Genetic variations in DNA‐repair genes (XRCC1, 3, and 7) and the susceptibility to hepatocellular carcinoma in a cohort of Egyptians

Abstract

Chronic hepatitis C (CHC) is a worldwide etiology of chronic hepatic insult particularly in Egypt. DNA‐repair systems are responsible for maintaining genomic integrity by countering threats posed by DNA lesions. Deficiency in the repair capacity due to genetic alterations in DNA‐repair genes can lead to genomic instability and increased risk of cancer development. The present work aimed at studying the possible association between XRCC1‐G28152A (rs25487), XRCC3‐C18067T (rs861539), and XRCC7‐G6721T (rs7003908) single nucleotide polymorphisms (SNPs) and the susceptibility to hepatocellular carcinoma (HCC) in Egyptian population. The study was conducted on 100 newly diagnosed HCC patients and 100 age‐ and sex‐matched healthy controls. Laboratory workup revealed that all HCC patients have chronic hepatitis C viral infection. Genotyping of the studied SNPs was performed by real‐time PCR. The heteromutant genotype of XRCC1 (GA) conferred an almost two‐fold increased risk of HCC (OR , 2.35; 95% CI, 1.33‐4.04). Regarding XRCC7, the heteromutant (TG) genotype conferred a two‐fold increased risk of HCC (OR , 2.17; 95% CI, 1.23‐3.82). Coinheritance of the polymorphic genotypes of XRCC1 and 7 was significantly higher in HCC cases than controls and was associated with an 11‐fold increased risk of HCC (OR , 11.66; 95% CI, 2.77‐49.13). The frequency of XRCC3 polymorphic genotypes in HCC patients was close to that of the controls.

Genetic variants of APEX1 p.Asp148Glu and XRCC1 p.Gln399Arg with the susceptibility of hepatocellular carcinoma

“…In a study performed among 50 HCC patients from the South Valley of Egypt, the authors revealed that the XRCC1 (rs25487*399Gln) allele was significantly increased with the progression of HCC ( p = 0.007) 47 . Likewise, in another study done among 100 HCC patients recruited from the Capital of Egypt, the authors identified that XRCC1 (rs25487*399Gln) allele revealed a statistically significant with an elevated risk of HCC ( p = 0.004) 13 . Furthermore, other reports confirmed the contribution of the XRCC1 (rs25487*p.Gln399Arg) variant with the elevated risk of HCC like those among Italian, 48 Chinese, 49 and Pakistani 50 subjects.…”

“…Besides that, our team recognized two reports that examined the correlation of the XRCC1 (rs25487*p.Gln399Arg) variant with the increased risk of HCC among Egyptian subjects but in the provinces rather than the delta region of Egypt 13,47 . In a study performed among 50 HCC patients from the South Valley of Egypt, the authors revealed that the XRCC1 (rs25487*399Gln) allele was significantly increased with the progression of HCC ( p = 0.007) 47 .…”

“…9,10 The apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1; OMIM#: 107748, other synonyms include APE, APE-1, and APEX) and the X-ray repair cross-complementing 1 (XRCC1; OMIM#: 194360, alternative name involve RCC) genes were the foremost key elements involved in the BER mechanism that recognized and repaired the DNA damage. [11][12][13] The APEX1 gene consists of 20 splice variants and is located on the long arm of chromosome 14q11.2, traversing about 2542 bases along the plus strand, 14 while the XRCC1 gene included nine transcripts and is situated on the minus strand of the chromosome 19q13.31 that spanned about 37,163 bases. 15 Furthermore, the APEX1 gene encoded a DNA repair enzyme; APEX endonuclease that is involved in the BER pathway and maintains the ability to restore the single-strand breaks.…”

“…The APEX1 gene consists of 20 splice variants and is located on the long arm of chromosome 14q11.2, traversing about 2542 bases along the plus strand, 14 while the XRCC1 gene included nine transcripts and is situated on the minus strand of the chromosome 19q13.31 that spanned about 37,163 bases 15 . Furthermore, the APEX1 gene encoded a DNA repair enzyme; APEX endonuclease that is involved in the BER pathway and maintains the ability to restore the single‐strand breaks 12,13,16 . Alternatively, the XRCC1 gene encoded a protein that cooperates with DNA ligase III and other elements to accelerate the gap‐filling and ligation process 17,18 …”

“…Lastly, the incorporation of the corrected base, gap filling, and ligation was achieved by the integration of polymerase β/XRCC1/DNA ligase leading to the restoration of the intact double‐strand DNA genome 7,23 . Intrinsically, several reports explored the contribution of the APEX1 p.Asp148Glu (rs1130409; c.444T>A) and the XRCC1 p.Gln399Arg (rs25487; c.1196A>G) variants with the increased risk of a variety of cancerous diseases, particularly HCC 11,13,24,25 . Thus, the crucial objective of this study is to explore the association of these two missense variants with the susceptibility of HCC among Egyptian subjects, as well as their contributions with clinical and laboratory variables.…”