Disparities In Hepatocellular Carcinoma Research Articles

Study of sex-biased differences in genomic profiles in East Asian hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is characterized by a notable sex disparity in incidence and tumor aggressiveness. Revealing differences in genetic landscapes between male and female HCCs may expand the understanding of sexual disparities mechanisms and assist the development of precision medicine. Although reports on the sex disparity of HCC are accumulated, studies focusing on sex-related biomarkers among Asian populations remain limited. Here, we conducted a comprehensive genomic profiling analysis to explore differences between male and female patients within a cohort of 195 Taiwanese HCC patients. We did not detect any sex-biased genomic alterations. However, when our investigation extended to the TCGA dataset, we found higher frequencies of gene copy gains in CCNE2 and mutations in CTNNB1 and TP53 among male patients. Besides, we further evaluated the associations between genomic alterations and patients’ prognosis by sex. The results showed that female patients harboring tumors with STAT3 gain and alterations in the JAK–STAT pathway displayed a poor prognosis. These two factors remained independently associated with unfavorable prognosis even after adjusting for the patient’s age and stage characteristics (Hazard ratio = 10.434, 95% CI 3.331–32.677, P < 0.001; Hazard ratio = 2.547, 95% CI 1.195–5.432, P = 0.016, respectively). In summary, this study provides valuable insights into understanding sex disparity in HCC in the East Asian population. Validation through larger cohorts and extensive sequencing efforts is warranted.

Study of sex-biased differences in genomic profiles in East Asian hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is characterized by a notable sex disparity in incidence and tumor aggressiveness. Revealing differences in genetic landscapes between male and female HCCs may expand the understanding of sexual disparities mechanisms and assist the development of precision medicine. Although reports on the sex disparity of HCC are accumulated, studies focusing on sex-related biomarkers among Asian populations remain limited. Here, we conducted a comprehensive genomic profiling analysis to explore differences between male and female patients within a cohort of 195 Taiwanese HCC patients. We did not detect any sex-biased genomic alterations. However, when our investigation extended to the TCGA dataset, we found higher frequencies of gene copy gains in CCNE2 and mutations in CTNNB1 and TP53 among male patients. Besides, we further evaluated the associations between genomic alterations and patients’ prognosis by sex. The results showed that female patients harboring tumors with STAT3 gain and alterations in the JAK–STAT pathway displayed a poor prognosis. These two factors remained independently associated with unfavorable prognosis even after adjusting for the patient’s age and stage characteristics (Hazard ratio = 10.434, 95% CI 3.331–32.677, P < 0.001; Hazard ratio = 2.547, 95% CI 1.195–5.432, P = 0.016, respectively). In summary, this study provides valuable insights into understanding sex disparity in HCC in the East Asian population. Validation through larger cohorts and extensive sequencing efforts is warranted.

Investigation of racial disparities in hepatocellular carcinoma and rates of liver transplant: A SEER 2000-2020 study.

e13754 Background: Hepatocellular carcinoma (HCC) most commonly occurs in patients with pre-established liver disease and is occurring with increasing incidence and mortality across the United States while disproportionately affecting all US racial/ethnic minority populations. Surgical resection or liver transplant is the preferred treatment for HCC if patient is a surgical candidate and offers the best chance to cure HCC. Previous literature analysis of HCC racial disparities using the Surveillance, Epidemiology, and End Results (SEER) database between the years 1998 and 2012 has been reported, however recent data has not yet been investigated to compare trends. Methods: The SEER database was used to identify 134,212 patients diagnosed with HCC between 2000 and 2020 in the US. Patients with HCC were identified using the ICD-0-3 primary site code C220 and histologic type codes 8170, 8172, 8173, 8174, and 8175. Patient race was categorized as White, Black, American Indian/Alaska Native, Asian or Pacific Islander, and Unknown based on SEER coding scheme. Racial disparities were then determined using chi-squared testing. Results: Patients with reported Unknown race or American Indian/Alaska Native had the greatest increase in proportion of new HCC diagnoses when comparing the years 2016-2020 to 2000-2005. Across all races, the average age at diagnosis was between 60-69 and males were more likely than females to be diagnosed with HCC. Those with Unknown race were more likely to present with Tumor grade I. American Indian/Alaskan Native patients were more likely to be reported as unstaged for HCC and also more likely to have surgery recommended, but not performed for an unknown reason. American Indian/Alaskan Native patients were less likely to receive liver transplant. Patients with Unknown race were more likely to be alive or dead of other cause and less likely to be dead from HCC diagnosis. When comparing this data to previously reported data from 1998-2012, there is an increase in proportion of patients having unstaged HCC especially in the American Indian/Alaskan Native cohort. Conclusions: Native American Indian/Alaskan Native patients continue to have significantly decreased rate of liver transplant (p&lt;0.001) compared to White patients (24.24% vs 30.31%). Previous rates reported 4.4% vs 5.5%.

