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Fulltext Homozygous Wildtype of XPD K751Q Polymorphism Is Associated with Increased Risk of Nasopharyngeal Carcinoma in Malaysian Population

Lye MS, Visuvanathan S, Chong PP, Yap YY, Lim CC, Ban EZ

PLoS One, 2015;10(6):e0130530.
PMID: 26086338 DOI: 10.1371/journal.pone.0130530

The xeroderma pigmentosum group D (XPD) gene encodes a DNA helicase, an important component in transcription factor IIH (TFIIH) complex. XPD helicase plays a pivotal role in unwinding DNA at the damaged region during nucleotide excision repair (NER) mechanism. Dysfunctional XPD helicase protein from polymorphic diversity may contribute to increased risk of developing cancers. This study aims to determine the association between XPD K751Q polymorphism (rs13181) and risk of nasopharyngeal carcinoma (NPC) in the Malaysian population. In this hospital-based matched case-control study, 356 controls were matched by age, gender and ethnicity to 356 cases. RFLP-PCR was used to genotype the XPD K751Q polymorphism. A significant association was observed between XPD K751Q polymorphism and the risk of NPC using conditional logistic regression. Subjects with homozygous Lys/Lys (wildtype) genotype have 1.58 times higher odds of developing NPC compared to subjects with recessive combination of heterozygous Lys/Gln and homozygous Gln/Gln genotypes (OR = 1.58, 95% CI = 1.05-2.38 p = 0.028) adjusted for cigarette smoking, alcohol and salted fish consumption. Our data suggests that Lys/Lys (wildtype) of XPD K751Q contributes to increased risk of NPC in the Malaysian population.

Matched MeSH terms: Xeroderma Pigmentosum Group D Protein/genetics*; Xeroderma Pigmentosum Group D Protein/metabolism
Fulltext Association of ERCC1 C8092A and ERCC2 Lys751Gln polymorphisms with the risk of glioma: a meta-analysis

Xin Y, Hao S, Lu J, Wang Q, Zhang L

PLoS One, 2014;9(4):e95966.
PMID: 24763305 DOI: 10.1371/journal.pone.0095966

To comprehensively evaluate the association of ERCC1 C8092A and ERCC2 Lys751Gln polymorphisms with the risk of glioma.

Matched MeSH terms: Xeroderma Pigmentosum Group D Protein/genetics*
Distribution and haplotype associations of XPD Lys751Gln, XRCC1 Arg280His and XRCC1 Arg399Gln polymorphisms with nasopharyngeal carcinoma in the Malaysian population

Visuvanathan S, Chong PP, Yap YY, Lim CC, Tan MK, Lye MS

Asian Pac J Cancer Prev, 2014;15(6):2747-51.
PMID: 24761895

BACKGROUND: DNA repair pathways play a crucial role in maintaining the human genome. Previous studies associated DNA repair gene polymorphisms (XPD Lys751Gln, XRCC1 Arg280His and XRCC1 Arg399Gln) with nasopharyngeal carcinoma. These non-synonymous polymorphisms may alter DNA repair capacity and thus increase or decrease susceptibility. The present study aimed to determine the genotype distribution of XPD codon 751, XRCC1 codon 280 and codon 399 polymorphisms and haplotype associations among NPC cases and controls in the Malaysian population.
MATERIALS AND METHODS: We selected 157 NPC cases and 136 controls from two hospitals in Kuala Lumpur, Malaysia for this study. The polymorphisms studied were genotyped by PCR-RFLP assay and allele and genotype frequencies, haplotype and linkage disequilibrium were determined using SNPstat software.
RESULTS: For the XPD Lys751Gln polymorphism, the frequency of the Lys allele was higher in cases than in controls (94.5% versus 85.0%). For the XRCC1 Arg280His polymorphism, the frequency of Arg allele was 90.0% and 89.0% in cases and controls, respectively and for XRCC1 Arg399Gln the frequency of the Arg allele was 72.0% and 72.8% in cases and controls respectively. All three polymorphisms were in linkage disequilibrium. The odds ratio from haplotype analysis for these three polymorphisms and their association with NPC was 1.93 (95%CI: 0.90-4.16) for haplotype CGC vs AGC allele combinations. The global haplotype association with NPC gave a p-value of 0.054.
CONCLUSIONS: Our study provides an estimate of allele and genotype frequencies of XRCC1Arg280His, XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms in the Malaysian population and showed no association with nasopharyngeal cancer.

