Ethnic differences in hepatocellular carcinoma prevalence and therapeutic outcomes

Abstract Background Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related death worldwide. The incidence of HCC is affected by genetic and non‐genetic factors. Genetically, mutations in the genes, tumor protein P53 (TP53), catenin beta 1 (CTNNB1), AT‐rich interaction domain 1A (ARIC1A), cyclin dependent kinase inhibitor 2A (CDKN2A), mannose 6‐phosphate (M6P), smooth muscle action against decapentaplegic (SMAD2), retinoblastoma gene (RB1), cyclin D, antigen presenting cells (APC), AXIN1, and E‐cadherin, have been shown to contribute to the occurrence of HCC. Non‐genetic factors, including alcohol consumption, exposure to aflatoxin, age, gender, presence of hepatitis B (HBV), hepatitis C (HCV), and non‐alcoholic fatty liver disease (NAFLD), increase the risk of HCC. Recent Findings The severity of the disease and its occurrence vary based on geographical location. Furthermore, men and minorities have been shown to be disproportionately affected by HCC, compared with women and non‐minorities. Ethnicity has been reported to significantly affect tumorigenesis and clinical outcomes in patients diagnosed with HCC. Generally, differences in gene expression and/or the presence of comorbid medical diseases affect or influence the progression of HCC. Non‐Caucasian HCC patients are significantly more likely to have poorer survival outcomes, compared to their Caucasian counterparts. Finally, there are a number of factors that contribute to the success rate of treatments for HCC. Conclusion Assessment and treatment of HCC must be consistent using evidence‐based guidelines and standardized outcomes, as well as international clinical practice guidelines for global consensus. Standardizing the assessment approach and method will enable comparison and improvement of liver cancer research through collaboration between researchers, healthcare providers, and advocacy groups. In this review, we will focus on discussing epidemiological factors that result in deviations and changes in treatment approaches for HCC.


| INTRODUCTION
In 2020, primary liver malignancy was the third most common cause of cancer related death among men and women worldwide and 75%-85% of those deaths were attributed to HCC. 1 Over the past few decades, the incidence rates of HCC have steadily increased in many countries, whereas the overall 5-year survival rate is less than 20%. 2,3 It has been estimated that the incidence of HCC will surpass one million people annually by the year 2025. 4 At diagnosis, HCC is frequently associated with a poor prognosis due to detection of advanced stage tumors. 5 This is partly due to the lack of timely diagnostic biomarkers, obvious symptomology in earlier stages, and a low frequency of radical resectable HCC at the time of diagnosis. 6 Clinical studies have reported a significant difference in the progression of HCC based on ethnicity. 7 Regardless of etiology, approximately 90% of HCC cases occur in the setting of chronic liver inflammation. 8 Prior to the development of HCC, a sustained inflammatory response leads to the concurrent remodeling and regeneration of hepatocytes, which causes fibrotic deposition that eventually progresses to cirrhosis. 9 Globally, chronic liver damage caused by infection with hepatitis B (HBV) or C virus (HCV) accounts for the majority of HCC cases. 10 The likelihood of HCC increases with chronic alcohol ingestion, consumption of aflatoxin, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hemochromatosis, and alpha-1-antitrypsin deficiency. 11 Comorbid conditions, such as diabetes mellitus, obesity, and metabolic syndrome, also facilitate the progression of HCC. 12 Notably, the prevalence of diabetes and obesity was significantly higher in patients with HCC, compared to patients diagnosed with viral and alcohol cirrhosis. 13 Differences in ethnicity and geography have been shown to significantly affect all-cause mortality and increase the risk of HCC. 16 The majority of HCC cases and the lowest survival rates after treatment primarily occur in Asia and Sub-Saharan Africa, predominately due to HBV infection, whereas HCV infections are the most common cause in the United States. 17 Figure 1 illustrates the global prevalence of HCC. HCC disproportionately affects disadvantaged minorities, leading to disparities in the initial detection, stage at diagnosis, and overall mortality rate. 18 A National Health and Nutrition Examination Survey reported that in the United States, individuals of African-American descent living in southern states are more likely than other ethnicities to be diagnosed with chronic HCC. 19 Asians have the highest overall incidence of HCC, followed by African-Americans, Hispanics, and non-Hispanic Caucasians. 20 HBV may be further classified into its 10 known genomes (A-J) and emerging research indicates that certain HBV genotypes play a role in determining clinical outcomes. [21][22][23] Native Alaskans have higher rates of HCC when infected with HBV genotypes A, C and F, compared to patients with genotype B or D. 24 Disparities in the incidence of HCC are also significantly correlated with an individual's age, sex, socioeconomic status, and place of residence. 25 Individuals of African descent have a significantly higher mortality rate from HCC compared to other ethnic groups. 26 Mathur et al. 12 reported that the mortality rate in these individuals are 12%, 10%-12% and 16% greater than Caucasians, Hispanics, and Asians, respectively. 27 There are significant differences in disease burden, treatment, and outcomes of HCC, based on ethnicity and gender. 28 Consequently, early detection, high-quality prevention, and evidence-based treatment will be necessary to significantly decrease these HCC disparities. 29 This review aims to discuss the epidemiology of ethnic and geographical disparities in patients who have been diagnosed with HCC, the gene-environment parameters, along with the types of treatments that have been shown to affect survival rates among these patients. 30

