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Inherited hematologic malignancies predisposition syndromes

Oct 13, 2020

Hereditary predispositions to hematologic malignancies occur in approximately 5─10% of cases. During the Society of Hematologic Oncology (SOHO) Eighth Annual Meeting, Courtney DiNardo gave a talk about the importance of recognizing patients with inherited cancer predisposition syndromes. 1

The identification of an inherited predisposition allows optimized treatment of the patient, more informed donor decisions (avoiding a related donor with the same predisposition), and opportunities for identification and screening of family members. 1

Inherited predisposition syndromes associated with leukemia and myeloproliferative neoplasms (MPN) are reported in Table 1.

Table 1.Leukemia and MPN predisposition syndromes 1

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; B-ALL, B-cell ALL; CLL, chronic lymphocytic leukemia; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasms; T-ALL, T-cell ALL.

Hematologic malignancy

Predisposition syndrome

Adult bone marrow failure/ hypocellular MDS/AML

Fanconi anemia

Dyskeratosis congenita

Shwachman–Diamond syndrome

Diamond Blackfan anemia

Familial aplastic anemia and hypocellular MDS

Familial MDS/acute leukemia

RUNX1familial platelet disorder/AML (and T-ALL)

GATA2familial MDS/AML (MonoMAC syndrome)

CEBPαfamilial AML

ANKRD26familial platelet disorder with propensity to MDS/AML

DDX41familial MDS/AML

ETV6familial MDS/AML/lymphoid malignancies

SAMD9/SAMD9Lfamilial MDS & immunodeficiency syndrome

Familial ALL

Li–Fraumeni syndrome: germline TP53mutations

PAX5: familial B-cell lymphoid leukemias/lymphomas

IKZF1-associated predisposition to B-ALL

Biallelic SH2B3mutations (also MPN risk?)

Familial CLL

POT1familial CLL/melanoma/cardiac myxomas

Familial MPN

JAK2V617I, R564Q & R867Q/N, others

 

MPLS505N, W515R, P106L, others

 

TET2D1858fs

 

700 kb duplication, with ATG2Band GSKIPoverexpression, leads to increased progenitor sensitivity to thrombopoietin

In 15─20% of cases, patients with either aplastic anemia, hypocellular myelodysplastic syndrome (MDS), or bone marrow failure have an inherited predisposition syndrome, such as Fanconi anemia, dyskeratosis congenita (DC), Shwachman–Diamond syndrome, Diamond Blackfan anemia, or others. These patients should be recognized and referred for genetic testing in order to provide optimal treatment strategies. 1

Genetic profiling of patients with inherited bone marrow failure syndromes is important because they

  • respond poorly to anti-thymocyte globulin and cyclosporine (a shorter telomere length by flow-FISH [fluorescent in situhybridization] in patients with aplastic anemia correlates with poor response to standard immune suppressive therapy);
  • respond well to growth factors and androgens (effective in ˃ 50% of patients);
  • should be treated with specialized reduced-intensity regimens to avoid excessive morbidity (avoid alkylating agents); and
  • need surveillance for solid tumors.

Clinical evaluation 1

Dyskeratosis congenita

DC (also called short telomere syndrome, telomere biology disorder, or telomeropathy)is caused by mutations in genes important for telomere maintenance. Telomeres protect chromosome ends from degradation, and their length regulates the ability of a cell to duplicate. The instability resulting from an inadequate telomere maintenance can lead to uncontrolled cell growth and development of cancer.

Telomere flow-FISH is the technique used to detect DC. With telomere flow-FISH it is possible to distinguish DC from other causes of bone marrow failure.

Familial GATA2(MonoMAC) syndrome

Familial GATA2syndrome, also known as MonoMAC or Emberger syndrome, is due to autosomal dominant mutations or deletion of GATA2and is associated with immunodeficiency and frequent infections. The median age at diagnosis is 18 years, and the lifetime risk of MDS/acute myeloid leukemia (AML) is 75–90%. It is particularly common in younger patients with MDS, with 10─15% of them having germline GATA2mutations, and occurs frequently in those with MDS carrying monosomy of chromosome 7:

  • 27% of children and young adults
  • 72% of patients aged 12─19

In cases of transplants from a related donor, it is important to test family members to be sure that they are not GATA2 mutation-positive. However, overall survival and stem cell transplant outcomes appear to be independent of GATA2status.

