Is family history of liver cancer a risk factor for hepatocellular carcinoma?
Authors: Michael L. Volk, Anna S.F. Lok
Journal: Journal of Hepatology (2008)

Hepatocellular carcinoma (HCC) is the fifth most common cause of cancer deaths worldwide [[1]Bosch F.X. Ribes J. Cleries R. Diaz M. Epidemiology of hepatocellular carcinoma.Clin Liver Dis. 2005; 9: 191-211Abstract Full Text Full Text PDF PubMed Scopus (745) Google Scholar]. In the United States and Europe the incidence of HCC is rising, and is expected to increase by another 81% by the year 2020 primarily due to the hepatitis C epidemic [[2]El-Serag H.B. Davila J.A. Petersen N.J. McGlynn K.A. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update.Ann Intern Med. 2003; 139: 817-823Crossref PubMed Scopus (837) Google Scholar]. The strongest risk factors for the development of HCC are chronic hepatitis B (HBV) and hepatitis C (HCV) virus infection, as well as cirrhosis of any cause [[3]Bruix J. Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5061) Google Scholar]. Other risk factors that have been reported include exposure to aflatoxin [[4]Mazzanti R. Gramantieri L. Bolondi L. Hepatocellular carcinoma: epidemiology and clinical aspects.Mol Aspects Med. 2008; 29: 130-143Crossref PubMed Scopus (82) Google Scholar], alcohol, tobacco, obesity [[5]Marrero J.A. Fontana R.J. Fu S. Conjeevaram H.S. Su G.L. Lok A.S. Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma.J Hepatol. 2005; 42: 218-224Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar], and diabetes [[6]El-Serag H.B. Tran T. Everhart J.E. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.Gastroenterology. 2004; 126: 460-468Abstract Full Text Full Text PDF PubMed Scopus (992) Google Scholar]. HCC has been well documented to cluster within families [7Yu M.W. Chang H.C. Liaw Y.F. Lin S.M. Lee S.D. Liu C.J. et al.Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives.J Natl Cancer Inst. 2000; 92: 1159-1164Crossref PubMed Scopus (200) Google Scholar, 8Chen C.H. Huang G.T. Lee H.S. Yang P.M. Chen D.S. Sheu J.C. Clinical impact of screening first-degree relatives of patients with hepatocellular carcinoma.J Clin Gastroenterol. 1998; 27: 236-239Crossref PubMed Scopus (20) Google Scholar], but this has been primarily in regions where HBV is endemic and may have been related to a high prevalence of chronic HBV infection in those families. Only one case-control study of family history and HCC has been performed in an area with a low prevalence of HBV, involving 287 cases and 450 controls in northern Italy [[9]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: 417-421Crossref PubMed Scopus (34) Google Scholar]. Given the rising incidence of HCC in the United States and Europe, further investigation into the contribution of genetic factors to this disease is needed. Such studies could pave the way towards a better understanding of the pathogenesis of HCC and potential therapeutic targets. In this issue of the Journal, Hassan et al. report on a case-control study of family history of HCC involving 347 cases and 1075 controls, of which 190 cases and 1039 controls had no HBV or HCV markers [[10]Hassan M.M. Spitz M.R. Thomas M.B. Curley S.A. Patt Y.Z. Vauthey J.-N. et al.The association of family history of liver cancer with hepatocellular carcinoma: a case-control study in the United States.J Hepatol. 2009; 50: 334-341Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar]. The HCC cases were all pathologically confirmed, and the control subjects were family members of patients at their medical center with non-smoking related cancers. The authors found that having a first degree relative with liver cancer was associated with a 3.9-fold increased risk of having HCC (95% confidence interval 1.4–11.5), compared to no family history of liver cancer, after adjusting for numerous factors including age, gender, race, education, tobacco, alcohol, diabetes, and viral hepatitis. Among the subgroup without viral hepatitis, family history of liver cancer was associated with a 4.1-fold increased risk of having HCC (95% confidence interval 1.3–12.9) in multivariate analysis. The strengths of this study include the relatively large sample size, the pathologic confirmation of HCC diagnosis, the structured and validated family history interview, and the attempt to control for numerous potential confounders. One limitation of the study is the potential for recall bias, which is inherent in any study of this design [[11]Friedenreich C.M. Howe G.R. Miller A.B. Recall bias in the association of micronutrient intake and breast cancer.J Clin Epidemiol. 1993; 46: 1009-1017Abstract Full Text PDF PubMed Scopus (31) Google Scholar]. Recall bias occurs when subjects are asked to recall past events such as family history, and may be more likely to report those events which are salient to their current diagnosis. The magnitude of bias in this study is likely small, since subjects were not informed about the aims of the study and the family history questions were nested in a long list of other questions. However, completely eliminating this bias would require a prospective longitudinal cohort study. Another limitation, as the authors point out, is the lack of information on family history of liver diseases such as genetic hemochromatosis and alpha-1-antitrypsin deficiency, which are associated with increased risk of HCC. This is particularly relevant in patients without viral hepatitis. A third limitation is the lack of weight measurement in cases and controls. Obesity has been shown to be a risk factor for HCC in some studies [[5]Marrero J.A. Fontana R.J. Fu S. Conjeevaram H.S. Su G.L. Lok A.S. Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma.J Hepatol. 2005; 42: 218-224Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar], and since obesity tends to run in families this could be a confounder which was overlooked. Despite these limitations, the authors should be congratulated on their performance of a large well-designed study on the importance of family history of liver cancer in a Western population. Although firm conclusions should never be drawn based upon subgroup analysis, some interesting observations arose from this study which merit further discussion. First, a family history of cancer of any type did not appear to increase the risk of having HCC, suggesting a genetic defect specific for the liver rather than mutation of a widely expressed tumor suppressor gene such as p53 [[12]Zhu Z.Z. Cong W.M. Liu S.F. Xian Z.H. Wu W.Q. Wu M.C. et al.A p53 polymorphism modifies the risk of hepatocellular carcinoma among non-carriers but not carriers of chronic hepatitis B virus infection.Cancer Lett. 2005; 229: 77-83Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar] or DNA synthesis gene such as thymidylate synthase [[13]Yuan J.M. Lu S.C. Van Den Berg D. Govindarajan S. Zhang Z.Q. Mato J.M. et al.Genetic polymorphisms in the methylenetetrahydrofolate reductase and thymidylate synthase genes and risk of hepatocellular carcinoma.Hepatology. 2007; 46: 749-758Crossref PubMed Scopus (70) Google Scholar]. Second, having a sibling with HCC appeared to confer a much higher risk than having a parent with HCC, suggesting the possibility of a recessive inheritance pattern. While these two observations seem to support a role for genetic factors, it is also possible that environmental factors, e.g. dietary habits or exposure to carcinogens such as aflatoxin may contribute to familial clustering of HCC. Cirrhosis due to non-alcoholic fatty liver disease (NAFLD) is becoming an increasingly important cause of HCC [[14]Marrero J.A. Fontana R.J. Su G.L. Conjeevaram H.S. Emick D.M. Lok A.S. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States.Hepatology. 2002; 36: 1349-1354Crossref PubMed Scopus (560) Google Scholar]. Numerous studies have shown that risk factors for NAFLD such as obesity, diabetes, and dyslipidemia run in the family [[15]Sanyal A.J. AGA technical review on nonalcoholic fatty liver disease.Gastroenterology. 2002; 123: 1705-1725Abstract Full Text Full Text PDF PubMed Scopus (909) Google Scholar], possibly due to a combination of genetic factors and shared lifestyle. With increasing prevalence of obesity and NAFLD in the US and worldwide, future studies should determine if family history of NAFLD, diabetes or metabolic syndrome is a risk factor for development of HCC. A final interesting observation was that family history of liver cancer was only a risk factor for HCC in men (adjusted odds ratio 9.2, 95% confidence interval 1.9–45.3) but not in women (adjusted odds ratio 1.6, 95% confidence interval 0.3–8.7). This finding has been consistently seen in other studies, including a prospective longitudinal 90,000-person cohort study in China [[16]Evans A.A. Chen G. Ross E.A. Shen F.M. Lin W.Y. London W.T. Eight-year follow-up of the 90,000-person Haimen City cohort: I. Hepatocellular carcinoma mortality, risk factors, and gender differences.Cancer Epidemiol Biomarkers Prev. 2002; 11: 369-376PubMed Google Scholar]. Hassan et al. postulated a gene–environment interaction such as cigarette smoking, which is more common among men and could interact synergistically with inherited genetic mutations. Of note, this hypothesis could be tested statistically by including an interaction term between family history and cigarette smoking in the multivariate model. Another possibility is that the hepato-carcinogenesis pathway may be different between men and women. For example, HCC in men is associated with shorter CAG repeats in the androgen receptor gene, but HCC in women is conversely associated with longer CAG repeats [[17]Yu M.W. Yang Y.C. Yang S.Y. Chang H.C. Liaw Y.F. Lin S.M. et al.Androgen receptor exon 1 CAG repeat length and risk of hepatocellular carcinoma in women.Hepatology. 2002; 36: 156-163Crossref PubMed Scopus (26) Google Scholar]. Hormonal differences may account for the higher incidence of HCC in men. Clearly, gender differences in the genetics of HCC are an important area for further study. In summary, Hassan et al. have strengthened the case for family history of liver cancer as a risk factor for HCC even among families without viral hepatitis. Future longitudinal cohort studies should gather detailed family histories to determine the role of genetic vs. environmental factors in familial clustering of HCC. These studies should include genetic profiling to identify the genetic factors associated with increased risk of HCC. Data from these studies may improve our understanding of the pathogenesis of HCC, may help identify targets for rational drug design, and perhaps even lead to chemoprevention for those at high risk of developing HCC.