| EPIDEMIOLOGY OF HCC
The majority of hepatocellular carcinoma (HCC) cases are due to chronic HBV and HCV infection. 31 Host variations in age, genetics, gender, as well as environmental factors, affect the ethnic-specific HCC rates in different geographical regions. These are likely due to differences in the severity and infectious capacity of HBV and HCV. 15 ( Figure 2).

| Hepatitis B virus (HBV)
HBV is a DNA virus transmitted by exposure to infectious blood or bodily fluids which includes vertical transmission. Globally, HBV is the leading causative factor of HCC. 32 37 HBV primarily affects the functionality of healthy hepatocytes by promoting replication which leads to liver damage, fibrosis, and cirrhosis in conjunction with the host immune response. A whole genome sequencing study in HBV-associated HCC patients was conducted to identify any genetically altered pathways that could be correlated with HCC progression. 36 There was a F I G U R E 1 Geographical prevalence of HCC. The prevalence of HCC varies geographically, which may be due to differences in predisposing factors that increase the risk of HCC. 14,15 significant correlation between the expression of SYT12, GATM and FN1 in patients with early onset HBV-related HCC, whereas there was a significant correlation in the expression of STAT1, ALB, MLL4 and TERT in patients with late onset HCC. 39 Additionally, HBV induces HCC formation through the activation or deactivation of various tumorigenic pathways. In the normal liver, β-catenin is a membrane localized protein which can be activated via HBV on hepatocytes. There is potential that activation of this pathway may be involved in the somatic genetic and nongenomic events in HCC. 37 Activation of β-catenin signaling is considered an early event in HCC pathogenesis. Prominent signaling can lead to the overexpression of β-catenin which results in the proliferation of cancer stem cells in HCC. 38 Mutations within the gene coding for ß-catenin (CTNNB1) was observed in 20%-35% of primary HCC patients. 39 HBV can damage DNA and create mutations within cancer promoting genes such as TP53. Oncogenic activation of certain genes can ultimately lead to tumor progression. 40 One study's results indicated that among 81 patients, the most frequently mutated oncogene was beta-catenin (15.9%) and the most frequently mutated tumor suppressor gene was TP53 (35.2%). The two major oncogenic mutations linked to the progression of HCC were the Wingless-related integration site (Wnt)/betacatenin and JAK/STAT pathways, which were altered in 62.5% and 45.5% of patients, respectively. 36 The risk of HCC development is significantly increased in patients with higher rates of HBV replication. 41 The incidence of HCC and mortality rates significantly increase when a country's prevalence of HBV is greater than 2%. 42 The annual risk of HCC is 0.5% for patients that are asymptomatic but express the protein hepatitis B serum antigen (HBsAg) and 0.8% for patients with chronic HBV. 43 Chronic HBV carriers have a 10%-25% risk of developing HCC with 80%-90% of HBV-related HCC cases occurring in patients with cirrhosis. 31,42 Notably, HBV-induced cirrhosis produces a 100-fold greater risk of developing HCC, compared to HBV infected patients without cirrhosis. 4

