title: The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes.
abstract: Nonsynonymous TP53 exon 4 single-nucleotide polymorphism (SNP), R72P, is linked to cancer and mutagen susceptibility. R72P associations with specific cancer risk, particularly hematological malignancies, have been conflicting. Myelodysplastic syndrome (MDS) with chromosome 5q deletion is characterized by erythroid hypoplasia arising from lineage-specific p53 accumulation resulting from ribosomal insufficiency. We hypothesized that apoptotically diminished R72P C-allele may influence predisposition to del(5q) MDS. Bone marrow and blood DNA was sequenced from 705 MDS cases (333 del(5q), 372 non-del(5q)) and 157 controls. Genotype distribution did not significantly differ between del(5q) cases (12.6% CC, 38.1% CG, 49.2% GG), non-del(5q) cases (9.7% CC, 44.6% CG, 45.7% GG) and controls (7.6% CC, 37.6% CG, 54.8% GG) (P=0.13). Allele frequency did not differ between non-del(5q) and del(5q) cases (P=0.91) but trended towards increased C-allele frequency comparing non-del(5q) (P=0.08) and del(5q) (P=0.10) cases with controls. Median lenalidomide response duration increased proportionate to C-allele dosage in del(5q) patients (2.2 (CC), 1.3 (CG) and 0.89 years (GG)). Furthermore, C-allele homozygosity in del(5q) was associated with prolonged overall and progression-free survival and non-terminal interstitial deletions that excluded 5q34, whereas G-allele homozygozity was associated with inferior outcome and terminal deletions involving 5q34 (P=0.05). These findings comprise the largest MDS R72P SNP analysis.
authors.affiliation: Hematology Department, H Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: McGraw
authors.affiliation: Molecular Genomics Core Lab, H Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Zhang
authors.affiliation: Cancer Epidemiology, H Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Rollison
authors.affiliation: 1] Hematology Department, H Lee Moffitt Cancer Center, Tampa, FL, USA [2] Cancer Biology PhD Program, University of South Florida, Tampa, FL, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Basiorka
authors.affiliation: Biostatistics and Bioinformatics Department, H Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: W
authors.initials: W
authors.lastname: Fulp
authors.affiliation: Mayo Clinic, Biostatistics-Division of Health Sciences Research, Jacksonville, FL, USA.
authors.forename: B
authors.initials: B
authors.lastname: Rawal
authors.affiliation: Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: Jerez
authors.affiliation: Celgene Corporation, Tampa, FL, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Billingsley
authors.affiliation: Biostatistics and Bioinformatics Department, H Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Arizona Cancer Center, Tucson, AZ, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Kurtin
authors.affiliation: Molecular Genomics Core Lab, H Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Yoder
authors.affiliation: Biostatistics and Bioinformatics Department, H Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH, USA.
authors.forename: K
authors.initials: K
authors.lastname: Guinta
authors.affiliation: Institut de Recerca Contra la Leucèmia Josep Carreras (IJC) Badalona, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Mallo
authors.affiliation: Institut de Recerca Contra la Leucèmia Josep Carreras (IJC) Badalona, Barcelona, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Solé
authors.affiliation: Hematology Department, Hospital Universitario La Fe, Valencia, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Calasanz
authors.affiliation: Hematology Department, Hospital Universitario La Fe, Valencia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Cervera
authors.affiliation: Hematology Department, Hospital Universitario La Fe, Valencia, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Such
authors.affiliation: Genomics Medicine Public Foundation, Hospital Clinico Universitario, Santiago de Compostela, Spain.
authors.forename: T
authors.initials: T
authors.lastname: González
authors.affiliation: British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: T J
authors.initials: TJ
authors.lastname: Nevill
authors.affiliation: Munich Leukemia Laboratory, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Haferlach
authors.affiliation: King's College London, King's College Hospital, London, UK.
authors.forename: A E
authors.initials: AE
authors.lastname: Smith
authors.affiliation: King's College London, King's College Hospital, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Kulasekararaj
authors.affiliation: King's College London, King's College Hospital, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Mufti
authors.affiliation: British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Karsan
authors.affiliation: Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Maciejewski
authors.affiliation: Hematology Department, H Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Sokol
authors.affiliation: Immunology Department, H Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: P K
authors.initials: PK
authors.lastname: Epling-Burnette
authors.affiliation: Immunology Department, H Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Wei
authors.affiliation: Hematology Department, H Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: A F
authors.initials: AF
authors.lastname: List
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002872:Chromosome Deletion; D005787:Gene Frequency; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53