Prevalence and clinical expression of germ line predisposition to myeloid neoplasms in adults with marrow hypocellularity

Abstract

Systematic studies of germ line genetic predisposition to myeloid neoplasms in adult patients are still limited. In this work, we performed germ line and somatic targeted sequencing in a cohort of adult patients with hypoplastic bone marrow (BM) to study germ line predisposition variants and their clinical correlates. The study population included 402 consecutive adult patients investigated for unexplained cytopenia and reduced age-adjusted BM cellularity. Germ line mutation analysis was performed using a panel of 60 genes, and variants were interpreted per the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines; somatic mutation analysis was performed using a panel of 54 genes. Of the 402 patients, 27 (6.7%) carried germ line variants that caused a predisposition syndrome/disorder. The most frequent disorders were DDX41-associated predisposition, Fanconi anemia, GATA2-deficiency syndrome, severe congenital neutropenia, RASopathy, and Diamond-Blackfan anemia. Eighteen of 27 patients (67%) with causative germ line genotype were diagnosed with myeloid neoplasm, and the remaining with cytopenia of undetermined significance. Patients with a predisposition syndrome/disorder were younger than the remaining patients and had a higher risk of severe or multiple cytopenias and advanced myeloid malignancy. In patients with myeloid neoplasm, causative germ line mutations were associated with increased risk of progression into acute myeloid leukemia. Family or personal history of cancer did not show significant association with a predisposition syndrome/disorder. The findings of this study unveil the spectrum, clinical expressivity, and prevalence of germ line predisposition mutations in an unselected cohort of adult patients with cytopenia and hypoplastic BM.

Graphical abstract

Figure 1.

Germ line mutation landscape, prevalence of somatic lesions, and myeloid malignancy diseases in the cohort included in the study. (A) Frequency of patients without germ line mutations in any of the 60 genes screened (green), patients harboring P/LP mutations identified as causative for a congenital syndrome or disorder (S/D) (red), patients carrying a unique heterozygous mutation in genes associated with autosomal recessive disorders (blue), or patients harboring VUS (purple). (B) Distribution of patients with S/D sustained by the heterozygous mutation in genes associated with dominant inheritance and of patients with S/D associated with homozygous/compound heterozygous mutations in genes associated with recessive inheritance (red bars) as well as of carriers of a unique heterozygous mutation in genes associated with autosomal recessive disorders (blue bars). (C) Pie charts depicting the prevalence of somatic lesions (mutations and/or cytogenetic abnormalities) (green, presence of somatic lesion[s]; orange, absence of somatic lesion[s]) (top), and the prevalence of myeloid neoplasm (MN) (lavender) or nonmalignant conditions (ICUS, CCUS, or AA) (light blue) (bottom), in patients with no germ line mutations (wild-type; WT), patients with S/D, and carriers of a unique heterozygous mutation in genes associated with autosomal recessive disorders. All patients without P/LP variants were included in the germ line WT group. (D) Distribution of the standard hematologic diagnosis (MN [lavender], and nonmalignant conditions [light blue]), in the 27 patients with S/D, based on the underlying syndromes/disorders. DBA, Diamond-Blackfan anemia; FA, Fanconi anemia; SCN, severe congenital neutropenia; SDS, Shwachman-Diamond syndrome.

Figure 2.

Age distribution at the time of standard hematologic diagnosis in patients with or without germ line mutation. (A) Density curves representing the age distribution at the time of standard diagnosis in patients who are germ line WT in the analyzed genes (gray), patients harboring P/LP mutations identified as causative of a congenital syndrome or disorder (S/D) (red), or carriers of a unique heterozygous mutation in genes associated with autosomal recessive disorders (orange). (B) Box plots showing the median age (horizontal line) and age distribution at the time of diagnosis of MN or nonneoplastic conditions (ICUS/CCUS/AA), in patients who are germ line WT (gray), S/D (red), and carriers (orange). Patients who are germ line mutated were significantly younger at the time of diagnosis of MN than those who are germ line WT (P = .018). (C) Age distribution at the time of diagnosis in patients who are germ line WT (gray), carriers of a unique heterozygous mutation in genes associated with autosomal recessive disorders (orange), and patients with DDX41-associated predisposition (red) (top), or with S/D other than DDX41-associated predisposition (red) (bottom). (D) Age distribution based on the germ line S/D (red dots); median age is indicated with a dashed line.

Figure 3.

Clinical correlates and outcomes of germ line mutations causative of a congenital syndrome or disorder. (A) Forest plot of the ORs for myeloid neoplasm (MN), high-risk MN, moderate-to-severe cytopenia, and pancytopenia in patients harboring germ line mutations identified as causative for a congenital syndrome or disorder (S/D). (B) Forest plot of the ORs for extrahematologic comorbidities, solid tumor(s), familiarity for hematologic/solid tumors (Fam Hem/Solid Tumor), or nonmalignant hematologic disorders (Fam Hem Disorder) in patients with S/D. (C) Forest plot of the HRs for OS, event-free survival, and cumulative incidence of AML or nonleukemic death in patients with S/D receiving a diagnosis of MN. (D) Forest plot of the HRs for OS, event-free survival, and cumulative incidence of MN or nonleukemic death in S/D patients receiving a diagnosis of nonneoplastic disorder. ORs and HRs are shown on a logarithmic scale with 95% confidence interval (CI).