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

Abstract

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 ¼ 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.

Clinical and Laboratory Parameters in a Cohort of CLL Patient: A Single Centre Experience

“…CLL patients carrying a del(17p) show marked resistance against chemotherapy. Mutations of TP53 are found in 4-37% of patients with CLL, and have been associated with very poor prognosis [19].…”

Impact of TP53 mutation and 17p deletion in mantle cell lymphoma

“…This pattern is similar to what has been reported for 26 608 TP53 mutations in cancer in general in the IARC database, including DLBCL and CLL, although the latter had a lower prevalence of transitions at CpG sites (15%). 13 The exons most frequently targeted by mutations were exons 8 (n ¼ 26) and 5 (n ¼ 21), followed by exons 7 (n ¼ 13), 6 (n ¼ 8) and 4 (n ¼ 1) (Figure 1a). The codons most frequently hit by mutations were at positions 176, 248 and 273 (Figure 1b), which indicates that the classical mutation hot spots are also commonly affected in MCL.…”

“…We trained an ensemble of decision trees 11,12 (Random Forest) with 3285 likely oncogenic somatic missense mutations from the COSMIC database 13 and 3300 'passenger' mutations synthetically generated by a computer algorithm to mimic the cancer mutation spectrum. To ensure an unbiased score, 13 unique BRAF amino…”

Protein expression analysis of chronic lymphocytic leukemia defines the effect of genetic aberrations and uncovers a correlation of CDK4, P27 and P53 with hierarchical risk

“…17 Intriguingly, in this study we found that CLL with trisomy 12 was characterized by low levels of P53. As cells that harbor mutations of P53 show strong induction of the aberrant P53 tumor suppressor protein, 22,32,33 our finding of low levels of P53 protein in CLL cases with trisomy 12 fits with an absence of P53 mutations in this subgroup. The levels of other proteins involved in response to DNA damage, such as ATM and RB, were also different in CLL cases with trisomy 12, although only as a trend (Figure 2).…”

“…31 Cases with trisomy 12 rarely show P53 mutations or acquire these over time. 32 In addition, CLL with trisomy 12 seems to be more sensitive to chemotherapy than other genetic subgroups of CLL. 17 Intriguingly, in this study we found that CLL with trisomy 12 was characterized by low levels of P53.…”