Abstract
Chromosome 4q is one of the most common regions with a high frequency of allelic loss in hepatocellular carcinoma (HCC). To identify the HCC-susceptibility locus on chromosome 4q, we have performed linkage and family-based association analyses on Chinese families with HCC from Taiwan, where hepatitis B is hyperendemic. Using 77 microsatellite markers spanning chromosome 4q on 52 multiplex families, we found suggestive evidence of linkage to 4q22.3–28.1 with a maximum two-point heterogeneity LOD (HLOD) score of 2.55 at marker D4S3240 on chromosome 4q25. Multipoint analyses with microsatellite markers in the region 4q22.3–28.1 resulted in a maximum HLOD score of 3.12 and a maximum nonparametric linkage (NPL) Z score of 1.98 (pointwise P=0.0080; region-wide empirical P=0.021) for D4S3240. The evidence for linkage to D4S3240 was seen mostly in a subset of 28 families lacking affected parents, which showed multipoint HLOD and NPL scores of 3.25 and 2.79 (pointwise P=0.0028; region-wide empirical P=0.008), respectively. Family-based association analyses of the 77 microsatellite markers in 191 families (53 multiplex plus 138 singleton families) using the pedigree disequilibrium test provide further support for observed linkage. Additional genotyping in the 52 multiplex families informative for linkage analyses was performed for 29 single-nucleotide polymorphisms around D4S3240. A common haplotype (at markers rs7442180 and rs221330) positioned ∼873 kb away from D4S3240 was associated with HCC, with P=0.0074.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Abecasis GR, Cherny SS, Cookson WO, Cardon LR . (2002). Nat Genet 30: 97–101.
Beasley RP . (1982). Hepatology 2(Suppl): 21–26.
Befeler AS, Di Bisceglie AM . (2002). Gastroenterology 122: 1609–1619.
Blackwelder WC, Elston RC . (1985). Genet Epidemiol 2: 85–97.
Bluteau O, Beaudoin JC, Pasturaud P, Belghiti J, Franco D, Bioulac-Sage P et al (2002). Oncogene 21: 1225–1232.
Buendia MA . (2000). Semin Cancer Biol 10: 185–200.
Cai RL, Meng W, Lu HY, Lin WY, Jiang F, Shen FM . (2003). World J Gastroenterol 9: 2428–2432.
Chen CJ, Chen DS . (2002). Hepatology 36: 1046–1049.
Ea CK, Sun L, Inoue J, Chen ZJ . (2004). Proc Natl Acad Sci USA 101: 15318–15323.
Kong X, Murphy K, Raj T, He C, White PS, Matise TC . (2004). Am J Hum Genet 75: 1143–1148.
Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES . (1996). Am J Hum Genet 58: 1347–1363.
Laurent-Puig P, Legoix P, Bluteau O, Belghiti J, Franco D, Binot F et al (2001). Gastroenterology 120: 1763–1773.
Liu K, Muse S . (2004). http://www.powermarker.net.
Martin ER, Monks SA, Warren LL, Kaplan N . (2000). Am J Hum Genet 67: 146–154.
Mitra AB, Murty VV, Li RG, Pratap M, Luthra UK, Chaganti RS . (1994). Cancer Res 54: 4481–4487.
Nyholt DR . (2004). Am J Hum Genet 74: 765–769.
O'Connell JR, Weeks DE . (1998). Am J Hum Genet 63: 259–266.
Okabe H, Ikai I, Matsuo K, Satoh S, Momoi H, Kamikawa T et al (2000). Hepatology 31: 1073–1079.
Ott J . (1986). Genet Epidemiol 1(Suppl): 251–257.
Pershouse MA, El-Naggar AK, Hurr K, Lin H, Yung WA, Steck PA . (1997). Oncogene 14: 369–373.
Piao Z, Park C, Park JH, Kim H . (1998). Int J Cancer 79: 356–360.
Roeder K, Bacanu SA, Sonpar V, Zhang X, Devlin B . (2005). Genet Epidemiol 28: 207–219.
Shen FM, Lee MK, Gong HM, Cai XQ, King MC . (1991). Am J Hum Genet 49: 88–93.
Thorgeirsson SS, Grisham JW . (2002). Nat Genet 31: 339–346.
Wacholder S, Chanock S, Garcia-Closas M, El ghormli L, Rothman N . (2004). J Natl Cancer Inst 96: 434–442.
Wands JR . (2004). N Engl J Med 351: 1567–1570.
Wang XL, Uzawa K, Imai FL, Tanzawa H . (1999). Oncogene 18: 823–825.
Yeh SH, Chen PJ, Lai MY, Chen DS . (1996). Gastroenterology 110: 184–192.
Yeh SH, Chen PJ, Shau WY, Chen YW, Lee PH, Chen JT et al (2001). Gastroenterology 121: 699–709.
Yu MW, Chang HC, Liaw YF, Lin SM, Lee SD, Liu CJ et al (2000). J Natl Cancer Inst 92: 1159–1164.
Yu MW, Chen CJ . (1994). Crit Rev Oncol Hematol 17: 71–91.
Acknowledgements
This work was supported by Grants NSC 92-2320-B-002-031 (to M-W Yu) and NSC 92-3112-B002-007 (to P-J Chen) from the National Science Council and DOH92-TD-1054 (National Research Program for Genomic Medicine) (to M-W Yu) from the Department of Health, Executive Yuan, Taiwan.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Shih, WL., Yu, MW., Chen, PJ. et al. Localization of a susceptibility locus for hepatocellular carcinoma to chromosome 4q in a hepatitis B hyperendemic area. Oncogene 25, 3219–3224 (2006). https://doi.org/10.1038/sj.onc.1209345
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1209345
Keywords
This article is cited by
-
Relationship between the mechanism of hepatitis B virus father–infant transmission and pregnancy outcome
Archives of Gynecology and Obstetrics (2017)
-
Genetic variation at 8q24, family history of cancer, and upper gastrointestinal cancers in a Chinese population
Familial Cancer (2014)
-
Evidence for association with hepatocellular carcinoma at the PAPSS1 locus on chromosome 4q25 in a family-based study
European Journal of Human Genetics (2009)