Matched MeSH terms: Xeroderma Pigmentosum Group D Protein/genetics*
Fulltext Association of hOGG1 Ser326Cys, ITGA2 C807T, TNF-A -308G>A and XPD Lys751Gln polymorphisms with the survival of Malaysian NPC patients

Ban EZ, Lye MS, Chong PP, Yap YY, Lim SYC, Abdul Rahman H

PLoS One, 2018;13(6):e0198332.
PMID: 29912899 DOI: 10.1371/journal.pone.0198332

BACKGROUND: Nasopharyngeal carcinoma is a rare form of cancer across the world except in certain areas such as Southern China, Hong Kong and Malaysia. NPC is considered a relatively radiosensitive tumor and patients diagnosed at early stages tend to survive longer compared to those with advanced disease. Given that early symptoms of NPC are non-specific and that the nasopharynx is relatively inaccessible, less invasive screening methods such as biomarker screening might be the key to improve NPC survival and management. A number of genes with their respective polymorphisms have been shown in past studies to be associated with survival of various cancers. hOGG1 and XPD genes encode for a DNA glycosylase and a DNA helicase respectively; both are proteins that are involved in DNA repair. ITGA2 is the alpha subunit of the transmembrane receptor integrin and is mainly responsible for cell-cell and cell-extracellular matrix interaction. TNF-α is a cytokine that is released by immune cells during inflammation.
METHODS: Restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) was used to genotype all the aforementioned gene polymorphisms. Kaplan-Meier survival function, log-rank test and Cox regression were used to investigate the effect of gene polymorphisms on the all-cause survival of NPC.
RESULTS: NPC cases carrying T/T genotype of ITGA2 C807T have poorer all-cause survival compared to those with C/C genotypes, with an adjusted HR of 2.06 (95% CI = 1.14-3.72) in individual model. The 5-year survival rate of C/C carriers was 55% compared to those with C/T and T/T where the survival rates were 50% and 43%, respectively.
CONCLUSION: The finding from the present study showed that ITGA2 C807T polymorphism could be potentially useful as a prognostic biomarker for NPC. However, the prognostic value of ITGA2 C807T polymorphism has to be validated by well-designed further studies with larger patient numbers.

Matched MeSH terms: Xeroderma Pigmentosum Group D Protein/genetics*
Fulltext Haplotype CGC from XPD, hOGG1 and ITGA2 polymorphisms increases the risk of nasopharyngeal carcinoma in Malaysia

Ban EZ, Lye MS, Chong PP, Yap YY, Lim SYC, Abdul Rahman H

PLoS One, 2017;12(11):e0187200.
PMID: 29121049 DOI: 10.1371/journal.pone.0187200

BACKGROUND: 8-oxoG, a common DNA lesion resulting from reactive oxygen species (ROS), has been shown to be associated with cancer initiation. hOGG1 DNA glycosylase is the primary enzyme responsible for excision of 8-oxoG through base excision repair (BER). Integrins are members of a family of cell surface receptors that mediate the cell-cell and extracellular matrix (ECM) interactions. Integrins are involved in almost every aspect of carcinogenesis, from cell differentiation, cell proliferation, metastasis to angiogenesis. Loss of ITGA2 expression was associated with enhanced tumor intravasation and metastasis of breast and colon cancer. XPD gene encodes DNA helicase enzyme that is involved in nucleotide excision repair (NER). It is shown in previous research that XPD homozygous wildtype Lys/Lys genotype was associated with higher odds of NPC.
METHODS: We conducted a 1 to N case-control study involving 300 nasopharyngeal carcinoma (NPC) cases and 533 controls matched by age, gender and ethnicity to investigate the effect of hOGG1 Ser326Cys, ITGA2 C807T and XPD Lys751Gln polymorphisms on NPC risk. Linkage disequilibrium and haplotype analysis were conducted to explore the association of allele combinations with NPC risk. Restriction fragment length polymorphism (RFLP-PCR) was used for DNA genotyping.
RESULTS: No significant association was observed between hOGG1 Ser326Cys and ITGA2 C807T polymorphisms with NPC risk after adjustment for age, gender, ethnicity, cigarette smoking, alcohol and salted fish consumption. Lys/Lys genotype of XPD Lys751Gln polymorphism was associated with increased NPC risk (OR = 1.60, 95% CI = 1.06-2.43). Subjects with history of smoking (OR = 1.81, 95% CI = 1.26-2.60), and salted fish consumption before age of 10 (OR = 1.77, 95% CI = 1.30-2.42) were observed to have increased odds of NPC. The odds of developing NPC of CGC haplotype was significantly higher compared to reference AGC haplotype (OR = 2.20, 95% CI = 1.06-4.58).
CONCLUSION: The allele combination of CGC from hOGG1, ITGA2 and XPD polymorphisms was significantly associated with increased odds of NPC.