Abstract 3943: Refined race and ethnicity categories for an EHR-based cohort to study disparities in liver cancer risk

Abstract Purpose: To develop a schema for harmonized, detailed characterization of race and ethnicity data for an electronic health record (EHR)-based cohort linked to cancer registry data to assess disparities in hepatocellular carcinoma (HCC) risk. Methods: We assembled an cohort of adults with 1+ encounter in 2000-2017 by pooling EHR data from three healthcare systems (Kaiser Permanente Hawai’i, Sutter Health, San Francisco Health Network). EHR data to define sociodemographic and clinical factors were linked to population-based state cancer registries for data on incident HCC (ICD-03 site/histology C22.0/8170-8175) through 2017. We extracted, harmonized and developed schemas to characterize multiple response race and ethnicity data across systems. We used Cox proportional hazards regression to examine disparities in HCC risk across racial and ethnic groups, comparing observations across categorization schema. Results: The cohort included 4,248,553 adults; 2,916 had incident HCC. A race and ethnicity schema that prioritized small populations and disaggregation of heterogenous groups defined 16 categories and was used to analyze pooled data from Kaiser Permanente Hawai’i and Sutter Health. With this schema, we observed variation in HCC risk across ethnic groups that are typically aggregated into larger ethno-racial categories (e.g., Asian American). Compared to non-Hispanic (NH) White males, Vietnamese American males had greater risk of HCC (hazard ratio (HR): 7.42; 95% CI: 4.25, 12.96) as did American Indian/Alaska Native, Black, Chinese American, Hispanic, Native Hawaiian, and Pacific Islander males; Asian Indian, Filipino, Japanese, and Korean American males did not. Among females, every group except American Indian/Alaska Native, Asian Indian American, and Pacific Islander females had greater risk of HCC than the NH White group. Due to less granular data from San Francisco Health Network during our study period, we developed a second, grouped schema aggregating categories from the detailed schema; it resulted in seven race and ethnicity categories and was used to analyze pooled data from all three healthcare systems. Compared to the categorization of race and ethnicity used by the US Census, which also has seven categories, we observed different patterns in HCC risk disparities for the smallest groups (i.e., American Indian/Alaska Native and Native Hawaiian). Conclusions: Analysis of a large EHR-based cohort linked to cancer registry data using a race and ethnicity characterization schema that prioritizes small populations yields valuable knowledge on disparities in HCC risk. Thus, to advance research on health disparities using EHR data, researchers must critically assess racial and ethnic categories typically available from healthcare system data repositories. We offer recommendations to operationalize EHR data on race and ethnicity to facilitate its meaningful use in research. Citation Format: Mindy C. DeRouen, Caroline A. Thompson, Alison J. Canchola, Alyssa Cortella, Pushkar Inamdar, Janet Chu, Sixiang Nie, Mai Vu, Ma Somsouk, Michele M. Tana, Anna D. Rubinsky, Iona Cheng, Mi-Ok KIm, Mark Segal, Chanda Ho, Yihe G. Daida, Su-Ying Liang, Hashem B. El-Serag, Scarlett L. Gomez, Salma Shriff-Marco. Refined race and ethnicity categories for an EHR-based cohort to study disparities in liver cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3943.

Racial and Ethnic Disparities in Hepatocellular Carcinoma Treatment Receipt in the United States: A Systematic Review and Meta-Analysis.

