TP53 Codon 72 Polymorphism and Risk of Acute Leukemia

Dunna, Nageswara Rao,Vure, Sugunakar,Sailaja, K.,Surekha, D.,Raghunadharao, D.,Rajappa, Senthil,Vishnupriya, S. Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.1

TP53 is the mostly commonly mutated gene in many cancers and the P53 tumor suppressor protein is involved in multiple cellular processes, including transcription, DNA repair, genomic stability, senescence, cell cycle control and apoptosis. A common single nucleotide polymorphism located within the proline rich region of TP53 gene at codon 72 in exon 4 encodes either proline or arginine. TP53 Arg 72 is more active than TP53 Pro 72 in inducing apoptosis. The aim of this study was to understand the association of the 72 codon polymorphism with acute leukemia development and prognosis. A total of 288 acute leukemia cases comprising 147 acute lymphocytic leukemia (ALL) and 141 acute myeloid leukemia (AML), as well as 245 controls were recruited for analysis of the TP53 72 polymorphism using PCR-RFLP method. Significant association of homozygous arginine genotype with AML was observed (${\chi}^2$- 133.53; df-2, p < 0.001. When data were analyzed with respect to clinical variables, elevation in mean WBC, blast %, LDH levels and slight reduction in DFS in ALL cases with the arginine genotype was observed. In contrast, AML patients with Pro/Pro had elevated WBC, Blast%, LDH levels with slightly reduced DFS. Our study indicates that Arg/Arg genotype might confer increased risk to development of acute myeloid leukemia.

Deletion of GSTM1 and T1 Genes as a Risk Factor for Development of Acute Leukemia

Dunna, Nageswara Rao,Vure, Sugunakar,Sailaja, K.,Surekha, D.,Raghunadharao, D.,Rajappa, Senthil,Vishnupriya, S. Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.4

The glutathione S-transferases (GSTs) are a family of enzymes involved in the detoxification of a wide range of chemicals, including important environmental carcinogens, as well as chemotherapeutic agents. In the present study 294 acute leukemia cases, comprising 152 of acute lymphocytic leukemia (ALL) and 142 of acute myeloid leukemia, and 251 control samples were analyzed for GSTM1 and GSTT1 polymorphisms through multiplex PCR methods. Significantly increased frequencies of GSTM1 null genotype (M0), GSTT1 null genotype (T0) and GST double null genotype (T0M0) were observed in the both ALL and AML cases as compared to controls. When data were analyzed with respect to clinical variables, increased mean levels of WBC, Blast %, LDH and significant reduction in DFS were observed in both ALL and AML cases with T0 genotype. In conclusion, absence of both GST M & GST T might confer increased risk of developing ALL or AML. The absence of GST enzyme might lead to oxidative stress and subsequent DNA damage resulting in genomic instability, a hallmark of acute leukemia. The GST enzyme deficiency might also exert impact on clinical prognosis leading to poorer DFS. Hence GST genotyping can be made mandatory in management of acute leukemia so that more aggressive therapy such as allogenic stem cell transplantation may be planned in the case of patients with a null genotype.

Primary Extra Nodal Non Hodgkin Lymphoma: A 5 Year Retrospective Analysis

Padhi, Somanath,Paul, Tara Roshni,Challa, Sundaram,Prayaga, Aruna K.,Rajappa, Senthil,Raghunadharao, D.,Sarangi, Rajlaxmi Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.10