| Hepatitis C virus (HCV)
HCV infection is another risk factor that increases the likelihood of HCC. The estimated global prevalence of HCV is approximately 2.5%, with the highest prevalence in Central Asia and Central Africa. 44 Globally, it has been estimated that approximately 170 million people are infected with HCV, and this varies among geographical regions. 45 From 1990 to 2005, there was a decrease in the incidence of HCV infected patients in certain higher-income areas, such as Western Europe, Southern Africa, and Australia; however, there was a significant increase in the incidence of HCC in lower-income areas, such as Central Africa and Central Asia. 44 Egypt has one of the highest rates of HCC in the world, which was primarily due to the parenteral treatment of schistosomiasis from 1950 to 1980. The reuse of needles that were inadequately sterilized during this time increased the transmission of blood-borne pathogens, including HCV. 46 Long-standing HCV may progress to liver fibrosis and cirrhosis, which increases the risk of HCC. 47 Approximately 15% -40% of patients spontaneously clear HCV, with 50% -80% developing a chronic infection, 20% -30% developing cirrhosis or liver failure, and 2% -5% developing HCV-induced HCC. 45,47,48 HCV is a major etiological factor for HCC, and studies indicated that at least 70% of patients with HCC have serum anti-HCV antibodies. 49 Patients that are infected with HBV F I G U R E 2 Factors affecting the risk of developing HCC. Factors influencing the development of HCC can primarily be classified as genetic or nongenetic factors. Genetic factors include telomerase reverse transcriptase (TERT) mutations, somatic mutations, alterations in the Janus kinase (JAK)-Signal transduction and activation of transcription (STAT) pathway and chromosomal remodeling. The nongenetic factors include HBV, HCV, alcohol consumption, obesity, fatty liver disease, exposure to aflatoxin and liver cirrhosis, among others. and HCV have a significantly higher risk of developing HCC compared to than those infected with HBV or HCV alone. 50,51 The proteins that have oncogenic potential in HCC are the core, nonstructural 3 (NS3), nonstructural 5A (NS5A) and nonstructural 5B (NS5B). 52 Clinical studies have shown that the levels of these proteins are positively correlated with an increased risk of HCC. 53 It has been hypothesized that HCV increases the risk of HCC by producing mutations that create chronic inflammation, by increasing the levels of certain pro-inflammatory cytokines, cell-cycle dysregulation, and inhibition of the transcription of tumor-suppressor genes. 54 HCV infection causes hepatocarcinogenesis by inducing the progressive accumulation of genetic mutations, which promotes malignant transformation, and by increasing hepatocyte turnover through chronic liver damage, which creates inflammatory and oxidative stress. 55 HCV infection induces inflammation within the liver, causing the accumulation of lymphocytes, an increase in the levels of reactive oxygen species (ROS), and certain cytokines. 56 The chronic inflammation produced by HCV can produce fibrinogenesis and hepatic stellate cell activation, angiogenesis, DNA damage and mutations due to dysfunctional apoptosis, thereby increasing the risk of HCC. 54,57

| Aflatoxin B 1
Aflatoxins are naturally occurring carcinogens produced by Aspergillus flavus and parasiticus that can contaminate food supplies of human and animals such as maize, wheat, and peanuts. 58 The consumption of aflatoxins can cause hepatotoxicity and immunotoxicity 59 and the most potent of these compounds is aflatoxin B 1 (AFB1). 60 Aflatoxin is recognized as a "Group A" because it can produce a significantly increase in the occurence of HCC. Aflatoxin consumption primarily occurs in countries that have warm and humid environments and thus exposure to AFB1 is most common in Southeast Asia, South America, and Sub-Saharan Africa. 61 A meta-analysis estimated that AFB1 alone increases the risk of HCC by 6-fold and exposure to AFB1 and HBV synergistically increases the risk of HCC by 54-fold. 62 In China, the replacement of maize with rice as a dietary staple decreased the incidence of HCC. 63 One study suggested that mutations of p53 contribute to the development of HCC approximately half of the time. AFB1 produces the mutation of G to T at codon 249 of the p53 gene, which leads to serine being replaced by arginine. 64 This mutation ultimately decreases the anti-tumor efficacy of the p53 gene, which increases the development of HCC. 65

| Genetic susceptibility
Ethnic and geographical disparities in the incidence of HCC are correlated with genetic factors that produce differences in the severity of HCC. 28 These genes can be separated into four different categories, depending on their function within the cell. The genes implicated in the pathogenesis of HCC include the regulation or modulation of: (1) DNA damage response (p53); (2) growth inhibition and apoptosis  (Adenomatous polyposis coli (APC; also known as deleted in polyposis 2.5) and E-cadherin). 66 Alterations in these genes are typically due to single nucleotide and copy number polymorphisms, which increase the susceptibility of developing and progressing to HCC. 67 Aberrant activation of telomerase by mutations secondary to chromosome translocations or gene amplification, are the most common genetic alterations that cause HCC. 68 Hereditary diseases, such as hemochromatosis (HFE), tyrosinemia (FAH), alpha-1-antitrypsin deficiency, porphyrias (HMBS, UROD), glycogen storage diseases, and Wilson's disease increase the probability of developing HCC. 69 Furthermore, mutations in the p36.22 region of chromosome 1, which contains genes that code for certain tumor suppression proteins, can increase the risk of HCC (Table 1). Patients with HCC have numerous gene mutations. TP53 and CTNNB1 are the most commonly mutated genes (by 29.1% and 28.6% of total cases, respectively). 70 Aflatoxin and vinyl chloride cause epoxidation, which is responsible for the TP53 mutation. By introducing vinyl chloride, A: T is inverted to T: A. 71 Subsequent responsible mutation present in HCC were AX1N1 (7.5%), ARID2 (8.2%), ALB (10.2%), APOB (9.8%), and ARID1A (8.8%).
The ARID2 and ARID1A leads to remodeling of regulatory mechanisms which also occur in other cancers such as ovarian, lung and pancreatic cancer. 72 The mutation predisposes to chronic liver disease primarily due to iron overload, copper overload, and metabolic disturbances. A mutation in HNF1A may develop into benign tumors with the potential to convert to malignancies. 73 2.5 | Nongenetic factors that increase the risk of HCC

