Understanding the Impact of Population and Cancer Type on Tumor Mutation Burden Scores: A Comprehensive Whole-Exome Study in Cancer Patients From India.

PURPOSE: The purpose of this study was to understand the impact of population diversity and geographic variation on tumor mutation burden (TMB) scores across cancers and its implication on stratification of patients for immune checkpoint inhibitor (ICI) therapy. MATERIALS AND METHODS: This retrospective study used whole-exome sequencing (WES) to profile 1,233 Indian patients with cancer across 30 different cancer types and to estimate their TMB scores. A WES-based pipeline was adopted, along with an indigenously developed strategy for arriving at true somatic mutations. A robust unsupervised machine learning approach was used to understand the distribution of TMB scores across different populations and within the population. RESULTS: The results of the study showed a biphasic distribution of TMB scores in most cancers, with different threshold scores across cancer types. Patients with cancer in India had higher TMB scores compared with the Caucasian patients. We also observed that the TMB score value at 90th percentile (predicting high efficacy to ICI) was high in four different cancer types (sarcoma, ovary, head and neck, and breast) in the Indian cohort as compared with The Cancer Genome Atlas or public cohort. However, in lung and colorectal cancers, the TMB score distribution was similar between the two population cohorts. CONCLUSION: The findings of this study indicate that it is crucial to benchmark both cancer-specific and population-specific TMB distributions to establish a TMB threshold for each cancer in various populations. Additional prospective studies on much larger population across different cancers are warranted to validate this observation to become the standard of care.

Association analysis of serotonin transporter gene polymorphism among the South-Indian migraineurs.

Background: Migraine is a multifactorial neurological disorder characterized by frequent moderate to severe intensity headaches. The genetic variations in synaptic and post-receptor signalling proteins have direct effect on the process of serotonergic neurotransmission. Methods: We aimed to investigate the genetic association of serotonin transporter (SERT) 5-hydroxytryptamine transporter-linked promoter region (5-HTTLPR) polymorphism and migraine risk in South-Indian population. A total of 304 subjects with migraine including with aura (MA) and without aura (MO) and 308 controls were included in the present study. The single nucleotide polymorphism (SNP) was detected using polymerase chain reaction (PCR) and confirmed by deoxyribonucleic acid (DNA) sequencing. Results: The genotyping analysis revealed insignificant relationship with migraine subjects when compared with controls (P > 0.05). The minor 'S' allele showed no association with odds ratio (OR) = 1.23 [95% confidence interval (CI): 0.90-1.66], heterozygote with OR = 1.18 (95% CI: 0.82-1.69), and homozygote with OR = 1.51 (95% CI: 0.52-4.35). Conclusion: Further clinical studies are required to validate the results of SERT 5-HTTLPR promoter polymorphism in diverse ethnic descents especially in Asian populations.

Genetic predisposition of TNFα gene polymorphism in South-Indian Migraineurs and meta-analysis.

Migraine (Mg) is a multifaceted neurovascular disorder caused by genetic and several environmental etiologies. We have implemented a case-control study of TNFα gene polymorphism in 212 Mg patients and 218 healthy controls utilizing the ARMS-PCR technique, followed by Sanger sequencing. Besides, we have conducted a meta-analysis of different genetic models (five genetic models) to combine and summarize the available data from 11 studies (including this present research). The strength of genetic associations in the meta-analysis used to assess by the pooled odds ratio (OR) and 95% confidence intervals (CI). The results of this case-control study discovered a significant relationship with Mg in recessive and homozygous genotype with OR = 2.35 (95% CI [0.96-5.74]), p-value = 0.045. Also, the outcomes of meta-analysis suggested an irrelevant relationship between TNFα gene (rs1800629) polymorphism and Mg susceptibility in the five genetic models. However, subgrouping based on ethnic background showed a significant association in the allelic genetic model with OR = 1.53 (95% CI [1.02-2.31]), p = 0.040 respectively. The meta-analysis results of TNFα gene polymorphism may represent a risk factor for Mg among Asians. In the future, large scale, multicentric case-control study by classification of patients with Mg with or without aura can be performed worldwide to identify the potential genetic risk factors leading to Mg pathogenesis.