Background and Aim: The incidence of extra nodal non Hodgkin lymphoma (ENL) is rising throughout the world. However, data regarding ENL as a group is limited. The aim was to study the epidemiological and histomorphological trends of primary ENL (pENL) in India. Material and Methods: The biopsy materials from sixty eight patients with pENL (45 male, 23 female, M:F= 1.9:1), diagnosed over a five year period (2005-2009), were analysed and pathologically reclassified according to the World Health Organization (WHO) classification, 2008 criteria. Results: Primary extra nodal non Hodgkin lymphomas constituted 22.0% (68/308) of all non Hodgkin lymphomas (NHL). The mean age at presentation for pENL and primary nodal NHL was 43 years and 58 years, respectively with a male predilection (M: F=2:1). Central nervous system (CNS) constituted the most common extranodal site (20/68, 29.5%) followed by gastrointestinal tract (17/68, 25%), and nose/nasopharynx (8/68, 11.8%). Diffuse large B-cell lymphoma (DLBCL, not otherwise specified), extranodal marginal lymphoma of mucosa associated lymphoid tissue (MALT) type, and B cell NHL unclassified (U) were the three most common histological types observed. T-cell phenotype was rarely noted (4%). Follicular lymphomas and anaplastic large cell lymphoma, seen among nodal NHL, were absent at extra nodal sites. Majority (41/68, 60%) of the patients with pENL were immunocompetent and 55% were in stage I-II with favorable prognosis. Conclusion: Central nervous system was the most common site of ENL, followed by gastrointestinal tract. Majority of pENL occurred in immunocompetent hosts with a favorable prognosis.

Role of the MDM2 Promoter Polymorphism (-309T>G) in Acute Myeloid Leukemia Development

Cingeetham, Anuradha,Vuree, Sugunakar,Jiwatani, Sangeeta,Kagita, Sailaja,Dunna, Nageswara Rao,Meka, Phanni Bhushann,Gorre, Manjula,Annamaneni, Sandhya,Digumarti, Raghunadharao,Sinha, Sudha,Satti, Vish Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.7

Background: The human homologue of the mouse double minute 2 (MDM2) gene is a negative regulator of Tp53. MDM2-309T>G a functional promoter polymorphism was found to be associated with overexpression thereby attenuation of Tp53 stress response and increased cancer susceptibility. We have planned to evaluate the possible role of MDM2-309T>G polymorphism with risk and response to chemotherapy in AML. Materials and Methods: A total of 223 de novo AML cases and 304 age and sex matched healthy controls were genotyped for the MDM2-309T>G polymorphism through the tetra-primer amplification refractory mutation system (ARMS)-PCR method. In order to assess the functional relationship of -309T>G SNP with MDM2 expression level, we quantified MDM2 mRNA in 30 primary AML blood samples through quantitative RT-PCR. Both the (-309T>G) genotypes and the MDM2 expression were correlated with disease free survival (DFS) rates among patients who have achieved complete remission (CR) after first induction chemotherapy. Results: MDM2-309T>G polymorphism was significantly associated with AML development (p<0.0001). The presence of either GG genotype or G allele at MDM2-309 confered 1.79 (95% CI: 1.12-2.86; p<0.001) and 1.46 fold (95%CI: 1.14-1.86; p= 0.003) increased AML risk. Survival analysis revealed that CR+ve cases with GG genotype had significantly increased DFS rates (16months, p=0.05) compared to CR+ve TT (11 months) and TG (9 months) genotype groups. Further, MDM2 expression was also found to be significantly elevated in GG genotype patients (p=0.0039) and among CR+ve cases (p=0.0036). Conclusions: The MDM2-309T>G polymorphism might be involved in AML development and also serve as a good prognostic indicator.

Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non-Small-Cell Lung Cancer

Scagliotti, Giorgio Vittorio,Parikh, Purvish,von Pawel, Joachim,Biesma, Bonne,Vansteenkiste, Johan,Manegold, Christian,Serwatowski, Piotr,Gatzemeier, Ulrich,Digumarti, Raghunadharao,Zukin, Mauro,Lee, American Society of Clinical Oncology 2008 Journal of clinical oncology Vol.26 No.21

<B>Purpose</B><P>Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting.</P><B>Patients and Methods</B><P>This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m<SUP>2</SUP>on day 1 and gemcitabine 1,250 mg/m<SUP>2</SUP>on days 1 and 8 (n = 863) or cisplatin 75 mg/m<SUP>2</SUP>and pemetrexed 500 mg/m<SUP>2</SUP>on day 1 (n = 862) every 3 weeks for up to six cycles.</P><B>Results</B><P>Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.</P><B>Conclusion</B><P>In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.</P>