| Alcohol abuse
The chronic consumption of alcohol is a well-established, nongenetic factor that is positively correlated with the development of HCC. 86 Globally, alcohol-induced liver damage is the most prevalent cause of chronic liver damage. 87 The metabolism of ethanol creates pathologic oxidative, metabolic, and inflammatory stress that causes hepatocyte injury and dysfunction. 88 Over time, chronic alcohol consumption may progress to steatosis, steatohepatitis, cirrhosis, and potentially HCC. 89 In recent years, the annual consumption of alcohol per capita has increased in the United States and it has been estimated that approximately 7% of adults meet the criteria for alcohol dependence or alcohol use disorder. 90 Furthermore, the consumption of alcohol has significantly increased in men and younger individuals in Asia. 91 Chronic liver disease, precipitated by long-term alcohol consumption, is responsible for 30% of HCC cases worldwide, and this number is expected to increase in the future. 87,92 Geographically, the rates of alcohol consumption vary by region, and as a result, countries with notable consumption have a higher incidence of alcohol-associated HCC. 90,93 Recent clinical data indicate that excessive alcohol consumption in European countries accounts for 40%-50% of all liver malignancies. 94 The Global Burden of Disease study of 2019 estimated that alcohol-associated HCC accounted for 35%, 33%, and 27% of overall HCC mortality in Europe, North and South America, and Southeast Asia, respectively. Eastern Mediterranean and Western Pacific countries reported the lowest rates of alcohol-associated HCC deaths at 10% and 11%, respectively. 93 The consumption of 80 g/day for more than a decade increases the probability of HCC by 5-fold. 57 A study in the U.S. reported that heavy drinkers (>7 drinks per day) had an 87% increased risk of developing HCC, compared to nondrinkers. 95 Similarly, a meta-analysis reported a 16% increase in the likelihood of the development of HCC in individuals that consumed more than three drinks a day. 96 In addition, there was a synergistic increase in the risk of developing HCC in people that consumed alcohol and were concurrently infected with HBV or HCV, compared to either factor alone. 97

| Nonalcoholic fatty liver disease (NAFLD)
Clinical studies have shown that patients diagnosed with diabetes, obesity, or metabolic syndrome, who drink little or no alcohol, are significantly more likely to be develop nonalcoholic fatty liver disease (NAFLD), 98 which can increase the risk of HCC. 99 The pathophysiology of NAFLD results from the accumulation of fat within the liver in the absence of a secondary cause which may ultimately progress into cirrhosis. 100,101 The estimated worldwide prevalence of NAFLD is approximately 25% and the incidence continues to increase. NAFLD's prevalence parallels the obesity epidemic that is primarily observed in western countries and it is the most rapid growing indication for liver transplantation. 102,103 The rapid rise in NAFLD is projected to become the primary etiological factor for producing HCC in certain countries.
One study from the United Kingdom reported a < 10% to 34.8% increase in NAFLD-associated HCC from 2000 to 2010. 104 Similarly, another study in France indicated that the prevalence of NAFLDassociated HCC increased from 2.6% (1995-1999) to 19.5% (2010-2014). 105 The prevalence of NAFLD-associated HCC will increase by 146% from 2015 to 2030, based on a Markov model that uses historical and projected rates of diabetes and obesity in the United States. 106 The BRIDGE international study (n = 18 031 from 2005 to 2011) reported that the geographical regions with the highest prevalence of NAFLD-associated HCC were North America (12%), Europe (10%), South Korea (6%), and Taiwan (5%). Furthermore, this large international study revealed that lower rates of NAFLD-associated HCC occurred in China (1%) and Japan (2%). 107 Based on the predictions from Este et al., 94 China and Japan are projected to have an increase in NAFLD-associated HCC by 86% and 47%, respectively. 106

