critical genes that drive the correct development of blood cells.

Mutations happen in your cells from time to time and, as such, are more frequent in elderly people. Accordingly, most of the myelodysplastic syndromes appear over the age of seventy. However, we all bear mutations in our DNA since we were born. Those are called germline mutations and may have an impact on our predisposition to develop myelodysplastic syndromes if critical genes are affected. Telling one from the other makes a great difference in terms of treatment and outcome for patients.

The current guidelines assume that germline mutations are mostly responsible for early diagnostics, typically in patients younger than 50, while those appearing in older ages would correspond to the accumulation of the so-called somatic mutations. Therefore, testing for germline mutations is currently encouraged only for people diagnosed before the age of 50.

A second parameter used by the guidelines is the relative abundance of a mutation in the body. Germline variants tend to be present in all the cells of the body, because they appear early during embryo development and are there since the beginning, while somatic mutations appear in a cell during lifetime and expand since then. As a general rule, abundances over 30% are considered germline by default and treated accordingly.

New research, however, argues otherwise. At the Josep Carreras Institute, a team led by Dr. Francesc Solé and Dr. Oriol Calvete interrogated a cohort of 168 patients diagnosed with myelodysplastic syndromes and found that germline mutations can be responsible for the onset of a myelodysplastic syndrome at virtually any age, confirming previous evidence from others.

Their research, published at the British Journal of Haematology together with colleagues from the Lerner Research Institute in Ohio (USA), proved that it is difficult to tell apart germline from somatic mutations only by age at onset, associated risk or relative abundance and, thus, advocates for all patients being tested for germline mutations, regardless of their age, to optimize its clinical management.

Reference article:

Oriol Calvete, Julia Mestre, Arda Durmaz, Carmelo Gurnari, Jaroslaw P. Maciejewski, Francesc Solé. “Are the current guidelines for identification of myelodysplastic syndrome with germline predisposition strong enough?”. British Journal of Haematology, 30 Jan 2023 https://doi.org/10.1111/bjh.18676