The route to development of myelodysplastic syndrome/acute myeloid leukaemia in Shwachman‐Diamond syndrome: the role of ageing, karyotype instability, and acquired chromosome anomalies

• Published in: British journal of haematology Vol. 145; no. 2; pp. 190 - 197
• Main Authors: Maserati, Emanuela, Pressato, Barbara, Valli, Roberto, Minelli, Antonella, Sainati, Laura, Patitucci, Francesco, Marletta, Cristina, Mastronuzzi, Angela, Poli, Furio, Lo Curto, Francesco, Locatelli, Franco, Danesino, Cesare, Pasquali, Francesco
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-04-2009; Blackwell
• Subjects: acute leukaemia; Adolescent; Adult; Age; ageing; Aging; Aging - genetics; Biological and medical sciences; Bone marrow; Bone Marrow Cells - ultrastructure; Child; Child, Preschool; chromosome 7; Chromosome Aberrations; Chromosome Breakage; Chromosome deletion; Chromosomes; Chromosomes, Human, Pair 20; Chromosomes, Human, Pair 7; Clonal deletion; Disease Progression; DNA Mutational Analysis; Female; Follow-Up Studies; Hematologic and hematopoietic diseases; Humans; In Situ Hybridization, Fluorescence; Isochromosomes; karyotype instability; Karyotypes; Karyotyping; Leukemia, Myeloid, Acute - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Myelodysplastic syndrome; Myelodysplastic Syndromes - genetics; Other diseases. Hematologic involvement in other diseases; Proteins - genetics; Shwachman‐Diamond syndrome; Young Adult; Acute myelogenous leukemia; Acquired; Shachman Diamond syndrome; Diseases of the osteoarticular system; Exocrine pancreas insufficiency; Myelodysplastic syndrome; Genetics; Anomaly; Pancreatic disease; Neutropenia; Shwachman-Diamond syndrome; Leukopenia; Hematology; Ageing; Acute leukemia; Chromosome; Malignant hemopathy; acute leukaemia; Genetic disease; Cytogenetics; Digestive diseases; Instability; karyotype instability; Karyotype; Cancer
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2009.07611.x

Summary
An investigation of 22 new patients with Shwachman‐Diamond syndrome (SDS) and the follow‐up of 14 previously reported cases showed that (i) clonal chromosome changes of chromosomes 7 and 20 were present in the bone marrow (BM) of 16 out of 36 cases, but if non‐clonal changes were taken into account, the frequency of anomalies affecting these chromosomes was 20/36: a specific SDS karyotype instability was thus confirmed; (ii) the recurrent isochromosome i(7)(q10) did not include short arm material, whereas it retained two arrays of D7Z1 alphoid sequences; (iii) the deletion del(20)(q11) involved the minimal region of deletion typical of myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML); (iv) only one patient developed MDS, during the rapid expansion of a BM clone with a chromosome 7 carrying additional material on the short arms; (v) the acquisition of BM clonal chromosome anomalies was age‐related. We conclude that karyotype instability is part of the natural history of SDS through a specific mutator effect, linked to lacking SBDS protein, with consequent clonal anomalies of chromosomes 7 and 20 in BM, which may eventually promote MDS/AML with the patients’ ageing.