RUNX1, ANKRD26, and ETV6variants

MDS and acute leukemia predisposition syndromes include autosomal dominant pathogenic variants in RUNX1(21q), ANKRD26(10p12), and ETV6(12p13), which are associated with mild to moderate thrombocytopenia, platelet aggregation defects, and abnormal megakaryocytes.

RUNX1was the first described, and about 40% of patients with germline mutations develop MDS/AML/T-cell acute lymphoblastic leukemia at a median age of 33 years. Thus, monitoring patients found to harbor these mutations is important to identify those at risk.

DDX41mutations

Autosomal dominant mutations in DDX41(5q35) have been recently identified to confer a predisposition to developing MDS/AML at a median age of 65 years. DDX41is mutated in 1% of all patients with MDS/AML, and retrospective studies have shown that these patients are particularly sensitive to lenalidomide. The majority of DDX41mutations leading to MDS/AML are germline mutations, and therefore inherited. The estimated risk of developing MDS/AML in family members of an individual with a DDX41mutation is   ̴20─30%.

Genetic characterization of disorders

An 81-gene panel, called EndLeukemia panel, was developed in 2017 to allow comprehensive molecular profiling of a variety of hematologic malignancies. 2Genes included in the panel, reported in Table 2, cover genetic alterations in AML, MDS, MPN, MDS/MPN, aplastic anemia, acute lymphoblastic leukemia, hairy cell leukemia, T-large granular lymphocytic leukemia, and T-prolymphocytic leukemia. 2

When suspected germline variants are detected, a multidisciplinary review is required to identify patients that should be further evaluated; the workflow is reported in Figure 1. 1,3

Table 2.Genes included in the EndLeukemia panel 1

Chromosome

Gene

1

BRINP3, CSF3R, GFI1, JAK1, MPL, NRAS,

2

ASXL2, DNMT3A, IDH1, SF3B1

3

CBLB, GATA2, STAG1, TERC

4

FBXW7, KIT, TET2

5

DDX41, IL7R, NPM1, TERT

7

BRAF, CUX1, EZH2, IKZF1

8

RAD21

9

HNRNPK, JAK2, NOTCH1, PAX5

10

A NKRD26, PTEN, SMC3

11

CBL, EED, HRAS, MLL, SF1, WT1

12

ETNK1, ETV6, KRAS, PTPN11, PRPF40B, SH2B3

13

FLT3

15

IDH2, MAP2K1, PML

16

CREBBP

17

NF1, RARA, SRSF2, STAT3, STAT5A, STAT5B, SUZ12, TP53

18

SETBP1

19

CALR, CBLC, CEBPA, ELANE, JAK3, U2AF2

20

ASXL1, GNAS

21

RUNX1, U2AF1

22

SF3A1

X

BCOR, BCORL1, CRLF2, GATA1, IL2RG, KDM6A, PHF6, PIGA, SMC1A, STAG2, ZRSR2

Figure 1.Workflow for the multidisciplinary review of suspected germline variants 3

HHMC, hereditary hematologic malignancies clinic; WHO, World Health Organization.

Current consensus statement 1

The recommendations for clinicians managing patients with familial hematologic malignancies syndrome are the following:

  • Clinical exam with complete blood count one or two times a year;
  • Bone marrow biopsy at the time of diagnosis, to identify any clonal changes or secondary mutations that may lead to the development of hematologic malignancies, and then every year for research surveillance;
  • Consider allogeneic stem cell transplant at time of development of dysplasia, or clonal somatic cytogenetic or molecular abnormality; and
  • For younger and interested patients, suggest reproductive counseling and preimplantation genetic testing.

  1. DiNardo C. Familial AML. Oral presentation #MTP11. SOHO Eighth Annual Meeting; Sep 9, 2020; Virtual.
  2. Ok CY, Singh R, Luthra R, et al. Endleukemia Assay v1: Enabling NGS-based comprehensive routine molecular profiling of leukemias in routine clinical care. 2017;130(S1):2679. DOI: 10.1182/blood.V130.Suppl_1.2679.2679
  3. DiNardo C, Routbort MJ, Bannon SA, et al. Improving the detection of patients with inherited predispositions to hematologic malignancies using next-generation sequencing-based leukemia prognostication panels. Cancer. 2018;124(13):2704-2713. DOI: 1002/cncr.31331