Comprehensive genetic analysis of cytarabine sensitivity in a cell-based model identifies polymorphisms associated with outcome in AML patients

Abstract

Key Points• A preclinical cell-based model identifies SNPs associated with cytarabine sensitivity that also associate with outcome in leukemia patients.• SNPs within the MCC gene were associated with cytarabine sensitivity in lymphoblastoid cell lines and leukemic blasts from patients.A whole-genome approach was used to investigate the genetic determinants of cytarabineinduced cytotoxicity. We performed a meta-analysis of genome-wide association studies involving 523 lymphoblastoid cell lines (LCLs) from individuals of European, African, Asian, and African American ancestry. Several of the highest-ranked single-nucleotide polymorphisms (SNPs) were within the mutated in colorectal cancers (MCC) gene. MCC expression was induced by cytarabine treatment from 1.7-to 26.6-fold in LCLs. A total of 33 SNPs ranked at the top of the meta-analysis (P < 10 25) were successfully tested in a clinical trial of patients randomized to receive low-dose or high-dose cytarabine plus daunorubicin and etoposide; of these, 18 showed association (P < .05) with either cytarabine 50% inhibitory concentration in leukemia cells or clinical response parameters (minimal residual disease, overall survival (OS), and treatment-related mortality). This count (n 5 18) was significantly greater than expected by chance (P 5 .016). For rs1203633, LCLs with AA genotype were more sensitive to cytarabine-induced cytotoxicity (P 5 1.31 3 10 26) and AA (vs GA or GG) genotype was associated with poorer OS (P 5 .015), likely as a result of greater treatment-related mortality (P 5 .0037) in patients with acute myeloid leukemia (AML). This multicenter AML02 study trial was registered at www.clinicaltrials.gov as #NCT00136084. (Blood. 2013;121(21):4366-4376) IntroductionAcute myeloid leukemia (AML) is the most common form of acute leukemia in adults and also occurs in children. Despite the genetic heterogeneity of the disease, patients have been treated for decades with similar combinations of cytarabine and anthracyclines with little improvement in overall survival (OS).1 Although the majority of patients (50%-60%) under 60 years achieve complete remission with traditional anthracycline-and cytarabine-based induction regimens, the long-term survival rates continue to be around 30% to 40% for adults and 60% for children. [2][3][4][5][6] Outcomes are worse for patients >60 years, with complete response rates in the range of 40% to 55% and poor long-term survival rates. 7 The main reason for treatment failure among patients with AML is resistance to therapy. [8][9][10] In addition, treatment with cytarabine is associated with a number of adverse side effects including myelosuppression, infections, mucositis, neurotoxicity, and acute pulmonary syndrome. 11Cytarabine requires activation through intracellular phosphorylation to araC-triphosphate (ara-CTP). The mechanism of action of cytarabine involves the incorporation of ara-CTP in place of deoxycytidine triphosphate, resulting in chain termination, blocking DNA and RNA synthesis and causing leukemic cell de...

Association between the MDM2 T309G Polymorphism and Leukemia Risk: a Meta-analysis

“…It is estimated that approximately 33.6 in every 1, 000, 000 children under 15 years old will develop ALL. While acute myeloid leukemia (AML) is the most common form of acute leukemia in adults as well as in children (Gamazon et al, 2013), it causing immature myeloid precursors to accumulate, and resulting in an estimated 13, 330 cases and an estimated 8, 950 deaths in the United States in 2010 (Wang et al, 2013). But unfortunately, the exact pathological mechanism of leukemia is still unclear recently.…”

SLC29A1 single nucleotide polymorphisms as independent prognostic predictors for survival of patients with acute myeloid leukemia: an in vitro study

“…Genetic variations, particularly SNPs, have been identified in these genes involved in Ara-C transport and metabolism [25][26][27]. Both in vivo and in vitro studies demonstrated that the activities of these enzymes are correlated with polymorphic gene variations [28,29], and some of these SNPs are even highly correlated with treatment response and survival of AML patients with Ara-C based chemotherapy [30][31][32][33]. Previous study found that rs329491 of SLC29A1 maybe a favorable survival factor for patients with pancreatic cancer [34].…”

MCC inhibits beta-catenin transcriptional activity by sequestering DBC1 in the cytoplasm

“…In liver cancer, MCC expression is lost through LINE‐1 retrotransposition events or microRNA targeting . Furthermore, SNPs within the MCC gene and its expression levels are associated with responsiveness to chemotherapy treatment in acute myeloid leukaemia . Limited data are available for other cancer types, except for lung cancer where expression of MCC is also variable but promoter methylation is rare …”