TY - JOUR
TI - High subclonal fraction of 17p deletion is associated with poor prognosis in multiple myeloma
AU - Thakurta, A.
AU - Ortiz, M.
AU - Blecua, P.
AU - Towfic, F.
AU - Corre, J.
AU - Serbina, N.V.
AU - Flynt, E.
AU - Yu, Z.
AU - Yang, Z.
AU - Palumbo, A.
AU - Dimopoulos, M.A.
AU - Gutierrez, N.C.
AU - Goldschmidt, H.
AU - Sonneveld, P.
AU - Avet-Loiseau, H.
JO - Blood advances
PY - 2019
VL - 133
TODO - 11
SP - 1217-1221
PB - American Society of Hematology
SN - null
TODO - 10.1182/blood-2018-10-880831
TODO - protein p53;  protein p53;  TP53 protein, human;  tumor marker, Article;  cancer prognosis;  chromosome 17p;  chromosome deletion;  cytogenetics;  fluorescence in situ hybridization;  gene mutation;  high risk patient;  human;  low risk patient;  major clinical study;  meta analysis;  multiple myeloma;  overall survival;  priority journal;  progression free survival;  whole exome sequencing;  chromosome 17;  clonal evolution;  genetics;  high throughput sequencing;  mortality;  multiple myeloma;  mutation;  pathology;  prognosis;  survival rate, Biomarkers, Tumor;  Chromosome Deletion;  Chromosomes, Human, Pair 17;  Clonal Evolution;  High-Throughput Nucleotide Sequencing;  Humans;  Multiple Myeloma;  Mutation;  Prognosis;  Survival Rate;  Tumor Suppressor Protein p53
TODO - Deletions of chromosome 17p (del17p) that span the TP53 gene are associated with poor outcome in multiple myeloma (MM), but the prognostic value of del17p cancer clonal fraction (CCF) remains unclear. We applied uniform cytogenetic assessments in a large cohort of newly diagnosed MM (NDMM) patients carrying varying levels of del17p. Incremental CCF change was associated with shorter survival, and a robust CCF threshold of 0.55 was established in discovery and replication data sets. After stratification on the 0.55-CCF threshold, high-risk patients had statistically significantly poorer outcomes compared with low-risk patients (median progression-free survival [PFS] and overall survival [OS], 14 and 32 vs 23.1 and 76.2 months, respectively). Analyses of a third data set comprising whole-exome sequencing data from NDMM patients identified presence of TP53 deletions/mutations as a necessary requirement for high-risk stratification in addition to exceeding the del17p CCF threshold. Meta-analysis conducted across 3 data sets confirmed the robustness of the CCF threshold for PFS and OS. Our analyses demonstrate the feasibility of fluorescence in situ hybridization– and sequencing-based methods to identify TP53 deletions, estimate CCF, and establish that both CCF threshold of 0.55 and presence of TP53 deletion are necessary to identify del17p-carrying NDMM patients with poor prognosis. © 2019 by The American Society of Hematology
ER -