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      Age-specific sex difference in the incidence of hepatocellular carcinoma in the United States

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          Abstract

          Background

          Hepatocellular carcinoma possesses a notable sex difference in incidence, and a protective role of estrogens has been hypothesized.

          Methods

          Using data from 13 cancer registries in the Surveillance, Epidemiology, and End Results Program, we describe the age-specific sex difference in the incidence of hepatocellular carcinoma in the United States during 1992-2013. We used a curve fitting by non-linear regression to quantitatively characterize the age-specific incidence rate of hepatocellular carcinoma by sex.

          Results

          A total of 44,287 incident cases of hepatocellular carcinoma (33,196 males and 11,091 females) were included, with an overall male-to-female ratio in age-standardized rate of 3.55. The sex ratio was below 2 at ages <25 years, increased with age from ages 25-29 years until peaking at 5.40 at ages 50-54 years, and declined thereafter. We also observed additional peaks in the age-specific sex ratio curves at ages 25-34 years across racial/ethnic groups. Modelling of age-specific incidence rates indicated a 15-year delayed increase with age in females compared with males in Asian and Pacific Islanders, and an 11-year delay in Hispanic whites.

          Conclusions

          The age-dependent patterns in the sex difference in the incidence of hepatocellular carcinoma support the hypothesis of a protective role of estrogens. The underlying reasons for the sex difference in hepatocellular carcinoma remain to be further explored in analytic epidemiological studies.

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          Most cited references16

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          Gender Disparity of Hepatocellular Carcinoma: The Roles of Sex Hormones

          Men have a higher incidence of hepatocellular carcinoma (HCC) than women. Epidemiologic and animal studies have suggested that it might be due to the stimulatory effects of androgen and the protective effects of estrogen. Recently, increasing molecular mechanisms underlying the carcinogenic effect of both sex hormones were reported. Knockout of androgen receptor (AR) expression in hepatocytes delayed the development of N′,N′-diethylnitrosamine (DEN)-induced HCC, suggesting the active AR pathway in augmenting the HCC risk. Moreover, an intriguing interaction between the viral protein of hepatitis B virus X protein (HBx) and the androgen pathway was established. HBx can enhance the transcriptional activity of AR in a ligand concentration-dependent manner, mainly through its effects on the c-Src and GSK-3β kinase pathways. The studies from the DEN-induced HCC mouse model further provided a mechanism for the protective role of estrogen in female HCC. Estrogen can protect hepatocytes from malignant transformation via downregulation of IL-6 release from Kupffer cells, a critical process in this mouse model. Intriguingly, suppression of the ERα protein by overexpression of miR-18a, which occurs preferentially in female HCC, was identified as a novel mechanism to block the tumor-protective function of estrogen in female HCC. In conclusion, the current studies demonstrated that the gender disparity of HCC is attributed by both androgen and estrogen sex hormone pathways, with distinct roles in each gender. Therefore, the ligand and the receptor factors of both sex hormones need to be included for assessing the relative risk of HCC patients of each gender.
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            Lifetime risk and sex difference of hepatocellular carcinoma among patients with chronic hepatitis B and C.

            Both hepatitis B (HBV) and C viruses (HCV) are causes of hepatocellular carcinoma (HCC), but lifetime risk and sex difference remain unclear. This study aimed to assess the lifetime risk and sex difference of HCC among patients with chronic HBV and/or HCV. A prospective cohort of 23,820 residents of Taiwan age 30 to 65 years were enrolled from 1991 to 1992, with 477 instances of HCC occurring subsequently. Serum samples collected at enrollment were tested for seromarkers and viral load of HBV and HCV. Newly developed HCC was ascertained through computerized data linkage with national cancer registry and death certification systems. The cumulative lifetime (age 30 to 75 years) incidences of HCC for men and women positive for both HBV surface antigen (HBsAg) and antibodies against HCV (anti-HCV) were 38.35% and 27.40%; for those positive for HBsAg only, 27.38% and 7.99%; for those positive for anti-HCV only, 23.73% and 16.71%; and for those positive for neither, 1.55% and 1.03%, respectively. There was a significant male predominance in incidence of HCC for chronic HBV carriers but not for chronic carriers of HCV or both. Multivariate adjusted hazard ratio of developing HCC decreased with age in HBsAg-seropositive men but increased with age in anti-HCV-seropositive women. Among dual-infected participants, there was an inverse association between HBV and HCV viral load. Risk of HCC increased significantly with increasing viral load of HBV and HCV. There exists a suppressive effect of HCV on HBV viral load. Individual and combined effects of the two viruses on HCC vary with sex and age.
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              Oesophageal and gastric intestinal-type adenocarcinomas show the same male predominance due to a 17 year delayed development in females.

              Upper gastrointestinal adenocarcinomas show an unexplained male predominance that is more apparent in oesophagus than stomach and in intestinal than diffuse histological subtype. We have conducted a population-based study to determine whether the gender phenomenon is primarily related to the anatomical site or the histological subtype. Of 3270 gastric and oesophageal cancers recorded in the West of Scotland Cancer Registry, 1998-2002, 812 were randomly selected for detailed analysis. The Lauren histological subtype of adenocarcinoma was determined by reviewing 1204 original reports and 3241 biopsies. Analysis included 405 non-cardia cancers, 173 cardia cancers and 209 oesophageal adenocarcinomas. Crude incidence rate of intestinal subtype was higher in males (23.86/100,000 person-years) versus females (9.00/100,000 person-years), giving a male/female (M/F) ratio of 2.65 whereas diffuse subtype was similar for both genders (5.58 vs 5.20/100,000 person-years) yielding M/F of 1.07. The M/F ratios for oesophageal, cardia and non-cardia gastric cancer were 3.5, 2.0 and 1.6, respectively. Multiple logistic regression indicated that the odds of male gender was related to the histological subtype rather than anatomical location (odds ratio 2.6, 95% confidence interval 1.78 to 3.9). Curve fitting of the age-specific incidence of intestinal subtype indicated that similar functions describe the rise in incidence with age in males and in females. However, the age-specific incidence of female intestinal subtype was delayed by 17.3 years. The M/F ratio of intestinal subtype was 3.41 at age <50 years, peaked at 7.86 at age 50-59 years and then showed a progressive decrease after 50-60 years of age. Male predominance of upper gastrointestinal adenocarcinoma is related to the intestinal histological subtype rather than tumour location and is due to marked delayed development of this subtype in females prior to 50-60 years of age.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                15 September 2017
                12 July 2017
                : 8
                : 40
                : 68131-68137
                Affiliations
                1 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
                2 Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm 17176, Sweden
                3 Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
                4 The First Clinical Medical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
                Author notes
                Correspondence to: Chen Zhang, zhang_chen@ 123456hust.edu.cn
                Article
                19245
                10.18632/oncotarget.19245
                5620243
                b02461f9-cdc4-4bbb-8754-8282fc556264
                Copyright: © 2017 Liu et al.

                This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 28 February 2016
                : 11 June 2017
                Categories
                Research Paper

                Oncology & Radiotherapy
                hepatocellular carcinoma,liver cancer,sex difference,incidence,estrogen
                Oncology & Radiotherapy
                hepatocellular carcinoma, liver cancer, sex difference, incidence, estrogen

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