What are the risk factors for hematologic malignancies?

Risk Factors for Hematologic Malignancies

Hematologic malignancies arise from a combination of inherited genetic predispositions, acquired clonal mutations, environmental exposures, and treatment-related factors, with germline predisposition syndromes accounting for up to 10% of cases in both children and adults. 1, 2

Inherited Genetic Predisposition Syndromes

High-Risk Germline Mutations (>15% lifetime risk)

The most critical inherited risk factors are germline mutations in specific genes that confer substantial lifetime risk of developing hematologic malignancies:

• GATA2 deficiency predisposes primarily to MDS and AML, with additional risk for CMML, and presents with other organ system dysfunction 3
• SAMD9/SAMD9L mutations carry high risk for MDS and AML, typically presenting with other organ system abnormalities 3
• ERG germline variants confer >15% risk of AML/MDS 3
• MBD4 mutations carry >15% risk for AML/MDS, though germline variants have not yet been reported in children 3
• ERCC6L2 mutations predispose to MDS/AML and T-ALL with >15% lifetime risk 3

Moderate-Risk Germline Mutations (5-15% risk)

• Bone marrow failure syndromes including Fanconi anemia (FANCA, FANCB, FANCC, FANCD1), Shwachman-Diamond syndrome (SBDS, EFL1), and telomere biology disorders (CTC1, DKC1, RTEL1, TERC, TERT, TINF2) all carry elevated risk for AML and MDS 3
• Severe congenital neutropenia (ELANE, CLPB, G6PC3, HAX1, CXCR4, CSF3R, GFI1) shows 11% cumulative incidence of MDS/AML at median age 16.2 years 3

Lower-Risk but Clinically Significant Mutations

• RUNX1, ETV6, and ANKRD26 mutations predispose to myeloid and/or lymphoid neoplasms, often presenting with thrombocytopenia 3
• DDX41 mutations increase risk for AML/MDS, NHL, HL, and ALL, though risk is not significantly elevated until later adulthood 3
• Diamond-Blackfan anemia (RPS19, RPL5, RPS24, RPL11, RPL35A) carries low risk (*) for AML/MDS 3

Syndrome-Associated Predispositions

• Bloom syndrome (BLM) predisposes to NHL, AML, and ALL 3
• Xeroderma pigmentosum (XPA, XPC, POLH, ERCC2) carries highest risk for AML/MDS when XPC is involved 3
• Li-Fraumeni syndrome, Noonan syndrome, and constitutional mismatch repair deficiency are additional recognized predisposition syndromes 3

Acquired Clonal Hematopoiesis

Clonal hematopoiesis represents somatic mutations in hematopoietic stem cells that increase with age and function as a precursor state for hematologic malignancies:

• Age-related clonal hematopoiesis affects 5-10% of individuals over age 70 but only ~1% of those under age 50, with mutations most commonly in DNMT3A, ASXL1, TET2, JAK2, TP53, GNAS, PPM1D, BCORL1, and SF3B1 3, 4
• Clonal hematopoiesis of indeterminate potential (CHIP) is defined as somatic mutations in myeloid neoplasm driver genes at variant allele fraction ≥2% without diagnostic criteria for hematologic malignancy or unexplained cytopenia 4
• CHIP functions as a strong predictor of subsequent hematologic cancer development, analogous to monoclonal gammopathy of undetermined significance (MGUS) 4

Familial Aggregation and Family History

Family history of hematopoietic malignancy confers approximately 2-fold increased risk for both NHL and Hodgkin lymphoma:

• Any first-degree relative with hematopoietic malignancy increases NHL risk (OR = 1.8,95% CI: 1.2-2.5) and HL risk 5
• Sibling history confers higher risk (OR = 3.2,95% CI: 1.3-7.6) than parental history (OR = 1.6,95% CI: 1.1-2.3) 5
• Family history of NHL or CLL increases risk of multiple NHL subtypes and HL 5
• Familial multiple myeloma specifically increases risk of follicular lymphoma 5
• Epidemiological studies demonstrate increased risk in relatives diagnosed with the same pathology, characterized by earlier age at diagnosis and higher severity compared to sporadic forms 6

Treatment-Related Risk Factors

Prior cancer treatment substantially increases risk of subsequent hematologic malignancies:

• Alkylating agents and epipodophyllotoxins cause therapy-related leukemia, with established surveillance protocols for exposed patients 3
• Radiation therapy is the primary therapeutic exposure associated with subsequent neoplasms in survivors of childhood hematologic malignancies 7
• Chemotherapy exposures (alkylating agents/anthracyclines) show emerging evidence of association with subsequent neoplasm development 7
• Hematopoietic stem cell transplantation has modified patterns of immunosuppression and subsequent malignancy risk compared to older therapies 3

Clinical Recognition and Surveillance Approach

Identifying patients with hereditary predisposition requires systematic evaluation:

• High index of suspicion based on family history, early age at diagnosis, multiple affected family members, or presence of characteristic physical findings 1, 2
• Variant allele frequency on somatic NGS panels can suggest germline predisposition when variants appear at ~50% VAF, though this must be distinguished from clonal hematopoiesis in older patients 3
• Multidisciplinary evaluation including genetic counseling is critical for diagnostic testing of individuals and at-risk family members 1
• Prompt recognition is imperative for personalized surveillance strategies and proper donor selection for stem cell transplantation to avoid familial donors sharing the same germline mutation 1

Key Surveillance Recommendations

• Regular blood count monitoring at least every 6 months for patients with documented CHIP 4
• More rigorous follow-up when clonal copy number-neutral loss of heterozygosity (CN-LOH) spans known myeloid neoplasm-associated genes 4
• Syndrome-specific surveillance protocols as outlined in updated 2024 guidelines for children with hematopoietic malignancy predisposition 3

Critical Clinical Pitfalls

• Do not assume all variants at ~50% VAF in blood represent germline mutations—particularly in patients over 70 or those who received chemotherapy, as these may represent clonal hematopoiesis rather than inherited predisposition 3, 4
• Tumor-normal paired sequencing resolves this ambiguity: variants present in blood but absent or at very low levels in tumor indicate clonal hematopoiesis 3
• Genetic predisposition prevalence is likely underestimated due to heterogeneity of clinical features and variable penetrance of variants 6
• Up to 10% of hematologic malignancies in both children and adults may result from underlying inherited genetic risk, making family history assessment essential 1, 2