Racial and ethnic disparities in hepatocellular carcinoma (HCC) prognosis exist, partly related to differential failures along the cancer care continuum. We characterized racial and ethnic disparities in treatment receipt among patients with HCC in the United States. We searched Medline, Embase, and CINAHL databases to identify studies published between January 2012 and March 2022 reporting HCC treatment receipt among adult patients with HCC, stratified by race or ethnicity. We calculated pooled odds ratios for HCC treatment using random effects models. We identified 15 studies with 320,686 patients (65.8% White, 13.9% Black, 10.4% Asian, and 8.5% Hispanic). Overall, 33.2% of HCC patients underwent any treatment, and 22.7% underwent curative treatment. Compared with White patients, Black patients had lower odds of any treatment (OR 0.67, 95% CI 0.55-0.81) and curative treatment (OR 0.74, 95% CI 0.71-0.78). Similarly, Hispanic patients had lower pooled odds of curative treatment (OR 0.79, 95% CI 0.73-0.84). There were significant racial and ethnic disparities in HCC treatment receipt, with Black patients having lower odds of receiving any and curative treatment while Hispanic patients having lower odds of curative treatment. Racial and ethnic differences in treatment receipt serve as an intervention target to reduce disparities in HCC prognosis.

Abstract C084: Quantifying racial disparities in hepatocellular carcinoma: A comprehensive meta-analysis of survival and early presentation

Abstract Background: Hepatocellular carcinoma (HCC) constitutes a significant burden on global cancer mortality, with distinct disparities in survival and early presentation observed across racial and ethnic groups. Despite previous research recognizing race as a critical prognostic factor in HCC, these studies have been limited by inconsistent findings and a lack of comprehensive, multi-population analysis. Given the diverse global demographics affected by HCC and the critical necessity of equitable healthcare, a detailed investigation of these disparities is crucial. Aim: Our study aimed to quantitatively synthesize existing literature on racial disparities in the early presentation and survival of HCC, comparing White patients to Black, Asian, and Hispanic groups. Methods: We searched PubMed, Embase, and Cochrane Library databases for studies published until May 2022 that reported racial disparities in HCC survival and early presentation. For early presentation, we employed relative risk (RR), and for survival outcomes, we utilized the hazard ratio (HR), applying random-effect models in both instances. All statistical analyses were conducted using R software (version 4.0.3) with metafor and meta packages. Results: Our search yielded 16 eligible studies, representing 241962 patients from various racial and ethnic backgrounds (172268 white, 33656 black, 12837 Hispanic, 23201 Asian). The pooled RR for early presentation was 0.89 (95% CI: 0.85-0.93, P&amp;lt;0.01, I2=58%) for Black, 1.01 (95% CI: 0.98-1.03, P=0.39, I2=0%) for Asian, and 0.96 (95% CI: 0.88-1.04, P=0.35, I2=77%) for Hispanic patients compared to White patients. These results suggest a lower rate of early presentation among Black and Hispanic patients, with no significant difference observed in the Asian cohort. The pooled HR for survival was 1.09 (95% CI: 1.06-1.12, P&amp;lt;0.01, I2=30%) for Black, 0.83 (95% CI: 0.75-0.92, P&amp;lt;0.01, I2=78%) for Asian, and 0.93 (95% CI: 0.89-0.98, P=0.02, I2=67%) for Hispanic patients compared to White patients. These findings point towards worse survival outcomes for Black patients and improved survival outcomes for Asian and Hispanic patients. Conclusion: This study underscores the significant racial disparities in HCC outcomes and early presentation, highlighting the need for targeted strategies to enhance health equity in HCC care. Future research should prioritize investigating the factors contributing to lower early presentation rates among Black and Hispanic populations and the varied survival outcomes across racial groups to inform the development of race-specific prevention, early detection, and treatment strategies. Citation Format: Muhammed Khaled Elfaituri, Ala Khaled. Quantifying racial disparities in hepatocellular carcinoma: A comprehensive meta-analysis of survival and early presentation [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C084.

Dysregulation of Type I Interferon (IFN-I) Signaling: A Potential Contributor to Racial Disparity in Hepatocellular Carcinoma (HCC).