Matched MeSH terms: Xeroderma Pigmentosum Group D Protein/genetics*
Fulltext Screening for XPD312 polymorphisms in human oral cancer: a preliminary study

Khor, Chai Wey, Ahmad Azlina, Ponnuraj, Kannan Thirumulu, Noor Hayati Abdul Razak

Archives of Orofacial Sciences, 2010;5(2):42-46.
MyJurnal

Xeroderma pigmentosum-D (XPD) is one of the genes that play a role in the Nucleotide-Excision Repair (NER). Polymorphisms in XPD gene have been identified and reported to be associated with many types of cancer with two common single nucleotide polymorphisms (SNPs), namely, XPD312 and XPD751. The XPD312 polymorphism is at exon 10 codon 312 Asp to Asn (A→G) and the association of this polymorphism with oral cancer is very little known, especially, in Malaysia. The aim of this study was to screen for XPD312 gene polymorphisms in human oral cancer patients attending Hospital Universiti Sains Malaysia (HUSM), Malaysia. Blood samples were collected from 10 oral cancer and 10 normal healthy subjects with their consent. DNA was extracted using commercial DNA extraction kit and Polymerase Chain Reaction (PCR) was performed to amplify the XPD312 gene. The PCR products were digested using restriction enzyme, Sty I and analyzed on a 3% agarose gel for the detection of polymorphisms. This was followed by DNA sequencing to confirm the findings. In the current study, only homozygous wild type polymorphisms in the XPD312 gene was noticed in the oral cancer tissues as revealed by the restriction enzyme and DNA sequencing analyses.

Matched MeSH terms: Xeroderma Pigmentosum
Fulltext Clinical manifestation and genetic analysis of familial rare disease genodermatosis xeroderma pigmentosum

Yuniati R, Sihombing NRB, Nauphar D, Tiawarman B, Kartikasari DS, Dewi M, et al.

Intractable Rare Dis Res, 2021 May;10(2):114-121.
PMID: 33996357 DOI: 10.5582/irdr.2020.03143

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease characterized by hypersensitivity of the skin to ultraviolet radiation and other carcinogenic agents. This ailment is characterized by increased photosensitivity, skin xerosis, early skin aging, actinic keratosis, erythematous lesions, and hyperpigmentation macules. In this serial case report, we presented four cases with XP from two families in Indonesia. Both families were referred from rural referral health centers, and each family has two affected siblings. They had freckle-like pigmentation on the face, trunk, and extremities, which progressed since childhood. One patient of family 2 died because of an infectious disease. Histopathological examination using cytokeratine (CK), CD10, and Ber-EP4 staining from available tissue biopsy of one affected case of family 1 identified basal cell carcinoma (BCC) on the cheek and melanoma on the right eye. Mutation analysis found ERCC2, c2047C>T and XPC, c1941T>A in the first and second families, respectively. We suppose that this is the first case report of XP in Indonesia that incorporates clinical examination, genetic analysis, and extensive histopathological examination, including immunohistochemistry staining, and a novel pathogenic variant of XPC was found in the second family.

Matched MeSH terms: Xeroderma Pigmentosum