Germline predisposition to myeloid neoplasms: Characteristics and management of high versus variable penetrance disorders.

Myeloid neoplasms with germline predisposition have been recognized increasingly over the past decade with numerous newly described disorders. Penetrance, age of onset, phenotypic heterogeneity, and somatic driver events differ widely among these conditions and sometimes even within family members with the same variant, making risk assessment and counseling of these individuals inherently difficult. In this review, we will shed light on high malignant penetrance (e.g., CEBPA, GATA2, SAMD9/SAMD9L, and TP53) versus variable malignant penetrance syndromes (e.g., ANKRD26, DDX41, ETV6, RUNX1, and various bone marrow failure syndromes) and their clinical features, such as variant type and location, course of disease, and prognostic markers. We further discuss the recommended management of these syndromes based on penetrance with an emphasis on somatic aberrations consistent with disease progression/transformation and suggested timing of allogeneic hematopoietic stem cell transplant. This review will thereby provide important data that can help to individualize and improve the management for these patients.

Hereditary acute myeloid leukemia associated with C-terminal CEBPA germline variants.

Acute myeloid leukemia with germline CEBPA mutation is a subtype of acute myeloid leukemia that is associated with a favorable prognosis. Most of the reported cases of acute myeloid leukemia with CEBPA germline variants involve a germline variant in the N-terminus and a somatic variant in the C-terminus. There are only a few reported cases where the CEBPA germline variant has been identified in the C-terminus and the somatic variant in the N-terminus. This case report and review of the literature illustrates that, although acute myeloid leukemia with CEBPA N- or C-terminal germline variants have certain similarities such as atypically young age at diagnosis, frequent relapse, and favourable overall prognosis, there are also significant differences such as lower life-time penetrance of acute myeloid leukemia and shorter time to relapse for germline C-terminal cases. These findings add important information on the natural history and clinical outcomes of acute myeloid leukemia with germline CEBPA C-terminal variants and these findings should be considered in the management of patients and their family members.

Germ line predisposition variants occur in myelodysplastic syndrome patients of all ages.

The frequency of pathogenic/likely pathogenic (P/LP) germ line variants in patients with myelodysplastic syndrome (MDS) diagnosed at age 40 years or less is 15% to 20%. However, there are no comprehensive studies assessing the frequency of such variants across the age spectrum. We performed augmented whole-exome sequencing of peripheral blood samples from 404 patients with MDS and their related donors before allogeneic hematopoietic stem cell transplantation. Single-nucleotide and copy number variants in 233 genes were analyzed and interpreted. Germ line status was established by the presence of a variant in the patient and related donor or for those seen previously only as germ line alleles. We identified P/LP germ line variants in 28 of 404 patients with MDS (7%), present within all age deciles. Patients with P/LP variants were more likely to develop higher-grade MDS than those without (43% vs 25%; P = .04). There was no statistically significant difference in outcome parameters between patients with and without a germ line variant, but the analysis was underpowered. P/LP variants in bone marrow failure syndrome genes were found in 5 patients aged less than 40 years, whereas variants in DDX41 (n = 4), telomere biology disorder genes (n = 2), and general tumor predisposition genes (n = 17) were found in patients aged more than 40 years. If presumed germ line variants were included, the yield of P/LP variants would increase to 11%, and by adding suspicious variants of unknown significance, it would rise further to 12%. The high frequency of P/LP germ line variants in our study supports comprehensive germ line genetic testing for all patients with MDS regardless of their age at diagnosis.

A Case Series of TERC Variant Telomere Biology Disorders in Unrelated Families From Atlantic Canada.

TERC variant telomere biology disorders (TBDs) are a rare, heterogenous group of disorders that arise from germline variants in TERC, a gene that encodes for the RNA component of telomerase. Variants in TERC lead to accelerated telomere attrition and can manifest as many different phenotypes. In this case series, we aimed to add to the literature describing TERC variant TBDs by reporting cases from two unrelated families from Atlantic Canada. The first case, a previously described germline TERC variant, n.107G>T (NR_001566.1), was identified in a young woman with myelodysplastic syndrome (MDS) and found to segregate with cytopenias in the family. This case represents a unique phenotypic presentation: this variant has not previously been described in patients with MDS and adds important segregation data to the literature. The second case, a novel TERC n.437T>G variant, was identified in a patient with both aplastic anemia and pulmonary fibrosis manifesting in his early 30s. We report these novel cases of germline TERC variants in order to help clinicians recognize TBDs, as well as to add important supporting information for the pathogenicity of these variants.