African-American (AA)/Black hepatocellular carcinoma (HCC) patients have increased incidence and decreased survival rates compared to non-Hispanic (White) patients, the underlying molecular mechanism of which is not clear. Analysis of existing RNA-sequencing (RNA-seq) data in The Cancer Genome Atlas (TCGA) and in-house RNA-sequencing of 14 White and 18 AA/Black HCC patients revealed statistically significant activation of type I interferon (IFN-I) signaling pathway in AA/Black patients. A four-gene signature of IFN-stimulated genes (ISGs) showed increased expression in AA/Black HCC tumors versus White. HCC is a disease of chronic inflammation, and IFN-Is function as pro-inflammatory cytokines. We tested efficacy of ginger extract (GE), a dietary compound known for anti-inflammatory properties, on HCC cell lines derived from White (HepG2), AA/Black (Hep3B and O/20) and Asian (HuH-7) patients. GE exhibited a significantly lower IC50 on Hep3B and O/20 cells than on HepG2 and HuH-7 cells. The GE treatment inhibited the activation of downstream mediators of IFN-I signaling pathways and expression of ISGs in all four HCC cells. Our data suggest that ginger can potentially attenuate IFN-I-mediated signaling pathways in HCC, and cells from AA/Black HCC patients may be more sensitive to ginger. AA/Black HCC patients might benefit from a holistic diet containing ginger.

Prognosis of patients with hepatocellular carcinoma: Sex does not matter

AbstractAlthough sex‐related disparities in hepatocellular carcinoma (HCC) incidence have been well‐reported, whether any such disparities exist in HCC prognosis remains controversial. We aim to characterize sex‐related differences in HCC presentation and prognosis. Consecutive patients who were newly diagnosed with HCC between 2011 and 2020 at our institution were enrolled in this retrospective study. Of the 3977 identified patients diagnosed with HCC between January 2011 and December 2020, 72.2% were men (n = 2871) and 27.8% were women (n = 1106). The age at HCC diagnosis was higher (p &lt; .001), the proportion positive for hepatitis B surface antigen was lower (p &lt; .001), the proportion positive for anti‐hepatitis C virus antibody was higher (p &lt; .001), the proportion of alcoholics was lower (p &lt; .001), the proportion with early stage tumor (i.e., Barcelona Clinic Liver Cancer [BCLC] stages 0 and A) was higher (p &lt; .001), the proportion with alpha‐fetoprotein (AFP) &gt;20 ng/mL was higher (p = .02), the proportion with cirrhosis was higher (p &lt; .001), the proportion in receipt of liver resection was lower, and the proportion in receipt of ablation was higher (p &lt; .001) among women than among men. Multivariate analysis showed that an age of &gt;65 years (hazard ratio [HR] = 1.162; 95% confidence interval [CI] = 1.051–1.285; p = .003), BCLC stages B–D (HR = 2.660; 95% CI = 2.372–2.983; p &lt; .001), AFP &gt;20 ng/mL (HR = 1.776; 95% CI = 1.599–1.971; p &lt; .001), and non‐curative treatment (HR = 3.248; 95% CI = 2.910–3.624; p &lt; .001) were associated with mortality, whereas sex was not. Sex was not an independent predictor of mortality of patients with HCC.

Investigating disparities in hepatocellular carcinoma and their effect on patterns of systemic care.

