Send orders for print-reprints and e-prints to reprints@benthamscience.net Current Molecular Medicine XXXX, XX, 1-9 1 RESEARCH ARTICLE 1566-5240/XX $65.00+.00 © XXXX Bentham Science Publishers NF-κB1 Intronic Region Polymorphisms as Risk Factor for Head and Neck Cancer in HPV-Infected Population from Pakistan Sumaira Sarwar 1,* , Muhammad Usman Tareen 1 , Maimoona Sabir 2 , Aneesa Sultan 1 and Salman A. Malik 1 1 Department of Biochemistry, Quaid-i-Azam University, Islamabad, 75500, Pakistan; 2 Department of Microbiology, University of Haripur, Khyber Pakhtunkhwa 75500, Pakistan A R T I C L E H I S T O R Y Received: October 06, 2020 Revised: January 27, 2021 Accepted: February 09, 2021 DOI: 10.2174/1566524021666210302144344 Abstract: Background: Head and neck cancer (HNC) develops due to a number of risk factors, including infection of Human Papillomavirus (HPV). The genetic predisposition also plays an important role in deregulating different signaling pathways including the NF-KB pathway. Certain polymorphisms are reported to affect the NF-kB pathway genes. Objectives: The present research was conducted to study the association of HPV with NF-KB1 (p50) gene polymorphisms in HNC patients of the Pakistani population. Methods: Genomic DNA from HNC tumors samples was extracted using the Exgene SV DNA extraction Kit. Allele-specific PCR and direct sequencing were done for analysis of NF-κB1 SNPs 94ins/del (rs28362491), rs1598858 and rs4648068. Results: The genotypes AGrs1598858, AGrs4648068 and GGrs4648068 were associated with significantly increased risk of head and neck cancer in studied population. Furthermore the HNC cases with genotypes AGrs1598858 and GGrs4648068 displayed growing risk of HPV related cancers. Promotor region SNP 94ins/del (rs28362491) was not detected in studied population. Tobacco use, lymph nodes involvement and poorly differentiated tumors were positively associated with HPV induced cancers. Conclusion: It is the first comprehensive study from Pakistan, to evaluate the polymorphic variants of NF-κB1. Genotypes AGrs4648068, GGrs4648068, and AGrs1598858 of NF-κB1 gene are associated with increased risk of head and neck cancers in the studied HPV infected Pakistani population. It can be concluded that HPV infection, involvement of lymph nodes and tobacco use can act synergetic and add up in modulating HPV induced HNC with intronic SNPs of NF-κB1 gene in Pakistani population. Keywords: NF-κB1, single nucleotide polymorphism, Human Papillomavirus, head and neck cancer, Pakistani population. 1. INTRODUCTION Head and neck carcinoma (HNC) is considered the sixth most common cancer, causing 350,000 deaths each year, with an annual incidence of 600,000 cases reported globally [1]. Oropharyngeal and tongue cancers are the predominant forms of HNC in western countries [2] while; oral cancer is common in India, Pakistan, and other South Asian countries [3, 4]. In Pakistan, carcinoma of oral cavity and oropharynx are the most frequent types of cancers in male and female with ratio of 2:1 [5, 6]. More than 90% of HNC occurs in squamous cells of oral cavity, oropharynx, and larynx *Address correspondence to this author at the Department of Biochemistry, Quaid-i-Azam University, Islamabad, 75500, Pakistan; Tel: 0092-3450733686; E-mail: sumairasarwark@gmail.com [7], and a gradual increase has been observed in the prevalence of tensile cancer and oropharyngeal cancer worldwide [8]. Head and Neck cancer develops owing to genetic and environmental factors one as well as the other. Smoking, excessive use of alcohol and viruses are the main risk factors. Among viruses, the Human Papillomavirus (HPV) has a significant role in causing oropharyngeal carcinogenesis [2], 60% of HPV positive cases are generally found in oropharynx and tonsils [9- 11]. HPVs are of three types; low-risk, intermediate- risk, and high-risk; HPV16, 18, 31, 33, and 45 are considered to be high-risk genotypes which are associated with different pathological conditions [12- 14]. High-risk HPV produces early proteins E6 and E7 that destroy the p53 and pRb respectively, E6 protein has the ability to bind with the p53, and E7 has the ability to attach with the pRb gene product [15]. HPV16