ABCMdb

PMID: 23065526

Tiribelli M, Fabbro D, Franzoni A, Fanin R, Damante G, Damiani D
Q141K polymorphism of ABCG2 protein is associated with poor prognosis in adult acute myeloid leukemia treated with idarubicin-based chemotherapy.
Haematologica. 2012 Oct 12., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys Q141K polymorphism of ABCG2 protein is associated with poor prognosis in adult acute myeloid leukemia treated with idarubicin-based chemotherapy by Mario Tiribelli, Dora Fabbro, Alessandra Franzoni, Renato Fanin, Giuseppe Damante, and Daniela Damiani Haematologica 2012 [Epub ahead of print] Citation: Tiribelli M, Fabbro D, Franzoni A, Fanin R, Damante G, and Damiani D. Q141K polymorphism of ABCG2 protein is associated with poor prognosis in adult acute myeloid leukemia treated with idarubicin-based chemotherapy. Login to comment 1 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys A recent report on the prognostic value of six ABCG2 gene polymorphisms in 184 Chinese acute leukemia patients seems to suggest that the presence of Q141K is associated with worse outcome.8 The aim of this study was to evaluate the frequency of the Q141K variant in a cohort of Caucasian patients with acute myeloid leukemia (AML) and to assess the impact of this polymorphism on the outcome of a treatment strategy that included idarubicin as the only anthracycline. Login to comment 5 ABCG2 p.Gln141Lys ABCG2 expression was studied on blast cells by flow cytometry, as previously described.1 ABCG2 genotype was analyzed with the TaqMan SNP Q141K assay (Applied Biosystems, C_15854163_70) and the test was performed in duplicate. Login to comment 6 ABCG2 p.Gln141Lys Q141K polymorphism was detected in 29 of 163 patients (18%), and 2 patients were homozygous for the mutation. Login to comment 7 ABCG2 p.Gln141Lys Of the 125 patients receiving chemotherapy, 26 displayed Q141K variant while 99 were ABCG2 wt. Login to comment 10 ABCG2 p.Gln141Lys No impact on CR was demonstrated for ABCG2 overexpression and Q141K polymorphism. Login to comment 13 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys Q141K polymorphism of ABCG2 protein is associated with poor prognosis in adult acute myeloid leukemia treated with idarubicin‐based chemotherapy Running title: ABCG2 Q141K polymorphism in acute myeloid leukemia Mario Tiribelli1,2 , Dora Fabbro3 , Alessandra Franzoni3 , Renato Fanin1,2 , Giuseppe Damante3,4 and Daniela Damiani1,2 1 Division of Hematology and Bone Marrow Transplantation, Azienda Ospedaliero‐Universitaria Udine, Udine, Italy; 2 Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy; 3 Institute of Genetics, Azienda Ospedaliero‐Universitaria Udine, Udine, Italy, and 4 Department of Medical and Biological Sciences, University of Udine, Udine, Italy Correspondence Daniela Damiani, MD, Clinica Ematologica Azienda Ospedaliero‐Universitaria, Piazzale S. M. Misericordia, 15, 33100 Udine, Italy. Login to comment 14 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys However, when patients were stratified in three groups according to ABCG2 expression (low or high) and presence of Q141K polymorphism, a negative impact of Q141K emerged. Login to comment 17 ABCG2 p.Gln141Lys Clinical characteristics of the 125 patients treated for AML, divided according to ABCG2 Q141K polymorphism. Login to comment 18 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys Q141K + (n = 26) Q141K - (n = 99) P Age: median (range) 56 (20-75) 60 (25-84) 0.36 WBC x109 /L): median (range) 10.2 (1.4-258.0) 16.0 (0.5-265.0) 0.63 FAB subtype: n. (%) 0.70 M0-M1 7/26 (27) 32/99 (32) M2 9/26 (35) 24/99 (24) M4-M5 10/26 (38) 43/99 (44) Karyotype: n. (%) 0.13 Favorable / Intermediate 19/22 (86) 55/82 (67) Unfavorable 3/22 (14) 27/83 (33) CD34+ : n. (%) 15/26 (58) 59/99 (60) 1.00 CD56+ : n. (%) 1/26 (4) 18/99 (18) 0.13 ABCG2 0.95 overexpression: n. (%) 15/26 (58) 54/99 (54%) mRNA: mean &#b1; SD 0.96&#b1;2.00 1.17&#b1;2.76 protein expression: mean &#b1; SD 0.37&#b1;0.28 0.30&#b1;0.19 Figure 1. Login to comment 19 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys (4) Among them, the 421C>A (Q141K), that is also the commonest in Caucasian ethnicity (around 10% (5), has been shown to alter protein function and to modify in vitro sensitivity to many anticancer drugs (6-7), including classical anthracyclines and mitoxantrone. Login to comment 20 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys A recent report on the prognostic value of six ABCG2 gene polymorphisms in 184 Chinese acute leukemia patients seems to suggest that the presence of Q141K is associated with worse outcome. Login to comment 21 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys (8) Aim of this study was to evaluate the frequency of the Q141K variant in a cohort of Caucasian patients with acute myeloid leukemia (AML) and to assess the impact of this polymorphism on the outcome of a treatment strategy that included idarubicin as the only anthracycline. Login to comment 26 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys Regarding DFS, Q141K polymorphism per se did not affect survival, but stratifying patients in the three groups, patients with low ABCG2 and wt gene had a longer OS compared to patients with Q141K ABCG2 or with high ABCG2 expression (55%, CI: 38-72% vs. 40%, CI: 20-60% vs. 27%, CI: 13-41, respectively) (c7;2 = 7.5, P=0.02) (Figure 1B). Login to comment 27 ABCG2 p.Gln141Lys (1) ABCG2 genotype was analyzed with the TaqMan SNP Q141K assay (Applied Biosystems, C_15854163_70) and the test was performed in duplicate. Login to comment 28 ABCG2 p.Gln141Lys Q141K polymorphism was detected in 29/163 patients (18%), and two patients were homozygous for the mutation. Login to comment 29 ABCG2 p.Gln141Lys Of the 125 patients receiving chemotherapy, 26 displayed Q141K variant while 99 were ABCG2 wt. Login to comment 31 ABCG2 p.Gln141Lys In a group of 184 Chinese patients with acute leukemia, C421A polymorphism was associated with worse survival.6 In our AML patients receiving a therapeutic program that includes idarubicin as the only anthracycline, Q141K is associated with poor outcome, comparable to that of patients over-expressing wild-type ABCG2 protein. Login to comment 32 ABCG2 p.Gln141Lys No impact on CR was demonstrated for ABCG2 overexpression and Q141K polymorphism. Login to comment 35 ABCG2 p.Gln141Lys Again, ABCG2 Q141K polymorphism had no impact on relapse: among Q141K+ patients, relapse occurred in 7/16 (44%), while 20 of the 57 patients (%) with wt ABCG2 who attained CR relapsed; 3-years DFS was 47% [CI: 30-64] in Q141+ cases, and 61% [CI: 47-75] in wt patients (p = 0.). Login to comment 36 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys However, stratifying patients in three groups according to ABCG2 expression (low or high) and presence of Q141K polymorphism, a negative impact of Q141K emerged. Login to comment 41 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys As for DFS, Q141K polymorphism per se did not affect survival, but stratifying patients in the three groups, patients with low ABCG2 and wt gene had a longer OS compared to patients with Q141K ABCG2 or with high ABCG2 expression (55%, CI: 38-72 vs 40%, CI: 20-60 vs 27%, CI: 13-41, respectively) (χ2 = 7.5, p = 0.02) (Figure 1B). Login to comment 43 ABCG2 p.Gln141Lys Q141K-ABCG2 is the most frequent polymorphism in Caucasians, and we detected it in 18%, slightly higher than what is reported in the literature (5, 9). Login to comment 47 ABCG2 p.Gln141Lys (6) In our AML patients receiving a therapeutic program that includes idarubicin as the only anthracycline, Q141K is associated with poor outcome, comparable to that of patients over-expressing wild type ABCG2 protein. Login to comment