496 Background: Hepatocellular carcinoma (HCC) disproportionately affects minorities, particularly Black and Hispanic patients, and patients of lower socioeconomic status. These patients are more likely to be diagnosed with advanced disease, less likely to receive curative therapies, and have higher mortality rates. Data on the impact of disparities on patterns of systemic treatment (STx) in these disadvantaged groups are limited. This retrospective observational study used a large real-world database to explore differences in patient characteristics and patterns of STx based on race/ethnicity (R/E) and insurance status. Methods: 1283 patients diagnosed with HCC from 2011 to 2021 with known race, insurance, documented metastatic disease (mHCC), and without prior transplant from the nationwide de-identified Flatiron Health EHR-derived database were selected and analyzed. Chi-squared tests, T-tests, and log-rank tests were used to assess how R/E and insurance (Medicaid vs non-Medicaid) were related to HCC risk factors, number of lines of systemic therapy (LOT), and time from metastatic diagnosis (mDx) to start of STx. Results: Of 1283 patients evaluated, there were 750 white (W), 175 Black (B), 122 Hispanic (H), 69 Asian (A), and 167 patients with other race. B and H patients had the highest rates of known HCV (B 74.3%, H 48.4%, W 41.2%, A 23.2%; p &lt; 0.001) and A patients were most likely to have known HBV (53.6%). More B and H patients had Medicaid (W 10.9%, A 14.3%, B 18.9%, H 28.5%, p &lt; 0.001) and had the lowest rates of Medicare with commercial insurance (W 25.9%, A 21.7%, B 12.6%, H 14.6%, p &lt; 0.001). H patients had the lowest rates of commercial insurance (H 39.3%, W 41.3%, A 44.9%, B 44.6%, p &lt; 0.001). There was no significant difference in likelihood of receiving approved STx after mDx based on R/E. A patients had the highest rates of receiving multiple LOT (A 37.5%, W 18.5%, B 18.9%, H 20.5%; p = 0.285). 30-40% of patients with mHCC did not receive any STx and only 18-27% received more than 1 LOT. Most patients received STx for mHCC within 2 months without a significant difference based on R/E. There was no difference in unadjusted time to treatment based on insurance. Conclusions: This large-scale analysis did not reveal significant differences in the likelihood of receiving STx after mDx based on R/E or insurance. This analysis has limited data from safety net hospitals, which may impact our ability to fully elucidate disparities in the medical management of advanced HCC. 30-40% of patients with mHCC did not receive any STx and only 18-27% received more than 1 LOT, indicating that a significant portion of patients with HCC may be undertreated even in academic and community practice settings. Large scale real-world database analysis is a critical way to better understand treatment and survival outcomes in this population, which is expected to have the highest rates of HCC over the next 10 years and has been underrepresented in HCC trials.

Promoting the Pipeline of Diverse Individuals Within Gastroenterology: Reflections From AGA FORWARD Program Scholars

Promoting the Pipeline of Diverse Individuals Within Gastroenterology: Reflections From AGA FORWARD Program Scholars

Asian American/Pacific Islander and Hispanic Ethnic Enclaves, Neighborhood Socioeconomic Status, and Hepatocellular Carcinoma Incidence in California: An Update.

Using more recent cancer registry data, we analyzed disparities in hepatocellular carcinoma (HCC) incidence by ethnic enclave and neighborhood socioeconomic status (nSES) among Asian American/Pacific Islander (AAPI) and Hispanic populations in California. Primary, invasive HCC cases were identified from the California Cancer Registry during 1988-1992, 1998-2002, and 2008-2012. Age-adjusted incidence rates (per 100,000 population), incidence rate ratios, and corresponding 95% confidence intervals were calculated for AAPI or Hispanic enclave, nSES, and the joint effects of ethnic enclave and nSES by time period (and the combination of the three periods), sex, and race/ethnicity. In the combined time period, HCC risk increased 25% for highest versus lowest quintile of AAPI enclave among AAPI males. HCC risk increased 22% and 56% for lowest versus highest quintile of nSES among AAPI females and males, respectively. In joint analysis, AAPI males living in low nSES areas irrespective of enclave status were at 17% to 43% increased HCC risk compared with AAPI males living in areas of nonenclave/high nSES. HCC risk increased by 22% for Hispanic females living in areas of low nSES irrespective of enclave status and by 19% for Hispanic males living in areas of nonenclave/low nSES compared with their counterparts living in areas of nonenclave/high nSES. We found significant variation in HCC incidence by ethnic enclave and nSES among AAPI and Hispanic populations in California by sex and time period. Future studies should explore how specific attributes of enclaves and nSES impact HCC risk for AAPI and Hispanic populations.

ERα inhibits mesenchymal and amoeboidal movement of liver cancer cell via Gα12.

