title: Inter- and intra-patient clonal and subclonal heterogeneity of chronic lymphocytic leukaemia: evidences from circulating and lymph nodal compartments.
abstract: Whole exome sequencing and copy number aberration (CNA) analysis were performed on cells taken from peripheral blood (PB) and lymph nodes (LN) of patients with chronic lymphocytic leukaemia (CLL). Of 64 non-silent somatic mutations, 54 (84·4%) were clonal in both compartments, 3 (4·7%) were PB-specific and 7 (10·9%) were LN-specific. Most of the LN- or PB-specific mutations were subclonal in the other corresponding compartment (variant frequency 0·5-5·3%). Of 41 CNAs, 27 (65·8%) were shared by both compartments and 7 (17·1%) were LN- or PB-specific. Overall, 6 of 9 cases (66·7%) showed genomic differences between the compartments. At subsequent relapse, Case 10, with 6 LN-specific lesions, and Case 100, with 6 LN-specific and 8 PB-specific lesions, showed, in the PB, the clonal expansion of LN-derived lesions with an adverse impact: SF3B1 mutation, BIRC3 deletion, del8(p23·3-p11·1), del9(p24·3-p13·1) and gain 2(p25·3-p14). CLL shows an intra-patient clonal heterogeneity according to the disease compartment, with both LN and PB-specific mutations/CNAs. The LN microenvironment might contribute to the clonal selection of unfavourable lesions, as LN-derived mutations/CNAs can appear in the PB at relapse.
authors.affiliation: Division of Haematology, Department of Cellular Biotechnologies and Haematology, Sapienza University, Rome, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Del Giudice
authors.affiliation: Division of Haematology, Department of Cellular Biotechnologies and Haematology, Sapienza University, Rome, Italy.
authors.forename: Marilisa
authors.initials: M
authors.lastname: Marinelli
authors.affiliation: Department of Biomedical Informatics, Center for Computational Biology and Bioinformatics, Columbia University, New York, US.
authors.forename: Jiguang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Haematology, Department of Cellular Biotechnologies and Haematology, Sapienza University, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bonina
authors.affiliation: Division of Haematology, Department of Cellular Biotechnologies and Haematology, Sapienza University, Rome, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Messina
authors.affiliation: Division of Haematology, Department of Cellular Biotechnologies and Haematology, Sapienza University, Rome, Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Chiaretti
authors.affiliation: Division of Haematology, Department of Cellular Biotechnologies and Haematology, Sapienza University, Rome, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Ilari
authors.affiliation: Division of Haematology, Department of Cellular Biotechnologies and Haematology, Sapienza University, Rome, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Cafforio
authors.affiliation: Division of Haematology, Department of Cellular Biotechnologies and Haematology, Sapienza University, Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Raponi
authors.affiliation: Division of Haematology, Department of Cellular Biotechnologies and Haematology, Sapienza University, Rome, Italy.
authors.forename: Francesca Romana
authors.initials: FR
authors.lastname: Mauro
authors.affiliation: Division of Haematology, Department of Cellular Biotechnologies and Haematology, Sapienza University, Rome, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Di Maio
authors.affiliation: Division of Haematology, Department of Cellular Biotechnologies and Haematology, Sapienza University, Rome, Italy.
authors.forename: Maria Stefania
authors.initials: MS
authors.lastname: De Propris
authors.affiliation: Division of Haematology, Department of Cellular Biotechnologies and Haematology, Sapienza University, Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Nanni
authors.affiliation: Division of Haematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Ciardullo
authors.affiliation: Division of Haematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.affiliation: Division of Haematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: Division of Haematology, Department of Cellular Biotechnologies and Haematology, Sapienza University, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Guarini
authors.affiliation: Department of Biomedical Informatics, Center for Computational Biology and Bioinformatics, Columbia University, New York, US.
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.affiliation: Division of Haematology, Department of Cellular Biotechnologies and Haematology, Sapienza University, Rome, Italy.
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D060965:Clonal Evolution; D056915:DNA Copy Number Variations; D004273:DNA, Neoplasm / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000473:pathology; D012008:Recurrence
chemical_list: D004273:DNA, Neoplasm
keywords: chronic lymphocytic leukaemia; copy number aberrations; lymph node; relapse; whole exome sequencing