title: Survival of Del17p CLL Depends on Genomic Complexity and Somatic Mutation.
abstract: OBJECTIVE
  Chronic lymphocytic leukemia (CLL) with 17p deletion typically progresses quickly and is refractory to most conventional therapies. However, some del(17p) patients do not progress for years, suggesting that del(17p) is not the only driving event in CLL progression. We hypothesize that other concomitant genetic abnormalities underlie the clinical heterogeneity of del(17p) CLL.
  
  
  METHODS
  We profiled the somatic mutations and copy number alterations (CNA) in a large group of del(17p) CLLs as well as wild-type CLL and analyzed the genetic basis of their clinical heterogeneity.
  
  
  RESULTS
  We found that increased somatic mutation number associates with poor overall survival independent of 17p deletion (P = 0.003). TP53 mutation was present in 81% of del(17p) CLL, mostly clonal (82%), and clonal mutations with del(17p) exhibit shorter overall survival than subclonal mutations with del(17p) (P = 0.019). Del(17p) CLL has a unique driver mutation profile, including NOTCH1 (15%), RPS15 (12%), DDX3X (8%), and GPS2 (6%). We found that about half of del(17p) CLL cases have recurrent deletions at 3p, 4p, or 9p and that any of these deletions significantly predicts shorter overall survival. In addition, the number of CNAs, but not somatic mutations, predicts shorter time to treatment among patients untreated at sampling. Indolent del(17p) CLLs were characterized by absent or subclonal TP53 mutation and few CNAs, with no difference in somatic mutation number.
  
  
  CONCLUSIONS
  We conclude that del(17p) has a unique genomic profile and that clonal TP53 mutations, 3p, 4p, or 9p deletions, and genomic complexity are associated with shorter overall survival. Clin Cancer Res; 23(3); 735-45. ©2016 AACR.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.|Harvard Medical School, Boston, MA.
authors: Lijian
authors: L
authors: Yu
authors: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA.
authors: Haesook T
authors: HT
authors: Kim
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.|Harvard Medical School, Boston, MA.
authors: Siddha
authors: S
authors: Kasar
authors: Brigham and Women's Hospital, Boston, MA.
authors: Parul
authors: P
authors: Benien
authors: Brigham and Women's Hospital, Boston, MA.
authors: Wei
authors: W
authors: Du
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors: Kevin
authors: K
authors: Hoang
authors: Division of Hematology, The Ottawa Hospital, Ottawa, Ontario.
authors: Andrew
authors: A
authors: Aw
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors: Bethany
authors: B
authors: Tesar
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.|Harvard Medical School, Boston, MA.
authors: Reina
authors: R
authors: Improgo
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors: Stacey
authors: S
authors: Fernandes
authors: Brigham and Women's Hospital, Boston, MA.
authors: Saranya
authors: S
authors: Radhakrishnan
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.|Harvard Medical School, Boston, MA.
authors: Josephine
authors: J
authors: Klitgaard
authors: The Jackson Laboratory for Genomic Medicine, Farmington, CT.
authors: Charles
authors: C
authors: Lee
authors: Broad Institute of Harvard and MIT, Cambridge, MA.|Massachusetts General Hospital Cancer Center and Department of Pathology, Boston, MA.
authors: Gad
authors: G
authors: Getz
authors: Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
authors: Sunita R
authors: SR
authors: Setlur
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.|Harvard Medical School, Boston, MA.
authors: Jennifer R
authors: JR
authors: Brown
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019457:Chromosome Breakage; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics / Q000648:ultrastructure*; D002999:Clone Cells; D018450:Disease Progression; D005260:Female; D018628:Gene Dosage; D018095:Germ-Line Mutation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012463:Saliva / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000073359:Exome Sequencing
chemical_list: D016159:Tumor Suppressor Protein p53