Hepatocellular carcinoma (HCC) is the second most common cancer worldwide, demonstrating aggressiveness and mortality more frequently in men than in women. Despite reports regarding the inhibitory ability of estrogen receptor alpha (ERα, ESR1) in certain cancer progression, targets and the basis of underlying gender disparity in HCC worsening remain elusive. Here, we report the ability of ERα to transcriptionally inhibit G protein subunit alpha 12 (Gα12) responsible for HCC worsening. First, using human samples and public database, the expression of ERα and Gα12 in HCC was examined. Then, quantitative real-time PCR, chromatin immunoprecipitation-assay, luciferase assay and immunoblottings of liver cancer cell lines confirmed the inhibitory ability of ERα on Gα12 and HCC progression. Gα12 promoted mesenchymal characteristics and amoeboidal movement, which was antagonized by ERα overexpression. Additionally, we found microRNA-141 and microRNA-200a as downstream targets of the Gα12 signaling axis for cancer malignancy regulation under the control of ERα. As for in-depth mechanism, PTP4A1 was found to be directly inhibited by microRNA-141 and microRNA-200a. Moreover, we found the inhibitory effect of ERα on amoeboidal movement by analyzing the morphology and blebbing of liver cancer cells and the active form of MLC levels. The identified targets and ESR1 levels are inversely correlated with human specimens, as well as with sex-biased survival rates of HCC patients. Collectively, ERα-dependent repression of Gα12 and consequent changes in the Gα12 signaling may explain the gender disparity in HCC, providing pharmacological clues for the control of metastatic HCC.

The role of racial segregation in treatment and outcomes among patients with hepatocellular carcinoma

BackgroundThere is a long history of segregation in the U.S.A with enduring impacts on cancer outcomes today. We evaluated the impact of segregation on racial disparities in Hepatocellular Carcinoma (HCC) treatment and outcomes. MethodsWe obtained data on black and white patients with HCC from the SEER program (2005–2015) within the 100 most populous participating counties. Our exposure was the index of dissimilarity (IoD), a validated measure of segregation. Outcomes were overall survival, advanced stage at diagnosis (Stage III/IV) and surgery for localized disease (Stage I/II). Cancer-specific survival was assessed using Kaplan–Meier estimates. ResultsBlack patients had a 1.18 times increased risk (95%CI 1.14,1.22) of presenting at advanced stage as compared to white patients and these disparities disappeared at low levels of segregation. In the highest quartile of IoD, black patients had a significantly lower survival than white (17 months vs 27 months, p < 0.001), and this difference disappeared at the lowest quartile of IoD. ConclusionsOur data illustrate that structural racism in the form racial segregation has a significant impact on racial disparities in the treatment of HCC. Urban and health policy changes can potentially reduce disparities in HCC outcomes.

Sex disparity in hepatocellular carcinoma owing to NAFLD and non-NAFLD etiology: epidemiological findings and pathobiological mechanisms

Hepatoma Research is an open access journal and focuses on all topics related to hepatoma. The following articles are especially welcome: pathogenesis, clinical examination and early diagnosis of hepatoma, complications of hepatoma, and their preventions and treatments, etc.

G-Protein-Coupled Estrogen Receptor 1 Promotes Gender Disparities in Hepatocellular Carcinoma via Modulation of SIN1 and mTOR Complex 2 Activity.

Due to its intricate heterogeneity and limited treatment, hepatocellular carcinoma (HCC) has been considered a major cause of cancer-related mortality worldwide. Increasing evidence indicates that G-protein-coupled estrogen receptor 1 (GPER1) can promote estrogen-dependent hepatocellular proliferation by activating AKT signaling. The mTOR complex 2 (mTORC2), whose integrity and activity are modulated by its subunit Sin1, controls the activation of AKT by phosphorylation at position S473. In this study, we investigate the modulation of Sin1 and how estrogen signaling may influence the mTORC2-AKT cascade in HCC cells and a DEN-induced mouse model. We have found that estradiol-dependent Sin1 expression is transcriptionally modulated by GPER1 as well as ERα. GPER1 is able to regulate Sin1 stability via nuclear translocation, therefore increasing Sin1-mTORC2-AKT activation. Moreover, Sin1 interacts with ERα and further enhances its transcriptional activity. Sin1 is highly expressed in acute liver injury and in cases of HCC harboring high expression of GPER1 and constitutive activation of mTORC2-AKT signaling. GPER1 inhibition using the antagonist G-15 reverses DEN-induced acute liver injury by suppressing Sin1 expression and mTORC2-AKT activation. Notably, SIN1 expression varies between male and female mice in the context of both liver injury and liver cancer. In addition, high SIN1 expression is predictive of good prognosis in both male and female patients with HCC who are free from hepatitis virus infection and who report low alcohol consumption. Hence, here we demonstrate that Sin1 can be regulated by GPER1 both through nongenomic and indirect genomic signaling. IMPLICATIONS: This study suggests that Sin1 may be a novel HCC biomarker which is gender-dependent and sensitive to particular risk factor.

