Pathobiology 2008;75:356–363
(DOI:10.1159/000164220)

Susceptibility of XRCC3, XPD, and XPG Genetic Variants to Cervical Carcinoma

He X.a · Ye F.c · Zhang J.b · Cheng Q.c · Shen J.c · Chen H.c
Departments of aGynecology and bGynecologic Oncology and cWomen’s Reproductive Health Laboratory of Zhejiang Province, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
email Corresponding Author


 goto top of outline Key Words

  • Cervical carcinoma
  • Single nucleotide polymorphism
  • XRCC3
  • XPD
  • XPG

 goto top of outline Abstract

Objective: DNA repair genes play a key role in maintaining genomic stability and integrity. DNA repair gene polymorphisms, such as those of XRCC3 and xeroderma pigmentosum, complementation group D and G (XPD, XPG), contribute to carcinogenesis. In this study, we investigated the correlation between cervical carcinoma risk and XRCC3, XPD, XPG genetic variants. Methods: A case-control study of 400 cases including 200 carcinoma, 200 cervical intraepithelial neoplasia (CIN) and 200 normal women was performed. Four single nucleotide polymorphisms (SNPs) (XRCC3 Thr241Met, XPG His1104Asp, XPD Asp312Asn, and XPD Lys751Gln) were genotyped by mismatch amplification polymerase chain reaction. Results: Women carrying homozygous Asp1104Asp genotypes had a significantly decreased risk of cervical or cervical squamous cell carcinoma compared to His1104Asp or His1104His genotypes. Similarly, XPD Asn312Asn (AA) reduced the risk of cervical or cervical squamous cell carcinoma. No association of XRCC3 Thr241Met or XPD Lys751Gln and cervical carcinoma was found. None of the 4 SNPs influenced the risk of CIN in our study. Conclusion: Our results support the hypothesis that genetic variations in DNA repair genes may contribute to an inherited genetic susceptibility to cervical carcinoma.

