A high TP53 mutation burden is a strong predictor of primary refractory mantle cell lymphoma

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F20%3A73603450" target="_blank" >RIV/61989592:15110/20:73603450 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11110/20:10418635 RIV/00098892:_____/20:N0000114 RIV/00064165:_____/20:10418635

Výsledek na webu

<a href="https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.17063" target="_blank" >https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.17063</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1111/bjh.17063" target="_blank" >10.1111/bjh.17063</a>

Jazyk výsledku

angličtina

Název v původním jazyce

A high TP53 mutation burden is a strong predictor of primary refractory mantle cell lymphoma

Popis výsledku v původním jazyce

The mantle cell lymphoma (MCL) International Prognostic Index is widely used as a strong prognostic stratifier, but it has rarely been used for the selection of therapeutic approaches.1 New molecular prognostic predictors, which would reflect critical aspects of MCL biology and that would help in therapy decisions, have been under investigation.2 Recently, several key studies provided evidence of the poor prognostic impact of tumour protein p53 (TP53) gene aberrations or high p53 protein expression in patients with MCL.3–6 There is a growing body of evidence that TP53 aberrations could contribute to chemoresistance.7 In the present study, we analysed the prognostic impact of the extent of a TP53 gene aberration (TP53 mutation burden and deletion of 17p frequency) in a real-world cohort of patients with MCL. This was a retrospective study of 114 consecutive unselected adult patients with newly diagnosed MCL between April 2006 and October 2016. Tumour tissues (bone marrow, peripheral blood, and lymph nodes) from all the patients who were analysed were obtained before the initiation of treatment. The samples were examined by fluorescence in situ hybridisation (FISH) and next-generation sequencing (NGS). The deletion frequency was defined as the percentage of nuclei carrying a deletion of 17p (del17) out of the total number of nuclei carrying the translocation t(11;14). The TP53mut burden was defined as the variant allele frequency (VAF) of the mutations that were detected or the highest VAF in the case of multiple mutations present in one patient. Patients with stable or progressive disease during induction or with relapse or progression within 6 months after the completion of induction were considered as primary refractory (PrR). In all, 27 (237%) of the 114 patients who were analysed exhibited PrR. More detailed characteristics are summarised in Table I. A total of 43 patients (377%) had some type of TP53 disruption. The overall (OS) and progression-free survival (PFS) curves were not statistically different between the TP53mut, del17, and TP53mut + del17 cohorts (TP53mut/ del17/TP53mut + del17) (P = 095 for OS; P = 086 for PFS) (Figure SA). A total of 24 patients had both TP53mut and del17, 13 patients had isolated TP53mut, and five had del17. The association between TP53mut and del17 was significant, at P &lt; 0001. Moreover, in the PrR cohort, there was almost unit correlation (c = 090, P &lt; 0001) between the TP53mut burden and del17 frequency (Figure SB). The TP53mut burden (mean 33%, range 3–85%) and del17 frequency (mean 47%, range 6–92%) varied significantly among the patients. As expected, a TP53 aberration was a strong predictor of PrR, regardless of age and therapeutic approach. Interestingly, PrR patients without a TP53 aberration tended to be older (Figure SC). This led us to use age, TP53mut burden, and del17 frequency to predict the probability of PrR. The tight correlation between the del17 frequency and TP53mut burden meant that only TP53mut burden remained as a significant variable. Thus, the final model reads probðPrRÞ¼ 1 1þexpðzÞ , (1) with z¼10:43þ0:1245∗ageþ0:0558∗TP53mut burden (2) Both the coefficients are significant, at P &lt; 0001. The value z in equation (1) is a linear combination of age and the mutation burden. Such a classifier produces a receiver operating characteristic curve (Figure SD). Thus, for any cutoff value of the probability, the decision boundary has the form of a line in the age-burden plane (Fig 1). The patients above the decision line are predicted as PrR and the patients below the line as non-PrR. In our cohort, the patients with MCL with an aberration of the TP53 gene had a significantly worse prognosis compared to those with the TP53-wild type. There was no difference in survival outcomes between those with TP53mut and del17. Our present findings thus further complement the results from Eskelund et al.3, who found lower OS and PFS in younger patients with MCL with TP53 mutations. In contrast to that study, our calculations were performed on a whole real-life spectrum of younger and older patients with MCL. The correlation between the TP53mut burden and del17 frequency in the PrR patients was almost perfect (Figure SB). Surprisingly, for the non-PrR patients, the del17 frequency tended to be higher than the TP53mut burden. We can hypothesise that an increasing TP53mut burden plays a more prominent role in the process of chemoresistance acquisition than del17. This is also supported by the observation that all the deletions were monoallelic.