Racial and Sex Disparities in Hepatocellular Carcinoma in the USA.

In this review, we aim to provide a summary of the current literature on race and gender disparities in hepatocellular carcinoma (HCC) incidence, stage at diagnosis, treatment and prognosis in the United States. HCC incidence rates are rising in the U.S. in all racial/ethnic groups except for Asian/Pacific Islanders, with disproportionate rises and the highest rates among Hispanics compared to Blacks and non-Hispanic whites. There are striking sex disparities in HCC incidence and mortality; however, with the shifting epidemiology of HCC risk factors in the U.S, there is recent evidence that HCC is trending towards less male predominance, particularly among younger birth cohorts. Despite significant advances in HCC treatment over the past decade, disparities in HCC surveillance and treatment receipt persist among racial and ethnic minorities and the socioeconomically disadvantaged. Black patients continue to experience worse survival outcomes than non-Black patients with HCC. There are significant racial and gender disparities in HCC incidence, treatment, and mortality in the U.S. Though these disparities are well-documented, data are still limited on the specific determinants driving disparities in HCC. To achieve health equity for all patients with HCC, we must advance beyond simply reporting on disparities and begin implementing targeted interventions to eliminate disparities.

Epigenetic changes associated with mechanisms of disparities in hepatocellular carcinoma.

In addition to socioeconomic influences, biological factors are believed to play a role in health disparities. In this paper, we investigate miRNA, mRNA, and DNA methylation patterns that contribute to disparities in hepatocellular carcinoma (HCC). This is accomplished by integration of mRNA-Seq, miRNA-Seq, and DNA methylation data we acquired by analysis of liver tissues from 30 HCC patients consisting of European Americans (EAs), African Americans (AAs), and Asian Americans (Asians). Mixed-ANOVA models are applied to identify miRNAs, mRNAs, and DNA methylation sites that are significantly altered in tumor vs. adjacent normal tissues in a race-specific manner. Through integrated analysis, a refined list of differentially expressed mRNAs is obtained by selecting those that are targets of differentially expressed miRNAs and consist of promoter regions that are differentially methylated.

Sex disparities in presentation and prognosis of 1110 patients with hepatocellular carcinoma.

Although sex disparities in hepatocellular carcinoma (HCC) incidence have been well described, there are limited data examining sex disparities in HCC prognosis. To characterise sex differences in HCC presentation and prognosis. We performed a retrospective study of consecutive patients (n=1110, 23.5% women) diagnosed with HCC between 2008 and 2017 at two US health systems. We used Cox proportional hazard and multivariable logistic regression models to identify factors associated with overall survival, early tumour detection and response to HCC treatment (per the modified Response Evaluation Criteria in Solid Tumors [mRECIST] criteria). Women were older at HCC diagnosis (mean 62.5 vs 59.2years, P<0.001) and had a higher proportion of early-stage tumours (53.1% vs 43.7% Barcelona Clinic Liver Cancer [BCLC] stage 0/A, P=0.04), but similar liver function compared to men (49.2% vs 47.1% Child Pugh A, P=0.27). In univariable analysis, women had significantly better overall survival than men (median 17.1 vs 12.0months, P=0.02). When stratified by age, younger (<65years) women had better overall survival than men (18.3 vs 11.2months, P=0.02); however, older (≥65years) women and men had similar overall survival (15.5 vs 15.7months, P=0.45). In multivariable analysis, female sex was independently associated with lower mortality after adjusting for age, race/ethnicity, alpha-fetoprotein, BCLC stage, Albumin-Bilirubin grade and Child Pugh score (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.68-0.98). In secondary analyses, female sex was independently associated with early tumour detection (odds ratio [OR] 1.46, 95% CI 1.05-2.02) and response to first HCC treatment (OR 1.72, 95% CI 1.18-2.53) after adjusting for the same covariates. In a large cohort of patients with HCC, women had significantly better prognosis than men.

