Clonal Evolution in the Setting of Germline Predisposition

Germline predisposition to haematological malignancy is an entity with an increasing awareness amongst hematologists in both clinical and research domains, with new predisposition genes being identified at a rapid rate. Recent advances in sequencing technologies, allowing the molecular profiling of hematological malignancies, have revealed clonal evolution of tumours in germline mutation carriers. RUNX1, as the first autosomal dominant hematological malignancy predisposition gene, is the best characterised in this regard. A consensus of findings from several groups indicates that in tumours of germline RUNX1 mutation carriers, somatic alteration of the second RUNX1 allele is the most frequent event observed. This is similarly true for DDX41 germline mutated tumours, where up to 50% of tumours have mutation of the second DDX41 allele, predominantly p.R525H. Studies on germline CEBPA mutated tumours also indicate a high selection for somatic mutation of the second allele, with temporally distinct leukemias arising in patients each carrying different somatic CEBPA mutations. These findings are in contrast to germline GATA2 mutated malignancy where biallelic mutations are rare and instead monosomy 7 and somatic mutation of ASXL1 are most commonly seen. How acquired mutations and epigenetic changes, as well as additional germline modifiers, can affect malignancy phenotype, age of onset and disease penetrance within families is an emerging theme that will also be discussed.

Germline predisposition syndromes also offer a unique opportunity to identify acquired changes that occur prior to overt malignancy development in carriers. Although not yet well understood, this is an area of great interest. Recent studies in germline RUNX1 mutation carries without malignancy, has identified acquired mutations in genes associated with clonal hematopoiesis (e.g. DNMT3A). These mutations occur at an earlier age than that observed in the general population for clonal hematopoiesis, raising the possibility that they may be triggers for early malignancy onset. In contrast to clonal evolution that promotes tumour development; somatic alterations may also act to rescue consequences of germline mutations through somatic revertant mosaicism. This is well established in bone marrow failure syndromes such as Fanconi Anemia and Diamond Blackfan Anemia. More recently, SAMD9 and SAMD9L germline mutated syndromes (MIRAGE syndrome and Ataxia Pancytopenia syndrome, respectively) have allowed the examination of both phenomena operating contemporaneously in families. Selective pressure to remove or correct germline gain of function mutations, that cause growth deficiencies in hematopoietic cells, leads to acquisition of mutations and chromosomal abnormalities that act to rescue cytopenias, but can also predispose to subsequent development of myelodysplastic syndrome (e.g. monosomy 7).

Finally, treatment related manipulation of the hematopoietic system offers its own risks for clonal evolution leading to tumour development where germline predisposition is concerned. In severe congenital neutropenia, treatment with G-CSF may lead to an increased risk of MDS and AML, associated with somatic CSF3R and RUNX1 mutations. Additionally, where asymptomatic germline carriers are inadvertently used as stem cell donors in genetic predisposition syndromes, stem cell stress experienced from reconstituting the hematopoietic system of the host may trigger development of donor cell leukemia.

A better understanding of the contexts in which clonal haematopoiesis in germline predisposition syndromes occur, offers the hope of more sensitive molecular monitoring techniques and development of improved and earlier treatment interventions.