Název v anglickém jazyce

A high TP53 mutation burden is a strong predictor of primary refractory mantle cell lymphoma

Popis výsledku anglicky

The mantle cell lymphoma (MCL) International Prognostic Index is widely used as a strong prognostic stratifier, but it has rarely been used for the selection of therapeutic approaches.1 New molecular prognostic predictors, which would reflect critical aspects of MCL biology and that would help in therapy decisions, have been under investigation.2 Recently, several key studies provided evidence of the poor prognostic impact of tumour protein p53 (TP53) gene aberrations or high p53 protein expression in patients with MCL.3–6 There is a growing body of evidence that TP53 aberrations could contribute to chemoresistance.7 In the present study, we analysed the prognostic impact of the extent of a TP53 gene aberration (TP53 mutation burden and deletion of 17p frequency) in a real-world cohort of patients with MCL. This was a retrospective study of 114 consecutive unselected adult patients with newly diagnosed MCL between April 2006 and October 2016. Tumour tissues (bone marrow, peripheral blood, and lymph nodes) from all the patients who were analysed were obtained before the initiation of treatment. The samples were examined by fluorescence in situ hybridisation (FISH) and next-generation sequencing (NGS). The deletion frequency was defined as the percentage of nuclei carrying a deletion of 17p (del17) out of the total number of nuclei carrying the translocation t(11;14). The TP53mut burden was defined as the variant allele frequency (VAF) of the mutations that were detected or the highest VAF in the case of multiple mutations present in one patient. Patients with stable or progressive disease during induction or with relapse or progression within 6 months after the completion of induction were considered as primary refractory (PrR). In all, 27 (237%) of the 114 patients who were analysed exhibited PrR. More detailed characteristics are summarised in Table I. A total of 43 patients (377%) had some type of TP53 disruption. The overall (OS) and progression-free survival (PFS) curves were not statistically different between the TP53mut, del17, and TP53mut + del17 cohorts (TP53mut/ del17/TP53mut + del17) (P = 095 for OS; P = 086 for PFS) (Figure SA). A total of 24 patients had both TP53mut and del17, 13 patients had isolated TP53mut, and five had del17. The association between TP53mut and del17 was significant, at P &lt; 0001. Moreover, in the PrR cohort, there was almost unit correlation (c = 090, P &lt; 0001) between the TP53mut burden and del17 frequency (Figure SB). The TP53mut burden (mean 33%, range 3–85%) and del17 frequency (mean 47%, range 6–92%) varied significantly among the patients. As expected, a TP53 aberration was a strong predictor of PrR, regardless of age and therapeutic approach. Interestingly, PrR patients without a TP53 aberration tended to be older (Figure SC). This led us to use age, TP53mut burden, and del17 frequency to predict the probability of PrR. The tight correlation between the del17 frequency and TP53mut burden meant that only TP53mut burden remained as a significant variable. Thus, the final model reads probðPrRÞ¼ 1 1þexpðzÞ , (1) with z¼10:43þ0:1245∗ageþ0:0558∗TP53mut burden (2) Both the coefficients are significant, at P &lt; 0001. The value z in equation (1) is a linear combination of age and the mutation burden. Such a classifier produces a receiver operating characteristic curve (Figure SD). Thus, for any cutoff value of the probability, the decision boundary has the form of a line in the age-burden plane (Fig 1). The patients above the decision line are predicted as PrR and the patients below the line as non-PrR. In our cohort, the patients with MCL with an aberration of the TP53 gene had a significantly worse prognosis compared to those with the TP53-wild type. There was no difference in survival outcomes between those with TP53mut and del17. Our present findings thus further complement the results from Eskelund et al.3, who found lower OS and PFS in younger patients with MCL with TP53 mutations. In contrast to that study, our calculations were performed on a whole real-life spectrum of younger and older patients with MCL. The correlation between the TP53mut burden and del17 frequency in the PrR patients was almost perfect (Figure SB). Surprisingly, for the non-PrR patients, the del17 frequency tended to be higher than the TP53mut burden. We can hypothesise that an increasing TP53mut burden plays a more prominent role in the process of chemoresistance acquisition than del17. This is also supported by the observation that all the deletions were monoallelic.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30205 - Hematology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2020

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

BRITISH JOURNAL OF HAEMATOLOGY

ISSN

0007-1048

e-ISSN

—

Svazek periodika

191

Číslo periodika v rámci svazku

5

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

4

Strana od-do

"'e103'"-"e'106'"

Kód UT WoS článku

000563738400001

EID výsledku v databázi Scopus

2-s2.0-85089969281