Copyright © 2008 S. Karger AG, Basel


 goto top of outline References
  1. Giuliano AR, Harris R, SedjGiuliano AR, Harris R, Sedjo RL, Baldwin S, Roe D, Papenfuss MR, Abrahamsen M, Inserra P, Olvera S, Hatch K: Incidence, prevalence, and clearance of type-specific human papillomavirus infections: the Young Women’s Health Study. J Infect Dis 2002;186:462–469.
  2. Wood RD, Mitchell M, Sgouros J, Lindahl T: Human DNA repair genes. Science 2001;291:1284–1289.
  3. Ford BN, Ruttan CC, Kyle VL, Brackley ME, Glickman BW: Identification of single nucleotide polymorphisms in human DNA repair genes. Carcinogenesis 2000;21:1977–1981.
  4. Matullo G, Palli D, Peluso M, Guarrera S, Carturan S, Celentano E, Krogh V, Munnia A, Tumino R, Polidoro S, Piazza A, Vineis P: XRCC1, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy subjects. Carcinogenesis 2001;22:1437–1445.
  5. Kuschel B, Auranen A, McBride S, Novik KL, Antoniou A, Lipscombe JM, Day NE, Easton DF, Ponder BA, Pharoah PD, Dunning A: Variants in DNA double-strand break repair genes and breast cancer susceptibility. Hum Mol Genet 2002;11:1399–1407.
  6. Butkiewicz D, Rusin M, Enewold L, Shields PG, Chorazy M, Harris CC: Genetic polymorphisms in DNA repair genes and risk of lung cancer. Carcinogenesis 2001;22:593–597.
  7. Shen MR, Jones IM, Mohrenweiser H: Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans. Cancer Res 1998;58:604–608.
  8. Dybdahl M, Vogel U, Frentz G, Wallin H, Nexo BA: Polymorphisms in the DNA repair gene XPD: correlations with risk and age at onset of basal cell carcinoma. Cancer Epidemiol Biomarkers Prev 1999;8:77–81.
  9. Sturgis EM, Zheng R, Li L, Castillo EJ, Eicher SA, Chen M, Strom SS, Spitz MR, Wei Q: XPD/ERCC2 polymorphisms and risk of head and neck cancer: a case-control analysis. Carcinogenesis 2000;21:2219–2223.
  10. Stern MC, Johnson LR, Bell DA, Taylor JA: XPD codon 751 polymorphism, metabolism genes, smoking, and bladder cancer risk. Cancer Epidemiol Biomarkers Prev 2002;11:1004–1011.
  11. Rybicki BA, Conti DV, Moreira A, Cicek M, Casey G, Witte JS: DNA repair gene XRCC1 and XPD polymorphisms and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 2004;13:23–29.
  12. Glaab WE and Skopek TR: A novel assay for allelic discrimination that combines the fluorogenic 5′ nuclease polymerase chain reaction (TaqMan) and mismatch amplification mutation assay. Mutat Res 1999;430:1–12.
  13. Scherly D, Nouspikel T, Corlet J, Ucla C, Bairoch A, Clarkson SG: Complementation of the DNA repair defect in xeroderma pigmentosum group G cells by a human cDNA related to yeast RAD2. Nature 1993;363:182–185.
  14. Cui Y, Morgenstern H, Greenland S, Tashkin DP, Mao J, Cao W, Cozen W, Mack TM, Zhang ZF: Polymorphism of Xeroderma Pigmentosum group G and the risk of lung cancer and squamous cell carcinomas of the oropharynx, larynx and esophagus. Int J Cancer 2006;118:714–720.
  15. Jeon HS, Kim KM, Park SH, Lee SY, Choi JE, Lee GY, Kam S, Park RW, Kim IS, Kim CH, Jung TH, Park JY: Relationship between XPG codon 1104 polymorphism and risk of primary lung cancer. Carcinogenesis 2003;24:1677–1681.
  16. Benhamou S Sarasin A: ERCC2/XPD gene polymorphisms and cancer risk. Mutagenesis 2002;17:463–469.
  17. Seker H, Butkiewicz D, Bowman ED, Rusin M, Hedayati M, Grossman L, Harris CC: Functional significance of XPD polymorphic variants: attenuated apoptosis in human lymphoblastoid cells with the XPD 312 Asp/Asp genotype. Cancer Res 2001;61:7430–7434.
  18. Palli D, Russo A, Masala G, Saieva C, Guarrera S, Carturan S, Munnia A, Matullo G, Peluso M: DNA adduct levels and DNA repair polymorphisms in traffic-exposed workers and a general population sample. Int J Cancer 2001;94:121–127.
  19. Hou SM, Falt S, Angelini S, Yang K, Nyberg F, Lambert B, Hemminki K: The XPD variant alleles are associated with increased aromatic DNA adduct level and lung cancer risk. Carcinogenesis 2002;23:599–603.
  20. Liang G, Xing D, Miao X, Tan W, Yu C, Lu W, Lin D: Sequence variations in the DNA repair gene XPD and risk of lung cancer in a Chinese population. Int J Cancer 2003;105:669–673.
  21. Winsey SL, Haldar NA, Marsh HP, Bunce M, Marshall SE, Harris AL, Wojnarowska F, Welsh KI: A variant within the DNA repair gene XRCC3 is associated with the development of melanoma skin cancer. Cancer Res 2000;60:5612–5616.
  22. Tomescu D, Kavanagh G, Ha T, Campbell H, Melton DW: Nucleotide excision repair gene XPD polymorphisms and genetic predisposition to melanoma. Carcinogenesis 2001;22:403–408.
  23. Casson AG, Zheng Z, Evans SC, Veugelers PJ, Porter GA, Guernsey DL: Polymorphisms in DNA repair genes in the molecular pathogenesis of esophageal (Barrett) adenocarcinoma. Carcinogenesis 2005;26:1536–1541.
  24. Khanna KK, Jackson SP: DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 2001;27:247–254.
  25. Matullo G, Guarrera S, Carturan S, Peluso M, Malaveille C, Davico L, Piazza A, Vineis P: DNA repair gene polymorphisms, bulky DNA adducts in white blood cells and bladder cancer in a case-control study. Int J Cancer 2001;92:562–567.
  26. Misra RR, Ratnasinghe D, Tangrea JA, Virtamo J, Andersen MR, Barrett M, Taylor PR, Albanes D: Polymorphisms in the DNA repair genes XPD, XRCC1, XRCC3, and APE/ref-1, and the risk of lung cancer among male smokers in Finland. Cancer Lett 2003;191:171–178.
  27. Altekruse SF, Lacey JV Jr, Brinton LA, Gravitt PE, Silverberg SG, Barnes WA Jr, Greenberg MD, Hadjimichael OC, McGowan L, Mortel R, Schwartz PE, Hildesheim A: Comparison of human papillomavirus genotypes, sexual, and reproductive risk factors of cervical adenocarcinoma and squamous cell carcinoma: Northeastern United States. Am J Obstet Gynecol 2003;188:657–663.
  28. Lacey JV Jr, Frisch M, Brinton LA, Abbas FM, Barnes WA, Gravitt PE, Greenberg MD, Greene SM, Hadjimichael OC, McGowan L, Mortel R, Schwartz PE, Zaino RJ, Hildesheim A: Associations between smoking and adenocarcinomas and squamous cell carcinomas of the uterine cervix (United States). Cancer Causes Control 2001;12:153–161.
  29. Giuliano AR, Harris R, Sedjo RL, et al: Incidence, prevalence, and clearance of type-specific human papillomavirus infections: The Young Women’s Health Study. J Infect Dis 2002;186:462–469.

 goto top of outline Author Contacts

Huaizeng Chen
Women’s Reproductive Health Laboratory of Zhejiang Province
Women’s Hospital, School of Medicine, Zhejiang University
Xueshi Rd No. 2, Hangzhou, 310006 (China)
Tel. +86 571 8706 1501, Fax +86 571 8706 1878, E-Mail chenhz@zju.edu.cn


 goto top of outline Article Information

Received: May 2, 2008
Accepted after revision: July 14, 2008
Published online: December 15, 2008
Number of Print Pages : 8
Number of Figures : 0, Number of Tables : 5, Number of References : 29


 goto top of outline Publication Details

Pathobiology (Exploring the basis of disease)

Vol. 75, No. 6, Year 2008 (Cover Date: December 2008)

Journal Editor: Borisch B. (Geneva), Yasui W. (Hiroshima)
ISSN: 1015-2008 (Print), eISSN: 1423-0291 (Online)

For additional information: http://www.karger.com/PAT


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.