Numerous studies[8, 14–24] have demonstrated that a positive family history of liver cancer increases the risk of developing HCC. However, no previous studies have examined the influence of family history of liver cancer on subsequent outcomes in patients with established cancer. In this study, for the first time, we investigated the effect of family history on the clinicopathologic characteristics and prognosis of HCC. Our results showed that there was no significant difference in clinicopathologic characteristics and prognosis for patients with or without family history of HCC, either in all patients or in subgroups.
This study is based on family history as reported by patients, and only cases with a family history of HCC in first-degree relatives were included and analyzed. In the Connecticut Family Health Study, reports from first-degree relatives were more accurate than those from second-degree relatives, with positive predictive values between 78% and 80% for lung and breast cancer. Furthermore, several studies[5, 8, 14, 24] have shown that only the family history of HCC in first-degree relatives increases the risk of developing HCC, but not second-degree relatives. Thus, we considered only first-degree relatives and second-degree relatives were not assessed in this study. We observed that 169 of the 1,313 patients (12.9%) had a family history of HCC in first-degree relatives. Our results were similar to those previous epidemiologic studies from Asian, USA, and European populations. Yu et al. from China demonstrated that 17.5% of 553 patients reported having first-degree family members with HCC. Hassan et al. from the USA observed that 6.1% of the 347 patients with HCC reported having first-degree family members with liver cancer. In a case-control study in Italy, 37 of 284 HCC patients (13.0%) reported having first-degree relatives with liver cancer.
Family history of the disease was found to be associated with improved survival in some kinds of cancers[9–12], including colon cancer, breast cancer, and so on. However there was some controversy in regards to gastric cancer. Han et al. and Palli et al. reported that a positive family history of gastric cancer in first-degree relatives was associated with a decreased risk of death and recurrence in patients after adjustments for known prognostic factors. However, a report from Japan found that a family history negatively affected survival among gastric cancer patients. In Taiwan, the survival curve of patients with a positive family history was similar to that of patients without a family history. In our study, the impact of family history of HCC on both OS and DFS were analyzed in all patients and in subgroups according to TNM-7 stage. However, no significant difference was identified in patients with or without family history of HCC in either OS or DFS, in all patients or in subgroups.
The synergism between HBV/HCV and a family history of HCC was noted by several studies[5, 8, 14, 24]. Turati et al. reported that the combination of family history of liver cancer and HBV/HCV serum markers is associated to a >70-fold elevated HCC risk. The prognosis of HBV-positive patients with or without a family history was compared in our study. Similarly, there was no significant difference in either OS or DFS, in all patients or in subgroups. Only a few patients (9.5%, 16/169) with a family history were HBV-negative, the survival of HBV-negative patients with or without a family history cannot be analyzed in the present study.
Hassan et al. observed that family history of liver cancer was only a risk factor for HCC in men but not in women. Similar results were also shown in a prospective longitudinal 90,000-person cohort study in China and a case-control study from Italy. But Turati et al. and two Japanese studies[20, 21] observed a non-significantly stronger association between HCC risk and family history of liver cancer for men. The OS and DFS of male patients with or without a family history of HCC were also compared in current study. However, no significant difference was identified either in OS or in DFS.
Several limitations of this study require commenting. First, as we relied on self-reported family history, misclassification of family history status may be possible. However, prior studies[25, 29] have demonstrated such data to be reliable. Moreover, because the data on family history were collected at study baseline before treatment, any errors in recall would have attenuated rather than exaggerated a true association with patient outcome. Second, we did not collect information regarding number of siblings, and the likelihood of having a family history of the disease may vary according to the number of siblings at risk for the disease. However, it is unlikely that family size independently affects survival. Another limitation is the lack of information on family history of chronic hepatitis, cirrhosis, and other inherited diseases such as genetic hemochromatosis and alpha-1-antitrypsin deficiency, which may be related to HCC risk and prognosis[30–32]. Third, because our study was based on a database in a single tertiary cancer center hospital and all patients received hepatectomy as initial treatment, our results may not be generalizable to a larger population of patients with HCC, or patients treated with other methods including transcather artery chemoembolization, local ablation therapy, systemic chemotherapy, and so on. However, the rate of family history in this cohort is similar to the general population of patients with HCC.
Finally, we cannot completely exclude the possibility that patients with a family history may experience an earlier detection of malignancy. However, the effect of family history persisted after adjusting for other patient and disease characteristics associated with cancer recurrence or survival. Additionally, administration of treatment, therapies for recurrence disease, and follow-up care were reasonably uniform among all participants. Moreover, the association between family history and survival remained largely unchanged across the TNM stage as well as HBV status.
Studies suggested the importance of genetic contributions to the development of HCC. However, the relationship between family history and outcome is likely to be complex and may be influenced by a confluence of genetic and environmental factors[33–35]. We considered whether shared environmental or lifestyle factors might contribute to our findings. Further investigation to explore the relationship between family history and these factors is required.