Inherited predisposition to haematopoietic malignancies: overcoming barriers and exploring opportunities.

Inherited predisposition to haematopoietic malignancies, due to deleterious germline variants in a variety of genes, is an important clinical entity with implications for the health and management of patients and their family members. Unfortunately, there remain several common misconceptions in this field that can result in patients going unrecognised and/or having incomplete or improper testing including: the impression that inherited haematological malignancy syndromes are rare, that myeloid and lymphoid malignancy predisposition syndromes are mutually exclusive, and that solid tumour predisposition syndromes are unique and distinct from haematopoietic malignancy predisposition syndromes. In the present review, we challenge these ideas with our insights into germline genetic testing for these conditions with the hope that increased awareness and knowledge will overcome barriers and lead to improved diagnosis and management.

Heterozygous germ line CSF3R variants as risk alleles for development of hematologic malignancies.

Colony-stimulating factor 3 receptor (CSF3R) encodes the receptor for granulocyte colony-stimulating factor (G-CSF), a cytokine vital for granulocyte proliferation and differentiation. Acquired activating heterozygous variants in CSF3R are the main cause of chronic neutrophilic leukemia, a hyperproliferative disorder. In contrast, biallelic germ line hypomorphic variants in CSF3R are a rare cause of severe congenital neutropenia, a hypoproliferative condition. The impact of heterozygous germ line CSF3R variants, however, is unknown. We identified CSF3R as a new germ line hematologic malignancy predisposition gene through analysis of 832 next-generation sequencing tests conducted in 632 patients with hematologic malignancies. Among germ line CSF3R variants, 3 were abnormal in functional testing, indicating their deleterious nature. p.Trp547* was identified in 2 unrelated men with myelodysplastic syndromes diagnosed at 76 and 33 years of age, respectively. p.Trp547* is a loss-of-function nonsense variant in the extracellular domain that results in decreased CSF3R messenger RNA expression and abrogation of CSF3R surface expression and proliferative responses to G-CSF. p.Ala119Thr is a missense variant found in 2 patients with multiple myeloma and acute lymphoblastic leukemia, respectively. This variant is located between the extracellular immunoglobulin-like and cytokine receptor homology domains and results in decreased G-CSF sensitivity. p.Pro784Thr was identified in a 67-year-old man with multiple myeloma. p.Pro784Thr is a missense variant in the cytoplasmic domain that inhibits CSF3R internalization, producing a gain-of-function phenotype and G-CSF hypersensitivity. Our findings identify germ line heterozygous CSF3R variants as risk factors for development of myeloid and lymphoid malignancies.

Somatic mutation panels: Time to clear their names.

With improvements in DNA sequencing technologies and the consequent reduction in costs, next generation sequencing is being utilized increasingly in panel-based testing to perform molecular profiling of tumors. Such tumor-based panels are often referred to as 'somatic' panels, but this term is misleading and should not be used, since not all DNA variants within a tumor are somatic in nature. Every cell in a person's body contains that person's germline DNA, including tumor cells. Moreover, tumor samples are invariably contaminated with blood, a tissue that can contain somatic mutations itself in a process now called clonal hematopoiesis. Differentiating between germline variants or tumor-associated somatic mutations versus clonal hematopoiesis can be challenging. In this review, we address how to interpret the results of somatic mutation panels, how to differentiate between germline and truly somatic events, and discuss the importance of this distinction.

Blastic plasmacytoid dendritic cell neoplasm: challenges and future prospects.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare CD4+ CD56+ myeloid malignancy that is challenging to diagnose and treat. BPDCN typically presents with nonspecific cutaneous lesions with or without extra-cutaneous manifestations before progressing to leukemia. Currently, there is no standard of care for the treatment of BPDCN and various approaches have been used including acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoma-based regimens with or without stem cell transplantation. Despite these treatment approaches, the prognosis of BPDCN remains poor and there is a lack of prospective data upon which to base treatment decisions. Recent work examining the mutational landscape and gene expression profiles of BPDCN has identified a number of potential therapeutic targets. One such target is CD123, the α subunit of the human interleukin-3 receptor, which is the subject of intervention studies using the novel agent SL-401. Other investigational therapies include UCART123, T-cell immunotherapy, and venetoclax. Prospective trials are needed to determine the best treatment for this uncommon and aggressive neoplasm.