Poor overall survival in hyperhaploid multiple myeloma is defined by double-hit bi-allelic inactivation of TP53
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Cody Ashby1, Ruslana G. Tytarenko1, Yan Wang1, Niels Weinhold1, Sarah K. Johnson1, Michael Bauer1, Christopher P. Wardell1, Carolina Schinke1, Sharmilan Thanendrarajan1, Mauricio Zangari1, Frits van Rhee1, Faith E. Davies1, Jeffrey R. Sawyer2, Gareth J. Morgan1 and Brian A. Walker1
1Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA
2Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Brian A. Walker, email: BWalker2@uams.edu
Keywords: myeloma; double-hit; bi-allelic; TP53; survival
Received: November 22, 2018 Accepted: December 29, 2018 Published: January 22, 2019
Hyperhaploid multiple myeloma is a rare numerical aberration group defined by a range of 24-34 chromosomes, which is associated with a poor prognosis with a 5-year survival rate of 23%. Hyperhaploid patient samples (n=8) were sequenced and copy number and mutations identified. Samples had a median of 13 monosomies (range 12-14), which in general were those not associated with trisomies in hyperdiploid samples. The chromosomes traditionally trisomic in hyperdiploid myeloma were disomic in hyperhaploid myeloma with retention of heterodisomy. We examined the hyperhaploid samples for frequently mutated genes and found that 8/8 (100%) hyperhaploid samples had a mutation in TP53, exceeding the overall rate of mutation in newly diagnosed patients (5.5%), indicating an oncogenic dependency in this group. All samples with TP53 mutation also had monosomy of chromosome 17, indicating bi-allelic inactivation of TP53. As such, this high risk group is part of double-hit myeloma.
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