Editors: Donna E. Hansel, MD, PhD, division head of pathology and laboratory medicine, MD Anderson Cancer Center, Houston; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, OHSU; Maedeh Mohebnasab, MD, assistant professor of pathology, University of Pittsburgh; Alicia Dillard, MD, clinical pathology chief resident, New York-Presbyterian/Weill Cornell Medical Center; and Richard Wong, MD, PhD, assistant professor of pathology, University of California San Diego.
Relationship between first-hit SETBP1 mutations and myeloproliferative disorder with bone marrow fibrosis
June 2024—Somatic mutations in SETBP1 occur in a variety of myeloid malignancies, including myelodysplastic/myeloproliferative neoplasms, typically as secondary events during oncogenesis. However, whether SETBP1 alterations can serve as an initiating event for myeloid neoplasia and what other factors may influence the phenotype of SETBP1-mutated myeloid neoplasms remains unclear. To determine if SETBP1 mutations can initiate leukemia in vivo, the authors generated a mouse model expressing mutated SETBP1 in hematopoietic tissue. They reported that SETBP1G870S-mutated mice developed a chronic myeloid disorder with massive hepatosplenomegaly, myelofibrosis, atypical megakaryocytes, and granulocytic hyperplasia without granulocytic or erythroid dysplasia. SETBP1G870S precursors showed significant alterations in the transcriptional programs of differentiating hematopoietic cells, promoting granulocytic/monocytic differentiation while suppressing erythroid differentiation. Overall, the SETBP1G870S mouse model recapitulated many clinical and pathologic features of primary myelofibrosis (PMF). Given this finding, the authors assessed SETBP1 mutations in the context of triple-negative PMF (that is, PMF negative for mutations in the driver genes JAK2, CALR, and MPL). They used exome or targeted sequencing to study 36 patients with triple-negative PMF. No recurrent somatic mutations were identified in 29 patients. In the remaining seven patients, mutations in SETBP1 were identified. The mutations were clustered in a mutational hotspot region between amino acids Asp868 and Ser871. Patients in the SETBP1-positive group showed a worse clinical course and markedly reduced overall survival. Single-cell clonal hierarchy reconstruction in three patients with SETBP1-positive, triple-negative PMF showed SETBP1 to be a very early event in oncogenesis. This pattern contrasts with previous reports of SETBP1 mutation in myelodysplastic/myeloproliferative neoplasms, in which SETBP1 mutations are primarily late clonal events. The authors postulated that the timing (early founding event versus secondary clonal acquisition) of the acquisition of the same clonal SETBP1 variants may dictate the phenotype of the disease groups. While further study would be beneficial for confirming and further elucidating these findings, this study establishes SETBP1 mutations as a possible biomarker for PMF and sheds additional light on how clonal hierarchy may influence disease phenotype in myeloid malignancies. The authors’ proposed model for SETBP1 mutations in the pathogenesis of triple-negative PMF also provides a possible pathway for exploring potential new therapeutic approaches to this clinically aggressive disease.
Crespiatico I, Zaghi M, Mastini C, et al. First-hit SETBP1 mutations cause a myeloproliferative disorder with bone marrow fibrosis. Blood. 2024;143(14):1399–1413.
Correspondence: Dr. Luca Mologni at luca.mologni@unimib.it, or Dr. Alessandro Sessa at sessa.alessandro@hsr.it, or Dr. Rocco Piazza at rocco.piazza@unimib.it
A biobank-scale reference for tandem repeat expansions in the human genome
Tandem repeat expansions profoundly impact evolution and human disease and have been widely used in the diagnosis of rare diseases. The Genome Aggregation Database (gnomAD) serves as a standard reference of human genetic variation and is invaluable for interpreting single-nucleotide variants and structural variants in research and clinical testing. However, no biobank-scale reference exists for genetic variation within tandem repeat (TR) expansions. Given the potential for variation within TR expansions and their importance in human disease, a more comprehensive reference map of TR expansions is warranted. Therefore, the authors introduced TR-gnomAD, developed at the University of California, Irvine. (While the names are similar, TR-gnomAD is unrelated to the Broad Institute’s gnomAD.) TR-gnomAD is a biobank-scale reference of TR expansions derived from whole genome sequencing data of 338,963 human genomes representing diverse ancestries (39.5 percent non-European). The reference includes approximately 0.86 million TRs with an average whole genome sequencing data coverage of 33 times. TR-gnomAD allows users to determine the prevalence of a particular TR repeat expansion within a given ancestry. By analyzing the disparities in TR unit number among ancestries, calculated as a TR disparity score (TRDS), the database also offers insight into ancestry-specific disease prevalence. These TRDSs can be viewed on an interactive world map that compares all ancestries represented in TR-gnomAD. Heat maps of TRDSs can also be used to compare ancestries. The variable frequency of expanded TR units in certain ancestries may directly impact the ancestry-specific prevalence of different TR-associated phenotypes. Users of TR-gnomAD may also be able to differentiate common, presumably benign TR expansions that are prevalent in the database from potentially pathogenic TR expansions. Among the limitations of TR-gnomAD is its failure to address certain underrepresented ancestries. It is also limited to approximately 0.86 million TRs, a fraction of the total number of TRs in the human genome. Further analysis of patient cohorts potentially affected by TRs is needed, as TR-gnomAD too has not been used to identify unknown disease risk repeat expansions or define risk thresholds for known pathogenic TRs. Furthermore, TR-gnomAD is limited to short-read whole genome sequencing data, which may underestimate the allele lengths of expansions greater than 150 bp. The authors plan to address many of these limitations in the next phase of the project. Bearing in mind current limitations, TR-gnomAD has enormous potential for assisting researchers, physicians, and genetic counselors who study and interpret TR expansions.
Cui Y, Ye W, Li JS, et al. A genome-wide spectrum of tandem repeat expansions in 338,963 humans. Cell. 2024. doi:10.1016/j.cell.2024.03.004
Correspondence: Dr. Ya Cui at yac7@uci.edu or Dr. Wei Li at wei.li@uci.edu