Genetics of Hereditary Hematologic Malignancies (PDQ®): Genetics - Health Professional Information [NCI]

Introduction

Inherited predisposition syndromes that lead to hereditary hematologic malignancy (HHM) are increasingly being recognized.[1,2,3,4] These syndromes were originally thought to be rare. However, recent estimates suggest that more than 10% of all hematologic malignancies (HM) may have an inherited component. The presentations of HHM syndromes occur on a spectrum. They can occur during childhood with conditions like inherited bone marrow failure syndromes, or they can occur in adulthood with conditions like DDX41-associated myeloid cancers, in which malignancy occurs at a median age of 68 years. Updated guidelines for the diagnosis and treatment of HMs (i.e., the World Health Organization, International Consensus Classification of Myeloid Neoplasms and Acute Leukemias [ICC], and European LeukemiaNet [ELN] guidelines) now include genetic testing considerations for HHM. Genetic testing for HHM is often challenging because it can be difficult to obtain a normal germline control tissue sample, such as a skin biopsy, to confirm the hereditary nature of a predisposing pathogenic variant. Allogeneic hematopoietic stem cell transplant (HSCT) is a curative treatment for many HMs. However, timely diagnosis of an HHM is essential for evaluation and management. Timely diagnosis allows for the identification of optimal transplant donors who are related to the patient (i.e., family members who are HSCT matches but do not have the same HHM), the selection of appropriate cytoreductive therapy, and the transplant conditioning regimen.

References:

1. Arber DA, Orazi A, Hasserjian RP, et al.: International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood 140 (11): 1200-1228, 2022.
2. Döhner H, Wei AH, Appelbaum FR, et al.: Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 140 (12): 1345-1377, 2022.
3. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016.
4. Sahoo SS, Kozyra EJ, Wlodarski MW: Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes. Best Pract Res Clin Haematol 33 (3): 101197, 2020.

Natural History of Hereditary Hematologic Malignancies

Since germline hematologic malignancy (HM) syndromes are rare and heterogenous, data on their natural histories are scarce. Initial hematologic manifestations in hereditary hematologic malignancy (HHM) syndromes can range from thrombocytopenia (in RUNX1-, ETV6-, ANKRD26-, and MECOM-associated syndromes), leukopenia and monocytopenia (in GATA2 deficiency syndrome), multilineage cytopenia (in classical inherited bone marrow failure syndromes), and B-cell or natural killer cell lymphopenias (caused by pathogenic variants in several different genes).[1,2,3,4,5,6,7,8,9] The progression from initial hematologic manifestations to an HM is typically gradual, with varying latency periods occurring from birth to leukemia development. Many patients exhibit dysplasia in the bone marrow or clonal genetic/cytogenetic aberrations, which can eventually lead to HMs.

In some pathogenic variant carriers of HHM syndromes, initial manifestations may include extra-hematopoietic abnormalities, such as the following:

• Constitutional and congenital defects (i.e., intrauterine growth restriction; failure to thrive; and skeletal, cardiac, urogenital, mucocutaneous, vascular, or neurological abnormalities).
• Increased sensitivity to chemotherapy (manifests as delayed blood count recovery or increased toxicity).
• Atypical systemic infections.
• Increased risk of solid tumors.

Complications of infection and malignancy risk increase with patient age and are the main causes of mortality in this population. These factors must be considered when selecting management strategies, which can include watchful waiting, supportive care, or curative hematopoietic stem cell transplant.

Various disease aspects are gene- or variant -specific, including risks to develop HMs and the heterogenous spectrum of acquired events that can occur (which may include cytogenic changes, leukemia driver variants and somatic genetic rescue events during hematopoiesis). However, the natural histories of these syndromes are often unpredictable, with identical pathogenic variants resulting in both indolent or rapidly progressing disease in different individuals. These differences are likely due to unknown disease-modifying factors.