Androgen receptor affects the response to immune checkpoint therapy by suppressing PD-L1 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with gender-related differences in onset and course. Androgen receptor (AR), a male hormone receptor, is critical in the initiation and progression of HCC. The role of AR in HCC has been mechanistically characterized and anti-AR therapies have been developed, showing limited efficacy. Immunotherapy targeting immune checkpoint proteins may substantially improve the clinical management of HCC. The mechanism by which AR influences HCC immune state remains unclear. In this study, we demonstrated that AR negatively regulated PD-L1, by acting as a transcriptional repressor of PD-L1. Notably, AR over-expression in HCC cells enhanced CD8+T function in vitro. We then verified the AR/PD-L1 correlation in patients. In animal experiment we found that lower AR expressed tumor achieved better response to PD-L1 inhibitor. Thus, AR suppressed PD-L1 expression, possibly contributing to gender disparity in HCC. Better understanding of the roles of AR during HCC initiation and progression will provide a novel angle to develop potential HCC immunotherapies.

Abstract C064: Neighborhood socioeconomic status, ethnic enclave, and hepatocellular carcinoma incidence in Hispanics and Asians/Pacific Islanders living in California: An update

Abstract Background: Disparities in hepatocellular carcinoma (HCC) incidence exist by sex and race/ethnicity, with rates higher in men than women and higher in Asians/Pacific Islanders (API) and Hispanics than non-Hispanic Whites. We sought to update previous studies that identified disparities in HCC incidence by neighborhood contextual factors such as SES and ethnic enclave among API and Hispanic populations in California by analyzing data from the California Cancer Registry (CCR) through 2012. Methods: All primary, invasive HCC cases diagnosed from 1988 through 2012 from the CCR were identified and their addresses geocoded. Neighborhood Hispanic or API ethnic enclaves are areas marked by greater immigrant composition and linguistic isolation, applicable to Hispanic and API residents, respectively. Neighborhood SES (nSES) is an index measure comprising data on education, occupation, and housing. Age-adjusted incidence rates (IRs; per 100,000 population; standardized to the 2000 U.S. standard million population), incidence rate ratios (IRRs) (with corresponding 95% confidence intervals (CI)) were calculated for each strata of nSES and ethnic enclave by sex and race/ethnicity. Results: The final analysis included 9,636 males (4,883 Hispanics, 4,753 APIs) and 3,524 females (1,744 Hispanics, 1,780 APIs). During 1988-2012, among Hispanics, there were no clear associations between HCC incidence and nSES or ethnic enclave when considered separately. However, compared to those in high nSES/low enclave neighborhoods, Hispanic males living in low nSES/low enclave neighborhoods and Hispanic females living in low SES/high enclave neighborhoods had higher incidence of HCC (males: IRR = 1.22, CI = 1.10 - 1.36; females: IRR = 1.20, CI = 1.04 - 1.38). Among APIs, there was no association between HCC incidence and ethnic enclave but there was a strong association of increased risk for those living in the lowest vs. highest nSES neighborhoods (males: IRR = 1.69, CI = 1.53 - 1.87; females: IRR = 1.32, CI = 1.12 - 1.56). API males living in low nSES/high enclave neighborhoods had higher incidence of HCC than those living in high nSES/low enclave neighborhoods (IRR = 1.36, CI = 1.22 - 1.52). Conclusions: We found significant variation in HCC incidence by two important neighborhood factors, nSES and ethnic enclave, among Hispanics and APIs living in California, with similar findings to previous studies. Future studies with longitudinal data are needed to explore which attributes of nSES and enclaves are impacting HCC risk and for which subpopulations (such as recent immigrants). Citation Format: Meera Sangaramoorthy, Alice Guan, Juan Yang, Jennfier Jain, Mindy C. DeRouen, Scarlett Lin Gomez, Salma Shariff-Marco. Neighborhood socioeconomic status, ethnic enclave, and hepatocellular carcinoma incidence in Hispanics and Asians/Pacific Islanders living in California: An update [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C064.