Discovery of novel predisposing coding and noncoding variants in familial Hodgkin lymphoma.

Autor:	Flerlage JE; Department of Oncology, St. Jude Children's Research Hospital and the University of Tennessee Health Sciences Center, Memphis, TN., Myers JR; Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN., Maciaszek JL; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN., Oak N; Department of Oncology, St. Jude Children's Research Hospital and the University of Tennessee Health Sciences Center, Memphis, TN., Rashkin SR; Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN., Hui Y; Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN., Wang YD; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN., Chen W; Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN., Wu G; Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN., Chang TC; Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN., Hamilton K; Department of Oncology, St. Jude Children's Research Hospital and the University of Tennessee Health Sciences Center, Memphis, TN., Tithi SS; Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN., Goldin LR; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD., Rotunno M; Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD., Caporaso N; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD., Vogt A; Leidos Biomedical, Inc, Frederick, MD., Flamish D; Westat, Inc, Rockville, MD., Wyatt K; Leidos Biomedical, Inc, Frederick, MD., Liu J; Leidos Biomedical, Inc, Frederick, MD., Tucker M; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD., Hahn CN; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.; Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia., Brown AL; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.; Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia., Scott HS; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.; Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.; School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia., Mullighan C; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN., Nichols KE; Department of Oncology, St. Jude Children's Research Hospital and the University of Tennessee Health Sciences Center, Memphis, TN., Metzger ML; Department of Oncology, St. Jude Children's Research Hospital and the University of Tennessee Health Sciences Center, Memphis, TN.; Department of Global Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, TN., McMaster ML; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN., Yang JJ; Department of Oncology, St. Jude Children's Research Hospital and the University of Tennessee Health Sciences Center, Memphis, TN.; Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN., Rampersaud E; Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2023 Mar 16; Vol. 141 (11), pp. 1293-1307.
DOI:	10.1182/blood.2022016056
Abstrakt:	Familial aggregation of Hodgkin lymphoma (HL) has been demonstrated in large population studies, pointing to genetic predisposition to this hematological malignancy. To understand the genetic variants associated with the development of HL, we performed whole genome sequencing on 234 individuals with and without HL from 36 pedigrees that had 2 or more first-degree relatives with HL. Our pedigree selection criteria also required at least 1 affected individual aged <21 years, with the median age at diagnosis of 21.98 years (3-55 years). Family-based segregation analysis was performed for the identification of coding and noncoding variants using linkage and filtering approaches. Using our tiered variant prioritization algorithm, we identified 44 HL-risk variants in 28 pedigrees, of which 33 are coding and 11 are noncoding. The top 4 recurrent risk variants are a coding variant in KDR (rs56302315), a 5' untranslated region variant in KLHDC8B (rs387906223), a noncoding variant in an intron of PAX5 (rs147081110), and another noncoding variant in an intron of GATA3 (rs3824666). A newly identified splice variant in KDR (c.3849-2A>C) was observed for 1 pedigree, and high-confidence stop-gain variants affecting IRF7 (p.W238∗) and EEF2KMT (p.K116∗) were also observed. Multiple truncating variants in POLR1E were found in 3 independent pedigrees as well. Whereas KDR and KLHDC8B have previously been reported, PAX5, GATA3, IRF7, EEF2KMT, and POLR1E represent novel observations. Although there may be environmental factors influencing lymphomagenesis, we observed segregation of candidate germline variants likely to predispose HL in most of the pedigrees studied. (© 2023 by The American Society of Hematology.)
Databáze:	MEDLINE
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