References:

1. Alter BP, Giri N, Savage SA, et al.: Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study. Br J Haematol 150 (2): 179-88, 2010.
2. Tamary H, Nishri D, Yacobovich J, et al.: Frequency and natural history of inherited bone marrow failure syndromes: the Israeli Inherited Bone Marrow Failure Registry. Haematologica 95 (8): 1300-7, 2010.
3. Niewisch MR, Giri N, McReynolds LJ, et al.: Disease progression and clinical outcomes in telomere biology disorders. Blood 139 (12): 1807-1819, 2022.
4. Brown AL, Hahn CN, Scott HS: Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA). Blood 136 (1): 24-35, 2020.
5. Dutzmann CM, Spix C, Popp I, et al.: Cancer in Children With Fanconi Anemia and Ataxia-Telangiectasia-A Nationwide Register-Based Cohort Study in Germany. J Clin Oncol 40 (1): 32-39, 2022.
6. Da Costa L, O'Donohue MF, van Dooijeweert B, et al.: Molecular approaches to diagnose Diamond-Blackfan anemia: The EuroDBA experience. Eur J Med Genet 61 (11): 664-673, 2018.
7. Myers KC, Furutani E, Weller E, et al.: Clinical features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia: a multicentre, retrospective, cohort study. Lancet Haematol 7 (3): e238-e246, 2020.
8. Rotulo GA, Beaupain B, Rialland F, et al.: HSCT may lower leukemia risk in ELANE neutropenia: a before-after study from the French Severe Congenital Neutropenia Registry. Bone Marrow Transplant 55 (8): 1614-1622, 2020.
9. Rosenberg PS, Zeidler C, Bolyard AA, et al.: Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy. Br J Haematol 150 (2): 196-9, 2010.

Risk Factors for Hereditary Hematologic Malignancies

Several environmental, occupational, and iatrogenic exposures increase the risk of developing hematologic malignancies (HMs) in the general population. These factors likely further increase risk in individuals with a germline predisposition to HM, although the precise interactions between these exposures and germline hereditary hematologic malignancies (HHMs) are not well known. For more information about risk factors for HMs in the general population, see the Risk Factors section in Myelodysplastic Syndromes Treatment.

Examples of exposures that increase risk for HMs include benzene (and other organic solvents), pesticides, radiation, and chemotherapy.[1,2] The latency period between initial exposure and diagnosis of a secondary HM is 2 to 3 years for patients who were exposed to topoisomerase II inhibitors and 5 to 7 years for those who were exposed to alkylating agents or radiation therapy.

Patients with DNA repair disorders, like Fanconi anemia, have very high risks of developing secondary malignancies after radiation or chemotherapy, and these malignancies often progress rapidly.[3] Patients with germline RUNX1 and CEBPA pathogenic variants who are treated for acute myeloid leukemia (AML) have very high rates of relapse and AML recurrence after initial rounds of chemotherapy.[4] A family history of HMs (even in the absence of a known, single-gene Mendelian hereditary predisposition) significantly increases an individual's risk of developing an HM.[5] This increase is likely caused by shared genetic and environmental risk factors.

References:

1. Patel AA, Rojek AE, Drazer MW, et al.: Therapy-related myeloid neoplasms in 109 patients after radiation monotherapy. Blood Adv 5 (20): 4140-4148, 2021.
2. Morton LM, Dores GM, Schonfeld SJ, et al.: Association of Chemotherapy for Solid Tumors With Development of Therapy-Related Myelodysplastic Syndrome or Acute Myeloid Leukemia in the Modern Era. JAMA Oncol 5 (3): 318-325, 2019.
3. Alter BP, Giri N, Savage SA, et al.: Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study. Br J Haematol 150 (2): 179-88, 2010.
4. Brown AL, Hahn CN, Scott HS: Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA). Blood 136 (1): 24-35, 2020.
5. Sud A, Chattopadhyay S, Thomsen H, et al.: Analysis of 153 115 patients with hematological malignancies refines the spectrum of familial risk. Blood 134 (12): 960-969, 2019.

Prevalence of Hereditary Hematologic Malignancies

The prevalence of germline predisposition syndromes is increasingly being recognized in individuals with hematologic malignancies (HM). The prevalence of these predisposition syndromes continues to be studied and defined. It varies widely depending on the patient's clinical diagnosis, age, and family history. A germline predisposition is estimated to underlie 10% to 20% of HM cases across the lifespan.[1,2,3,4,5,6,7,8,9,10,11] Studies of pediatric HM/bone marrow failure (BMF) cohorts suggest that 10% to 30% of diagnoses are caused by underlying germline pathogenic variants, typically in genes like SAMD9, SAMD9L, GATA2, genes in the Fanconi anemia pathway, and genes involved in telomere biology. The prevalence of inherited predisposition syndromes in adult-onset HM/BMF is less understood, but evidence is growing as genetic testing is offered to a growing number of affected individuals. Recent studies imply that approximately 10% to 20% of familial myeloid malignancies, like acute myeloid leukemia and myelodysplastic syndrome (MDS), are inherited. Furthermore, it is becoming increasingly common to diagnose a BMF syndrome (typically with pediatric onset), such as Fanconi anemia or a telomere biology disorder, in an adult whose personal and family history may not align with conventional descriptions of the phenotype.

