FaCD Online Syndrome Fact Sheet

Last updated: 15 Jan 2010

Name: Hepatocellular Cancer, Familial Clustering of

Mode of Inheritance: AD?/ AR?/ multifact?

Tumor features

hepatocellular cancer (hepatoma)

Non-tumor features

liver cirrhosis

Comment

Familial clusters of hepatocellular cancer (HCC) have been documented and might be due to shared genetic susceptibility [1-3,19]. A family history of HCC has been found to be associated with a relative risk (RR) of 1.6-7.1 to develop this tumor[4,18,20]. In a recent detailed study by Hassan et al[20] in an North-American population of 347 HCC patients and 1075 controls, the association family history of liver cancer and HCC development was significantly different for men (AOR = 9.2 and women (AOR = 1.6 [95% CI, 0.3–8.7]). In subjects without HBV/HCV the estimated AORs were 7.1 and 1.9 for men and women, respectively. AOR for those with a single family member with liver cancer; was 3.7 for all subjects and 4.1 for HBV/HCV negative population (Table 3). A history of liver cancer among parents (AOR = 3.8), P = 0.09 and siblings (AOR = 4.3), P = 0.04 was associated with HCC development in absence of HBV/HCV.

Chen et al[5] screened 1,046 first-degree relatives older than 20 years of HCC patients, with abdominal ultrasound and tumor markers. They detected HCC in 1.9% of these relatives, more common among male (3.1%) than female relatives (0.8%). Tumor occurrence was associated with Hepatitis-B Virus (HBV) carrier status, which was underlined by Yu et al[6] and Hassan et al[20]. The latter also observed this for Hepatitis C infection status. Family history of HCC in individuals with chronic HBV or HBC can lead to relative risks/adjusted odds ratios of up to 70[20,211].

A segregation study in Chinese HCC families suggested that individuals homozygous for a postulated HCC susceptibility allele, in the presence of an HBV infection have a life-time risk to develop HCC of 84 % (males) and 46 % (females)[7]. A similar study of Alaskan HCC families supported this suggestion that chronic HBV infection against the background of an inherited susceptibility can explain familial clustering[1]. Both studies revealed much lower life-time risks of HCC associated with (postulated) genetic susceptibility in the absence of HBV infection (almost zero in the Chinese study and 25 % in the Alaskan study).

Familial hepatocellular cancer has been reported as complication of hepatitis associated cirrhosis[8]. Familial HBsAg-positive hepatocellular cancer in the absence of an underlying cirrhosis has also been observed[9]. Several inherited polymorphisms of genes, including those coding for enzymes important for (pro)carcinogen metabolism have been shown to increase HCC risk, they are not listed separetely in this file[10-17,19].

