Clinical implications of TP53 mutations in a southeast asian cohort of acute myeloid leukaemia patients

Background: TP53 gene is a tumour suppressor gene located in the short arm of chromosome 17. TP53 plays a pivotal role in maintaining genomic stability in response to DNA damage. It is mutated in more than 50% of the human cancer. TP53 mutation (TP53mut) is commonly associated with therapy-related acute myeloid leukemia (AML) and complex karyotype. The incidence of TP53mutn was between 5-10% in de novo AML. This study described the clinicopathologic features of TP53mut AML and their clinical outcome in an Asian cohort. Method: 166 consecutively cell-banked marrow samples of AML were tested for TP53 mutations using a next generation sequencing platform. Baseline disease characteristic and clinical outcomes were retrospectively collected with approval granted by institutional review board. Results: 9/166 had TP53mut (5.4%). 6/9 of TP53mut AML was associated with complex karyotype (p<0.001). The remaining 3 cases were two acute promyelocytic leukemia (APML) and one with normal cytogenetics. TP53mut was mutually exclusive with FLT3 mutation. Two cases had concomitant NPM1 mutation and another two had ASXL1 mutation. TP53mut AML appeared to be associated with TET2 mutation (3/9, 33.3%) compared to 10.2% of the TP53wt (p=0.069). TP53mut AML had a lower CR rate compared to TP53wt (28.6% vs 84.3%, p=0.003). Only two cases achieved CR, one was an APML who remained in continuous remission after 4 years. The other case achieved CR after allogeneic transplant but, relapsed 8 months later. TP53mut AML was significantly associated with inferior OS compared to TP53wt (p=0.001). 0.8 months (95%CI: 0.159 1.484) and 36.8 months (95%CI: 0.000 92.676) respectively. It remains an independent predictor of OS in multivariate analysis that include cytogenetic risk, WBC, LDH and BM blasts (HR 43.07, 95%CI: 6.87-272.41, p<0.001). Conclusion: Our results confirmed the extremely dismal prognosis of TP53mut AML. TP53 mutation testing should be included as part of the pre-chemotherapy workout since this is not a standard practice as yet. The significance of its association with TET2 mutation requires further exploration in a larger study cohort. *Correspondence to: Chin-Hin Ng, Molecular Diagnostic Centre, Department of Laboratory Medicine, National University Hospital, Singapore, E-mail: Chin_ Hin_NG@nuhs.edu. sg Received: August 07, 2018; Accepted: August 20, 2018; Published: August 23, 2018 Introduction Acute myeloid leukaemia (AML) is a clonal disorder, characterized by accumulation of immature myeloid progenitor cells [1,2], resulting from uncontrolled cell division and impaired differentiation. It is the most common form of acute leukemia affecting adults [2]. AML is a heterogenous group of condition, consisting chromosomal abnormalities, recurrently mutated genes and microRNA deregulations [3], and it has varied clinical outcome. Risk stratification is conventionally done based on cytogenetic profile and it divides patients into three categories: favourable, intermediate and poor [4]. However, a significant number of AML patients with normal karyotype are classified as intermediate risk despite differing clinical outcomes due to underlying molecular mutations [5]. Hence, more recently, recurrent genetic mutations have been incorporated into risk stratification to refine individual prognosis and management of AML [2]. With next-generation sequencing (NGS), the discovery of recurrent molecular mutations found in AML patients with normal cytogenetics is accelerated [1]. An overview of these recurrent mutations is now available due to the presence of NGS. Such parallel sequencing of a large number of genes reduces cost and time needed [1,6], making molecular genetic testing a viable part of a potential diagnostic measure. After much study on these recurrent gene mutations and their prognostic significance, NPM1, CEPBA and FLT3-ITD have been incorporated into the 2010 recommendations by European LeukemiaNet (ELN) [7]. In the recent 2017 ELN guidelines, TP53, the most commonly mutated gene in human tumours [8,9], has also been included. TP53 is a tumour suppressor gene located in the short arm of chromosome 17 and it plays a pivotal role in maintaining genomic stability in response to DNA damage [10]. It activates DNA-repair programs and triggers cell-cycle arrest. Some of the common forms of inactivation of TP53 include deletion of the short arm of chromosome 17 and missense point mutations. The incidence of TP53 mutation has been reported to be between 5-10% in de novo AML [10]. It is also associated with therapyrelated AML, complex cytogenetics, low blast counts, and an underrepresentation of concomitant mutations in FLT3, RAS, NPM1, and RUNX1 [10]. These patients exhibit lower response rates to intensive chemotherapy and shorter complete remission (CR) durations [11,12], translating into inferior survival in both younger and older patients [13]. In this study, we aim to evaluate the prognostic significance of TP53 mutational status in a South East Asian cohort. Singapore is a racially diverse country with the majority of its citizens being from around the Abinaya P (2018) Clinical implications of TP53 mutations in a southeast asian cohort of acute myeloid leukaemia patients Volume 2(2): 2-6 Clin Diagn Pathol, 2018 doi: 10.15761/CDP.1000129 Southeast Asian region, providing unique population demographics for this study. Material and methods