Importantly, somatic testing (which is routinely performed on individuals with HMs), may detect pathogenic variants that originate in the germline. Additionally, several genomic features are pathognomonic for certain germline pathogenic variants associated with hereditary hematologic malignancies (HHMs). In one study, 94% (33/35) of patients with somatic DDX41 variants that exceeded a 40% variant allele frequency harbored a germline DDX41 pathogenic variant.[12] When a DDX41 p.R525H variant presented in trans with another DDX41 variant, it was especially indicative of a germline DDX41 pathogenic variant. Another study of pediatric (<18 y) MDS showed that 8% of patients carried a germline SAMD9/9L pathogenic variant, and 7% (38/548) carried a germline GATA2 pathogenic variant.[10] In contrast, many of the genes implicated in inherited HM predisposition may also acquire somatic pathogenic variants, which can be detected in the bone marrow or peripheral blood at varying allele frequencies. Follow-up germline evaluation can be helpful to discern the genomic origin of these pathogenic variants. The understanding of somatic and germline variants in HM and the way that these variants interact is expected to evolve since several studies on this topic are ongoing.

References:

1. Bluteau O, Sebert M, Leblanc T, et al.: A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. Blood 131 (7): 717-732, 2018.
2. Feurstein S, Trottier AM, Estrada-Merly N, et al.: Germ line predisposition variants occur in myelodysplastic syndrome patients of all ages. Blood 140 (24): 2533-2548, 2022.
3. Douglas SPM, Lahtinen AK, Koski JR, et al.: Enrichment of cancer-predisposing germline variants in adult and pediatric patients with acute lymphoblastic leukemia. Sci Rep 12 (1): 10670, 2022.
4. Lahtinen AK, Koski J, Ritari J, et al.: Clinically relevant germline variants in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 58 (1): 39-45, 2023.
5. Singhal D, Hahn CN, Feurstein S, et al.: Targeted gene panels identify a high frequency of pathogenic germline variants in patients diagnosed with a hematological malignancy and at least one other independent cancer. Leukemia 35 (11): 3245-3256, 2021.
6. DiNardo CD, Bannon SA, Routbort M, et al.: Evaluation of Patients and Families With Concern for Predispositions to Hematologic Malignancies Within the Hereditary Hematologic Malignancy Clinic (HHMC). Clin Lymphoma Myeloma Leuk 16 (7): 417-428.e2, 2016.
7. Churpek JE, Pyrtel K, Kanchi KL, et al.: Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia. Blood 126 (22): 2484-90, 2015.
8. Holme H, Hossain U, Kirwan M, et al.: Marked genetic heterogeneity in familial myelodysplasia/acute myeloid leukaemia. Br J Haematol 158 (2): 242-248, 2012.
9. Lindsley RC, Saber W, Mar BG, et al.: Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation. N Engl J Med 376 (6): 536-547, 2017.
10. Sahoo SS, Pastor VB, Goodings C, et al.: Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes. Nat Med 27 (10): 1806-1817, 2021.
11. Kim B, Yun W, Lee ST, et al.: Prevalence and clinical implications of germline predisposition gene mutations in patients with acute myeloid leukemia. Sci Rep 10 (1): 14297, 2020.
12. Bannon SA, Routbort MJ, Montalban-Bravo G, et al.: Next-Generation Sequencing of DDX41 in Myeloid Neoplasms Leads to Increased Detection of Germline Alterations. Front Oncol 10: 582213, 2020.

