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.
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http://dx.doi.org/10.1182/bloodadvances.2020002013 | DOI Listing |
EJHaem
October 2024
Department of Molecular Medicine NSW Health Pathology, John Hunter Hospital Waratah Australia.
Introduction: Variants of uncertain significance (VUS) are commonly reported in cancer with the widespread adoption of diagnostic massive parallel sequencing. The rate of reclassification of VUS in patients with haematological malignancy is not known and we evaluated this retrospectively. We also investigated whether re-evaluating VUS in 12-24 months or greater than 24 months post-initial classification was significant.
View Article and Find Full Text PDFCasitas B-cell lineage (CBL) syndrome is a rare RASopathy known to predispose to CBL-mutated juvenile myelomonocytic leukemia (JMML) in childhood. Adulthood acute myeloid leukemia arising out of a genetic aberrancies consistent with prior CBL-mutated JMML has been twice previously described, but chronic myeloproliferative neoplasia has not. We present a case of progressive myeloproliferative neoplasm in adulthood in the context of CBL syndrome alongside a novel CSF3R variant.
View Article and Find Full Text PDFCancer Res Commun
February 2024
Department of Medical Oncology, Tata Memorial Centre, Mumbai.
Unlabelled: We report a deep next-generation sequencing analysis of 13 sequentially obtained tumor samples, eight sequentially obtained circulating tumor DNA (ctDNA) samples and three germline DNA samples over the life history of 3 patients with triple-negative breast cancer (TNBC), 2 of whom had germline pathogenic BRCA1 mutation, to unravel tumor evolution. Tumor tissue from all timepoints and germline DNA was subjected to whole-exome sequencing (WES), custom amplicon deep sequencing (30,000X) of a WES-derived somatic mutation panel, and SNP arrays for copy-number variation (CNV), while whole transcriptome sequencing (RNA-seq) was performed only on somatic tumor.There was enrichment of homologous recombination deficiency signature in all tumors and widespread CNV, which remained largely stable over time.
View Article and Find Full Text PDFIndian J Hematol Blood Transfus
January 2024
Department of Hematology, Core Diagnostics, Gurugram, 122016 India.
Br J Haematol
March 2024
Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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