References

[1] Buetow KH. Genetic studies of human primary hepatocellular carcinoma. Prog Clin Biol Res 1992; 376:155-172.
[2] Olsson R. Hepatitis and cancer: Genetic aspects. Scand J Gastroenterol 31, 115-120. 1996.
[3] Drinkwater NR, Lee GH. Genetic susceptibility to liver cancer. In: Jirtle RL, editor. Liver Regeneration and Carcinogenesis. Academic Press Inc, 1995: 301-321.
[4] Fernandez E, La Vecchia C, D'Avanzo B, Negri E, Franceschi S. Family history and the risk of liver, gallbladder, and pancreatic cancer. Cancer Epidemiol Biomarkers Prev 1994; 3(3):209-212.
[5] Chen CH, Huang GT, Lee HS, Yang PM, Chen DS, Sheu JC. Clinical impact of screening first-degree relatives of patients with hepatocellular carcinoma. J Clin Gastroenterol 27[3], 236-239. 1998.
[6] Yu MW, Chang HC, Liaw YF, Lin SM, Lee SD, Liu CJ, Chen PJ, Hsiao TJ, Lee PH, Chen CJ. Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives [see comments]. J Natl Cancer Inst 2000; 92(14):1159-1164.
[7] Shen FM, Lee MK, Gong HM, Cai XQ, King MC. Complex segregation analysis of primary hepatocellular carcinoma in Chinese families: Interaction of inherited sesceptibility and hepatisis B viral infection. Am J Hum Genet 1991; 49:88-93.
[8] Denison EK, Peters RL, Reynolds TB. Familial hepatoma with hepatitis-associated antigen. Ann Intern Med 1971; 74(3):391-394.
[9] Johnson PJ, Wansbrough Jones MH, Portmann B, Eddleston AL, Williams R, Maycook WD, Calne RY. Familial HBsAg-positive hepatoma: treatment with orthotopic liver transplantation and specific immunoglobulin. Br Med J 1978;216.
[10] Agundez JAG, Olivera M, Ladero JM, Rodriguez-Lescure A, Ledesma MC, Diaz-Rubio M, Meyer UA, Benitez J. Increased risk for hepatocellular carcinoma in NAT2-slow acetylators and CYP2D6-rapid metabolizers. Pharmacogenetics 6[6], 501-512. 1996.
[11] Chen CJ, Yu MW, Liaw YF, Wang LW, Chiamprasert S, Matin F, Hirvonen A, Bell DA, Santella RM. Chronic hepatitis B carriers with null genotypes of glutathione S- transferase M1 and T1 polymorphisms who are exposed to aflatoxin are at increased risk of hepatocellular carcinoma. Am J Hum Genet 59[1], 128-134. 1996.
[12] Agundez JAG, Ledesma MC, Benitez J, Ladero JM, Rodriguez-Lescure A, Diaz-Rubio E, Diaz-Rubio M. CYP2D6 genes and risk of liver cancer. Lancet 1995; 345:830-831.
[13] Ladero JM, Agundez JAG, Rodriguez-Lescure A, Diaz-Rubio M, Benitez J. RsaI polymorphism at the cytochrome P4502E1 locus and risk of hepatocellular carcinoma. Gut 39[2], 330-333. 1996.
[14] Yu MW, Gladek-Yarborough A, Chiamprasert S, Santella RM, Liaw YF, Chen CJ. Cytochrome p450 2E1 and glutathione S-transferase M1 polymorphisms and susceptibility to hepatocellular carcinoma. GASTROENTEROLOGY 1995; 109:1266-1273.
[15] Hsieh LL, Huang RC, Yu MW, Chen CJ, Liaw YF. L-myc, GST M1 genetic polymorphism and hepatocellular carcinoma risk among chronic hepatitis B carriers. Cancer Lett 103[2], 171-176. 1996.
[16] Zhu ZZ, Cong WM, Liu SF, Xian ZH, Wu WQ, Wu MC, Gao B, Hou LF, Zhu GS. A p53 polymorphism modifies the risk of hepatocellular carcinoma among non-carriers but not carriers of chronic hepatitis B virus infection. Cancer letters 2005; 229(1):77-83.
[17] Yu MW, Yang YC, Yang SY, Chang HC, Liaw YF, Lin SM, Liu CJ, Lee SD, Lin CL, Chen PJ, Lin SC, Chen CJ. Androgen receptor exon 1 CAG repeat length and risk of hepatocellular carcinoma in women. Hepatology (Baltimore, Md.) 2002; 36(1):156-63.
[18] Hemminki K, Li X. Familial liver and gall bladder cancer: a nationwide epidemiological study from Sweden. Gut 2003; 52(4):592-6.
[19] Dragani TA. Risk of HCC: Genetic heterogeneity and complex genetics. J Hepatol. 2009 Nov 24. [Epub ahead of print]
[20] Hassan MM, Spitz MR, Thomas MB, Curley SA, Patt YZ, Vauthey JN, Glover KY, Kaseb A, Lozano RD, El-Deeb AS, Nguyen NT, Wei SH, Chan W, Abbruzzese JL, Li D. The association of family history of liver cancer with hepatocellular carcinoma: a case-control study in the United States. J Hepatol. 2009 Feb;50(2):334-41.
[21] Donato F, Gelatti U, Chiesa R, Albertini A, Bucella E, Boffetta P, et al. A case-control study on family history of liver cancer as a risk factor for hepatocellular carcinoma in North Italy. Brescia HCC study Cancer Causes Control. 1999;10:417–421.