Risk Assessment and Genetic Testing for Hereditary Hematologic Malignancies

Considerations for Risk Assessment and Identification of Individuals at Risk for Hereditary Hematologic Malignancies (HHM)

It is recommended that thorough personal and family histories be obtained for all patients who present with hematologic malignancies (HMs).[1] Some disorders are associated with specific hematologic or nonhematologic disease manifestations. For example, germline RUNX1, ETV6, and ANRKD26pathogenic variants are associated with lifelong mild- to moderate-thrombocytopenia and qualitative platelet deficits. Other germline pathogenic variants, like those in GATA2, SAMD9, and SAMD9L, are associated with immunodeficiency and frequent infections. For more information about cancer genetics risk assessment and genetic counseling, see Cancer Genetics Risk Assessment and Counseling.

The absence of a family history of HMs does not preclude the need for genetic testing since a hereditary predisposition to HMs can occur de novo, and some HHMs exhibit only mild to moderate penetrance. While an HM diagnosis at a young age can raise suspicion for an HHM, an older age at diagnosis does not eliminate the need for genetic testing, since some HHMs (i.e., DDX41) typically present in older patients, with a median age of HM onset in the mid-60s.

Indications for Genetic Testing

Since phenotypes for HHM have become better defined, indications for germline genetic evaluation have emerged. National and international guideline-issuing bodies (National Comprehensive Cancer Network [NCCN], International Consensus Classification [ICC], World Health Organization [WHO], and European LeukemiaNet [ELN]) recently updated their guidelines to include recognition of HHM.[2,3,4]

When evaluating patients, key factors that prompt consideration of germline genetic testing include the following:[1]

• A personal history of a hematologic disease or malignancy.
• A family history of hematologic disease, early-onset cancers, or treatment-related toxicities.
• A personal or family history of malignancy characteristics such as early-onset cancers or an HM with atypical features.

Despite meeting clinical indications for HHM genetic testing, referral for genetic evaluation remains inconsistent.[5] Therefore, unbiased, expansive germline genetic panel testing is emerging as a key diagnostic tool to identify hereditary HM predisposition, thanks to increased availability of multigene panels, accessible genetic counseling, and growing awareness.[6]

Technical Aspects of Genetic Testing for HHM

Accurate identification of an underlying HHM is achieved by testing DNA from nonhematopoietic germline cells. In individuals without HMs, germline DNA (for genetic testing) is typically obtained from blood, saliva, or buccal swabs. However, in those with HMs, white blood cells (which are present in the saliva and buccal swabs) harbor somatic variants that can confound interpretation of germline genetic test results.[7] Somatic variants acquired in hematopoietic cells can occur in genes that also cause HHM, like RUNX1, CEBPA, GATA2, and TP53, making it difficult to discriminate between germline and somatic variants.[8] Variants detected via somatic testing (i.e., on myeloid malignancy panels) may identify germline pathogenic variants, but these panels are not substitutes for germline genetic testing.

Obtaining true germline DNA is critical when evaluating patients for HHM. Cultured skin fibroblasts (collected via punch biopsies) are the most common germline DNA source for HHM genetic testing.[1] Other options, like fingernail clippings or hair follicles, are not widely available. It may take 6 to 8 weeks to receive genetic test results when using these sample types. Therefore, it is important that patients be referred to genetics in a timely manner to inform therapeutic decision making and the donor selection process for hematopoietic stem cell transplant (HSCT). For individuals who have received allogeneic HSCT, their blood and buccal swab samples contain their donor's DNA.[9] Therefore, cultured fibroblasts may be needed to determine the germline statuses of these individuals.

Standard methodological approaches for HHM genetic testing include the following:

• Multigene next-generation sequencing (NGS) panels: These panels use NGS to analyze a set of genes that are associated with HHM and HHM-related disorders.
• Single nucleotide polymorphism (SNP) microarray analysis: SNP arrays detect copy number variations and regions with loss of heterozygosity (LOH), which are often indicative of clonal hematopoiesis and can be associated with a specific HHM.
• Whole exome sequencing (WES) and whole genome sequencing (WGS): WES and WGS provide sequencing of the entire protein-coding region (exome) or full genome, respectively. These approaches allow analysis of virtual gene panels (different panels can be applied to the full sequencing data to analyze specific subsets of genes) from full sequencing data and unbiased analysis across all genes. WES and WGS can also enable detection of LOH through bioinformatic algorithms.

The optimal genetic testing approach depends on the patient's clinical presentation and local genetic testing resources. WES and WGS are emerging as a standards since they can reanalyze data over time as new genetic associations are reported. Consultations with genetic counselors help guide the patient's genetic testing strategy.

