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Germline mutations in patients with hematologic malignancies

Apr 22, 2021

Germline mutations in patients with neoplasms are more common than expected and have been found not only in children but also adults with cancer, with a frequency of around 8%. Many of these mutations affect genes where somatic mutations have previously been described for the disease, such as TP53, RUNX1, GATA2, IKZF1, and ETV6. These mutations predispose to the development of familial and sporadic hematologic malignancies, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic syndromes (MDS). These germline mutations may not necessarily be associated with a history of familial disposition and can arise spontaneously.

A review, recently published in Nature Reviews Cancer by Jeffery M. Klco and Charles G. Mullighan, described the different genes impacted by germline mutations predisposing to hematologic malignancies. Here, we report the major genes and pathways discussed in this review.1

Predisposition to MDS and acute leukemias

A summary of the genes and pathways impacted by germline mutations is shown in Table 1. Germline mutations in genes encoding for transcription factors are associated with lineage development: mutations in ETV6 and TP53 can lead to hematopoietic neoplasms in both myeloid and lymphoid lineages; mutations in CEBPA, GATA2, and RUNX1 predispose to myeloid malignancy; mutations in PAX5 and IKZF1 result in malignancies restricted to the lymphoid lineage.

Table 1. Genes and pathways impacted by germline mutations predisposing to MDS and acute leukemias*

Gene or pathway

Other acquired mutations

Hematologic malignancy (estimated penetrance)

Additional hematologic abnormality



Progression to AML frequently associated with acquisition of mutation in the WT CEBPA allele

Adult AML
(almost 100% of carriers)


Familial AML with mutated CEBPA


Somatic mutations in the WT DDX41 allele. In patients with advanced MDS or AML, TP53 secondary mutations

Adult MDS, AML, less commonly lymphoma


Familial AML with mutated DDX41



Childhood ALL, MDS, AML
(ca. 30% of carriers)

Thrombo-cytopenia, decreased platelet function

Thrombocytopenia 5


Progression to AML associated with acquisition of mutations in ASXL1, monosomy 7, trisomy 8

Pediatric MDS (up to 15% of carriers), AML

Immuno-deficiency, bone marrow failure, monocytopenia, B-cell lymphopenia

Emberger syndrome, MonoMAC syndrome



Pediatric B-ALL, less commonly T-ALL





Pediatric B-ALL



RAS–MAPK pathway: CBL, NF1, PTPN11



JMML-like proliferation with spontaneous regression

Noonan syndrome, NF1, other RASopathies


Progression associated with acquired somatic mutations in the WT RUNX1 allele or in the GATA2 gene; less commonly in CBL, DNMT3A, KRAS, FLT3

MDS, AML, less commonly T-ALL

Thrombo-cytopenia, decreased platelet function

Familial platelet disorder with propensity for myeloid malignancy


Patients with advanced disease present additional somatic mutations in SETBP1, RUNX1, ETV6

Childhood MDS, AML with monosomy 7

Bone marrow failure

MIRAGE syndrome, myelodysplasia and leukemia syndrome with monosomy 7


Patients with advanced disease present additional somatic mutations in SETBP1, RUNX1, ETV6

Childhood MDS, AML with monosomy 7

Systemic auto-inflammatory disease, bone marrow failure

Ataxia pancytopenia syndrome, myelodysplasia and leukemia syndrome with monosomy 7



Pediatric ALL (ca. 2% of carriers, most commonly low hypodiploid ALL), therapy-related myeloid neoplasms


Li–Fraumeni syndrome

Trisomy 21

Commonly, patients who develop TMD and ML-DS also have somatic GATA1 mutation

Childhood AML and ALL

Transient abnormal myelopoiesis

Down syndrome

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; B-ALL, B-cell ALL; JMML, juvenile myelomonocytic leukemia; MDS, myelodysplastic syndromes; ML-DS, myeloid leukemia associated with Down syndrome; MonoMAC, monocytopenia with mycobacterium avium complex infection; T-ALL, T-cell ALL; TMD, transient myeloproliferative disease.
*Adapted from Klco and Mullighan.1

Additional predisposing variants for AML

Recently described mutations include

  • germline mutations in the 5′ regulatory region of ANKRD26, with families carrying these mutations having an approximately 30-fold increase in risk of developing AML; and
  • deficiency in MBD4, associated with early-onset AML.

Also, other leukemia-predisposing variants include mutations in the Nijmegen breakage syndrome gene NBN, FLT3, SH2B3, CREBBP, PMS1, ABL1, and MYH9.

Predisposition to myeloproliferative neoplasms

Considering that individuals with relatives with myeloproliferative neoplasms (MPN) have a higher risk of developing an MPN than the general population, some MPN may be part of a germline predisposition. A germline haplotype in the 3′ region of the JAK2 gene is associated with a three- to four-fold increase in acquiring the JAK2 V617F mutation, and with an overall increase in non–JAK2-mutated MPN. Also, an increased risk of MPN has been associated with polymorphisms in TERT, MECOM, and the intergenic region between HBS1L and MYB. Other predisposing variants include germline variants in RBBP6, SH2B3, and duplications of ATG2B and GSKIP.

Clinical management of germline predisposition

Genetic testing on patients with hematopoietic tumors is important to identify and estimate the frequency of germline alterations. For germline analysis, the use of genomic DNA isolated from a skin biopsy or other non-hematopoietic source is preferable.

Even in patients without a strong family history of disease, it is important to test the immediate family members as germline alterations may reflect a pattern of familial inheritance or may result from a de novo mutation. The distinction between de novo germline variants versus inherited variants is clinically important because it will influence the management of the patient, including the option for future hematopoietic stem cell transplantation. In this regard, donor-derived acute myeloid leukemias have been described as a result of the transfer of germline DDX41 or GATA2 mutations within family members during allogeneic hematopoietic stem cell transplantation.

Model of disease development

Progression to disease in patients with MDS or acute leukemia predisposition syndromes is a stepwise process, initiated by a germline loss-of-function mutation in one allele of a gene that is often followed by later acquisition of somatic mutations in the remaining wild type allele and by additional cooperating mutations in other genes. By contrast, in predispositions involving SAMD9 and SAMD9L, progression to disease initiates with a gain-of-function mutant allele, and usually presents with monosomy 7 leading to haploinsufficiency of numerous genes on chromosome 7, such as EZH2, SAMD9, SAMD9L, CUX1, and MLL3.

Conclusions and future perspectives

The use of genome sequencing has led to an expansion of the list of variants associated with an increased risk of hematologic disorders.

Many germline mutations, as demonstrated in studies showing germline DDX41 mutations in adults with MDS and AML, usually do not present in childhood but may take until adulthood to be diagnosed. For this reason, genetic screening should not be restricted to children.

However, the development of optimal algorithms is required for the identification of non-coding alterations and structural variants. An improved understanding of the biological mechanisms leading to disease initiation and progression is also required. In addition, functional data are needed to define the pathogenicity of novel germline variants.

  1. Klco JM, Mullighan CG. Advances in germline predisposition to acute leukaemias and myeloid neoplasms. Nat Rev Cancer. 2021;21(2):122-137. DOI: 1038/s41568-020-00315-z