TP53 mutation profile in chronic lymphocytic leukemia: evidence for a disease specific profile from a comprehensive analysis of 268 mutations.

The TP53 mutation profile in chronic lymphocytic leukemia (CLL) and the correlation of TP53 mutations with allele status or associated molecular genetics are currently unknown. We performed a large mutation analysis of TP53 at four centers and characterized the pattern of TP53 mutations in CLL. We report on 268 mutations in 254 patients with CLL. Missense mutations appeared in 74% of cases compared with deletions and insertions (20%), nonsense (4%) and splice site (2%) mutations. The majority (243 of 268) of mutations were located in the DNA-binding domain. Transitions were found in 131 of 268 mutations, with only 41 occurring at methylated CpG sites (15%), suggesting that transitions at CpGs are uncommon. The codons most frequently mutated were at positions 175, 179, 248 and 273; in addition, we detected a common 2-nt deletion in the codon 209. Most mutations (199 of 259) were accompanied by deletion of the other allele (17p-). Interestingly, trisomy 12 (without 17p-) was only found in one of 60 cases with TP53 mutation (without 17p-) compared with 60 of 16 in the cohort without mutation (P=0.006). The mutational profile was not different in the cohorts with and without previous therapy, suggesting that the mechanism underlying the development of mutations may be similar, independent of treatment.

p53 mutation, deprivation and poor prognosis in primary breast cancer.

BACKGROUND: The deprivation gap for breast cancer survival remains unexplained by stage at presentation, treatment, or co-morbidities. We hypothesised that p53 mutation might contribute to the impaired outcome observed in patients from deprived communities. METHODS: p53 mutation status was determined using the Roche Amplichip research test in 246 women with primary breast cancer attending a single cancer centre and related to deprivation, pathology, overall, and disease-free survival. RESULTS: p53 mutation, identified in 64/246 (26%) of cancers, was most common in 10 out of 17 (58.8%) of the lowest (10th) deprivation decile. Those patients with p53 mutation in the 10th decile had a significantly worse disease-free survival of only 20% at 5 years (Kaplan-Meier logrank chi(2)=6.050, P=0.014) and worse overall survival of 24% at 5 years (Kaplan-Meier logrank chi(2)=6.791, P=0.009) than women of deciles 1-9 with p53 mutation (c.f. 56% and 72%, respectively) or patients in the 10th decile with wild-type p53 (no disease relapse or deaths). CONCLUSION: p53 mutation in breast cancer is associated with socio-economic deprivation and may provide a molecular basis, with therapeutic implications, for the poorer outcome in women from deprived communities.

The detection of TP53 mutations in chronic lymphocytic leukemia independently predicts rapid disease progression and is highly correlated with a complex aberrant karyotype.

The poor prognosis of chronic lymphocytic leukemia (CLL) patients with del (17p) is well established. We analyzed whether mutation of TP53 on the remaining allele adds to the poor prognosis or whether even TP53 mutation alone may be an adverse prognostic factor. We analyzed TP53 mutations in 193 CLL patients by denaturing high performance liquid chromatography in combination with direct DNA sequencing and a TP53 resequencing research microarray. Mutations were correlated to chromosomal aberrations defined by interphase fluorescent in situ hybridization and chromosome banding analyses and to the clinical course of patients. TP53 mutations were detected in 13.5% (26 of 193) of samples, whereas the incidence of del (17p) was 9.3% (18 of 193). TP53 mutations were significantly associated with del (17p) (concordance 94%, P<0.001) and complex cytogenetic abnormalities (concordance 50%, P<0.001). Among 147 patients whose clinical data were available, patients with TP53 abnormalities (n=20) had a significantly decreased time to treatment compared to patients without TP53 aberration (P<0.001). Median time to treatment was short in patients with isolated TP53 mutation (n=6, 2.0 months) and in those with del (17p) (n=14, 21.3 months) as compared to patients without TP53 aberration (n=127, 64.9 months, P<0.001). In multivariate Cox regression analysis, VH status, TP53 mutations and also isolated TP53 mutations independently predicted rapid disease progression.

Association between CYP2D6 genotype and tardive dyskinesia in Korean schizophrenics.

The CYP2D6 gene codes for human cytochrome P450 2D6 enzyme, which is responsible for the metabolism of many psychiatric drugs. In schizophrenic patients treated with neuroleptics, decreased or loss of function CYP2D6 alleles may contribute to the development of tardive dyskinesia (TD), a movement disorder that frequently occurs with chronic neuroleptic treatment. The goal of this study was to determine whether the occurrence of TD is associated with CYP2D6 genotype in a cohort of Korean schizophrenics by employing a CYP450 GeneChip((R)) oligonucleotide microarray and PCR assays to screen for 19 CYP2D6 alleles. Our results revealed that males with at least one decreased or loss of function allele have a moderately greater chance of developing TD than males with only wild-type alleles. Female schizophrenics did not have a significantly greater chance of developing TD. Our results demonstrate the utility of CYP2D6 microarrays to assess genotype status in this Korean cohort.

Disruption of the IFN-gamma cytokine network in chronic lymphocytic leukemia contributes to resistance of leukemic B cells to apoptosis.

Recent evidence indicates that the slowly expanding population of CD5+ B cells that characterizes chronic lymphocytic leukemia (CLL) results primarily from defects in responses to cytokines that regulate apoptosis (e.g. I1-4, TGF-beta, IFN-alpha, IFN-gamma). We have now demonstrated not only that the enhanced anti-apoptotic effect of IFN-gamma on these neoplastic B cells is apparently mediated through increased levels of IFN-gamma receptors but also that there are increased numbers of IFN-gamma-expressing CD4 and CD8 T cells in these patients. This is the strongest evidence to date that multiple alterations in the IFN-gamma cytokine network contribute to the pathogenesis of CLL.