References:

1. DiNardo CD, Bannon SA, Routbort M, et al.: Evaluation of Patients and Families With Concern for Predispositions to Hematologic Malignancies Within the Hereditary Hematologic Malignancy Clinic (HHMC). Clin Lymphoma Myeloma Leuk 16 (7): 417-428.e2, 2016.
2. Arber DA, Orazi A, Hasserjian RP, et al.: International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood 140 (11): 1200-1228, 2022.
3. Döhner H, Wei AH, Appelbaum FR, et al.: Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 140 (12): 1345-1377, 2022.
4. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016.
5. Clifford M, Bannon S, Bednar EM, et al.: Clinical applicability of proposed algorithm for identifying individuals at risk for hereditary hematologic malignancies. Leuk Lymphoma 60 (12): 3020-3027, 2019.
6. Roloff GW, Godley LA, Drazer MW: Assessment of technical heterogeneity among diagnostic tests to detect germline risk variants for hematopoietic malignancies. Genet Med 23 (1): 211-214, 2021.
7. Hamilton KV, Fox LC, Nichols KE: How I communicate with patients and families about germ line genetic information. Blood 141 (26): 3143-3152, 2023.
8. Drazer MW, Kadri S, Sukhanova M, et al.: Prognostic tumor sequencing panels frequently identify germ line variants associated with hereditary hematopoietic malignancies. Blood Adv 2 (2): 146-150, 2018.
9. Imanishi D, Miyazaki Y, Yamasaki R, et al.: Donor-derived DNA in fingernails among recipients of allogeneic hematopoietic stem-cell transplants. Blood 110 (7): 2231-4, 2007.

Genes Associated with Hereditary Hematologic Malignancies

All described inherited predispositions to hematologic malignancies follow well-defined Mendelian inheritance patterns: autosomal dominant, autosomal recessive, and X-linked. Penetrance varies depending on the hereditary hematologic malignancy (HHM).

References:

1. Arber DA, Orazi A, Hasserjian RP, et al.: International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood 140 (11): 1200-1228, 2022.
2. Döhner H, Wei AH, Appelbaum FR, et al.: Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 140 (12): 1345-1377, 2022.
3. Bluteau D, Masliah-Planchon J, Clairmont C, et al.: Biallelic inactivation of REV7 is associated with Fanconi anemia. J Clin Invest 126 (9): 3580-4, 2016.
4. Park JY, Virts EL, Jankowska A, et al.: Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene. J Med Genet 53 (10): 672-680, 2016.
5. Mirabello L, Khincha PP, Ellis SR, et al.: Novel and known ribosomal causes of Diamond-Blackfan anaemia identified through comprehensive genomic characterisation. J Med Genet 54 (6): 417-425, 2017.
6. O'Donohue MF, Da Costa L, Lezzerini M, et al.: HEATR3 variants impair nuclear import of uL18 (RPL5) and drive Diamond-Blackfan anemia. Blood 139 (21): 3111-3126, 2022.
7. Toufektchan E, Lejour V, Durand R, et al.: Germline mutation of MDM4, a major p53 regulator, in a familial syndrome of defective telomere maintenance. Sci Adv 6 (15): eaay3511, 2020.
8. Kermasson L, Churikov D, Awad A, et al.: Inherited human Apollo deficiency causes severe bone marrow failure and developmental defects. Blood 139 (16): 2427-2440, 2022.
9. Sahoo SS, Kozyra EJ, Wlodarski MW: Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes. Best Pract Res Clin Haematol 33 (3): 101197, 2020.
10. Hakkarainen M, Kaaja I, Douglas SPM, et al.: The clinical picture of ERCC6L2 disease: from bone marrow failure to acute leukemia. Blood 141 (23): 2853-2866, 2023.

Latest Updates to This Summary (08 / 13 / 2024)

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About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of hereditary hematologic malignancies. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Genetics of Hereditary Hematologic Malignancies are:

• Julia Cooper, MS, CGC (Ohio State University)
• Courtney DiNardo, MD, MSC (University of Texas, M.D. Anderson Cancer Center)
• Marcin Wlodarski, MD, PhD (St. Jude Children's Research Hospital)

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Last Revised: 2024-08-13