Genetic polymorphisms in cyclin H gene are associated with oxaliplatin-induced acute peripheral neuropathy in South Indian digestive tract cancer patients.

PURPOSE: Digestive tract cancer patients treated with oxaliplatin are often associated with the development of peripheral neuropathy. The aim of the present study is to identify the influence of single-nucleotide polymorphisms (SNPs) in genes involved in oxaliplatin metabolism, cell cycle control, detoxification or excretion pathways with the development of oxaliplatin-induced acute peripheral neuropathy (acute OXAIPN) and its severity among digestive tract cancer patients treated with oxaliplatin-based chemotherapy. PATIENTS AND METHODS: A total of 228 digestive tract cancer patients undergoing with the oxaliplatin-based chemotherapy between November 2014 and December 2016 were included in the current study. Genomic DNA was extracted from peripheral blood by standard phenol-chloroform method. Genotyping of five SNPs in four genes [GSTP1 (rs1965), ABCG2 (rs3114018), CCNH (rs2230641, rs3093816), AGXT (rs4426527)] was carried out by Real-Time TaqMan SNP genotyping assay. RESULTS: We found that the two genetic variants rs2230641 and rs3093816 in cyclin H (CCNH) gene were significantly associated with both the incidence and severity of acute OXAIPN. For CCNH-rs2230641 (AA vs AG+GG; dominant model) Incidence: OR 2.62, 95% CI 1.44-4.75, p = 0.001, severity; OR 4.64, 95% CI 1.58-13.62, p = 0.002. For CCNH-rs3093816 (AA vs AG+GG; dominant model); incidence: OR 3.43, 95% CI 1.57-7.50, p = 0.001; severity: OR 2.36, 95% CI 1.05-5.30, p = 0.033. CONCLUSIONS: The results of the present study found significant association between CCNH polymorphisms and acute OXAIPN development. However, further studies are warranted from independent groups to validate our study results.

Frequency distribution of BLMH, XPO5 and HFE gene polymorphisms in the South Indian population and their association with Hodgkin Lymphoma.

BACKGROUND: Hodgkin lymphoma, a highly curable malignancy is currently treated with an adriamycin, bleomycin (BLM), vinblastine, and dacarbazine (ABVD) regimen. BLM-induced pulmonary toxicity (BPT) is one of the dose-limiting toxicities. Previous reports have revealed that genetic variants rs1050565, rs11077, and rs1800562 are involved in the development of BPT. These results cannot be extrapolated to the South Indian population because of their ethnic difference. This study aimed to determine the frequency of rs1050565, rs11077, and rs1800562 variants in South Indian healthy individuals and Hodgkin lymphoma cases. These frequencies were compared with 1000 genome populations' data. We also assessed if these variants modified the risk to Hodgkin lymphoma. MATERIAL AND METHODS: A total of 200 healthy individuals and 101 cases with Hodgkin lymphoma were recruited for this case-control study after ethical approval. Blood samples were collected from the study participants and DNA was extracted. Genotyping of rs1050565, rs11077, and rs1800562 variants was done using real-time polymerase chain reaction. A chi-square test was used to assess the differences in genotype frequency data between cases and controls. RESULTS: The minor allele frequencies of rs1050565 and rs11077 were 4.3% and 39%, respectively, whereas all the individuals were wild-type for rs1800562 mutation. The frequencies significantly differed from 1000 genome data. The variants did not alter the risk for Hodgkin lymphoma. CONCLUSIONS: We determined the frequencies of rs1050565, rs11077, and rs1800562 variants in South Indian healthy individuals, and the frequencies differed significantly from 1000 genome populations. We also found that the studied polymorphisms are not associated with Hodgkin lymphoma risk in the South Indian population.

Association of Voltage-Gated Sodium Channel Genetic Polymorphisms with Oxaliplatin-Induced Chronic Peripheral Neuropathy in South Indian Cancer Patients

Oxaliplatin is a platinum drug active against digestive tract cancers. Among its side effects, peripheral neuropathy is one of the dose-limiting toxicities. This affects around 50 to 70% of patients but the pathophysiology of development of oxaliplatin-induced peripheral neuropathy (OXAIPN) remains unclear. Sodium channels (SCNAs) play major role in neuronal electrical signaling processes and mutations in SCNAs lead to various neuronal diseases involving the central and peripheral nervous systems. In this study, we evaluated whether SCNA genetic variants might be associated with risk of chronic OXAIPN in patients with digestive tract cancers treated with oxaliplatin. Methodology: Blood samples from 228 digestive tract cancer patients who had received oxaliplatin in adjuvant and neoadjuvant or metastatic settings were obtained and genomic DNA was extracted by phenol-chloroform extraction. Genotyping was performed with the real-time polymerase chain reaction (RT-PCR) using validated real-time TaqMan single nucleotide polymorphism (SNP) genotyping assays. Neuropathy was evaluated and graded according to National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.03. Results: We found that the rs6746030 polymorphic variant of SCN9A was significantly associated with a higher incidence of chronic OXAIPN (GA+AA vs GG: OR=1.8, 95% CI=1.04-3.4, P=0.04; dominant model) while the rs6754031 variant was linked with a lower incidence (OR=0.45, 95% CI=0.22-0.77, P=0.005; dominant model). The SCN 10A polymorphic variant was associated with severity of chronic OXAIPN (P=0.006, OR=2.0, 95% CI=1.2 - 3.3). Conclusion: The results of the present prospective study provide evidence in support of a causal relationship between chronic OXAIPN and voltage gated sodium channel polymorphisms. However, further studies from independent groups are required to validate these results.

Oxaliplatin-induced Peripheral Neuropathy in South Indian Cancer Patients: A Prospective Study in Digestive Tract Cancer Patients.

PURPOSE: The aim of the current study is to report our prospective experience on the prevalence of oxaliplatin-induced peripheral neuropathy (OXAIPN) in patients with digestive tract cancers treated with oxaliplatin-based combination therapy. MATERIALS AND METHODS: A total of 219 patients scheduled to be treated with oxaliplatin-based combination therapy were prospectively examined at baseline and follow-up during the therapy between November 2014 and December 2016. The incidence of acute OXAIPN was measured using a descriptive questionnaire (yes/no question) based on sum of number of symptoms present and NCI-CTCAE version 4.03 was applied to clinically grade the severity of chronic OXAIPN. RESULTS: Acute and chronic OXAIPN was found in 108 of 219 (49.3%) and 127 of 219 (58%) patients, respectively. Out of 11 acute OXAIPN symptoms, the vast majority of patients manifested cold-induced pharyngolaryngeal (63.8%) dysesthesias or perioral (61.1%) paresthesias. Development of acute OXAIPN was predictive of subsequent development of chronic OXAIPN (P = 0.0001). All the patients received a median cumulative dose of 780 mg/m2 (range: 130-1040 mg/m2). There was a significant correlation between the patients who received the median cumulative dose and the development of chronic OXAIPN. The incidences of OXAIPN in patients with median cumulative dose of ≤780 mg/m2 was 51/120 (42.5%) and >780 mg/m2 was OXAIPN 76/99 (76.7%) (P = 0.0001). CONCLUSION: The current study results demonstrate that the vast majority of patients who receive oxaliplatin-based combination chemotherapy will manifest acute OXAIPN that may contribute to the development of chronic peripheral neuropathy on repeated courses of drug administration.