| Nonalcoholic steatohepatitis (NASH)
As NAFLD progressively worsens, it can potentially transform into its inflammatory subtype known as NASH. 108 The transition from NAFLD to NASH is hypothesized to result from: (1) the accumulation of lipids within the liver, which increases insulin resistance and (2) chronic insulin resistance induces molecular and cellular changes within the hepatocytes, while also producing hepatic inflammation. 108 Insulin resistance produced by NAFLD causes a compensatory hyperinsulinemic response 109 which facilitates the development of primary liver malignancy. 110 It has been estimated that approximately 20% of all cases of NASH slowly progress to advanced cirrhosis. 111 Risk factors associated with the development of NASH are similar to those for NAFLD, such as metabolic syndrome, obesity, and insulin resistance. 112 Similar to NAFLD, the incidence of NASH-associated HCC parallels the obesity epidemic and is increasing worldwide. 113 As countries adapt a more sedentary lifestyle with poorer diets, the risk of developing NASH increases. One study in the United States reported that the prevalence of NASH increased from 1.51% in 2010 to 2.79% in 2020. 114 The increase incidence of NASH among individuals is also expected to occur in China, India, Indonesia, Pakistan, Bangladesh and the Philippines, where the prevalence of type 2 diabetes has been increasing over the past decade. 115

| Obesity
Obesity has been identified as an independent risk factor for the occurrence of primary liver malignancy. 120 Clinical data indicates that obese patients, compared to nonobese patients, have higher plasma levels of leptin, which is a proinflammatory, proangiogenic, and profibrogenic cytokine. 121 Leptin activates the JAK pathway, which increases the probability of increase cell growth, thereby leading to cancer progression. 122 Excess body fat has been shown to decrease the ultrasound detection of HCC and this is 3-to 8-fold more likely to occur in obese patients, compared to patients of healthy weight. 123 Finally, obese patients are significantly more likely to die from liver cancer, compared to individuals of normal weight. 124 The ethnic disparity in the outcomes of HCC, as a result of inadequate healthcare access in vulnerable populations, suggest that implementation of large-scale interventions will be required to mitigate the mortality due to HCC.

| Difference in epigenetics
Epigenetics involves alterations in gene expression by the external environment that occurs in the absence of changes in the DNA sequences. 159 Alterations in epigenetic factors have been reported to be significantly correlated with the progression and outcomes in patients diagnosed with HCC. 160

| VARIATIONS IN HCC TREATMENT AND INTERVENTION
It has been estimated that HCC causes 90% of all primary liver cancer diagnoses. 7 Although HCC occurs throughout the world, it has an uneven distribution. 42 Sub-Saharan Africa and East Asia account for the highest number of age-related HCC cases. 168 In China, liver cancer accounts for approximately 50% of all cancer-related deaths. 169 Insufficient treatment resources and a lack of timely diagnosis can be linked to the HBV epidemic in Sub-Saharan Africa. 170 In these regions, less than 1% of HBV patients are diagnosed, although appropriate diagnostic methods are available. 171 In Sub-Saharan Africa, only 15% of patients that receive an early diagnosis of HBV go to hospitals and pharmacies for the required treatment. 171 Tenofovir is one of the most commonly used drugs to treat HBV. 171 175 The high rate of HBV transmission from mothers to children that occurs in nations, such as Africa, can be prevented using tenofovir, telbivudine, or lamivudine, during the last third trimester. [176][177][178] A study in 1509 patients from Taiwan and 2015) reported that 9% of the cases of HCC were secondary to NAFLD. 194 It is predicted that by 2030, 50% of the population in the USA will be diagnosed as being obese. 195 The prevalence of NAFLD is 1%-2% in the United States, whereas its prevalence is 7.6%-34.2% in the pediatric population worldwide. 196,197 It has been reported that up to 20% of patients diagnosed with NAFLD-HCC undergo liver resection. 198 NAFLD is common in South America and the Middle East, but it is rare in Africa. 199 Diabetes, NASH, age, steatosis, and obesity are positively correlated with a diagnosis of NAFLD-HCC, which increases the probability of liver failure after liver resection surgery. 200 221 The efficacy of mAbs for the treatment of HCC is dependent upon age, progression of the disease, comorbidities, geographical location, and genetic variation. Figure 3 summarizes the BCBL classification of liver malignancy and its associated treatment algorithm, including several novel approaches for the treatment of HCC.

| LIMITATIONS THAT PRODUCE DISPARITIES IN CLINICAL OUTCOMES FOR HCC PATIENTS
Ethnic and gender differences impact the prevalence, mortality and treatment outcomes of HCC. 28 However, the scientific and medical community must look beyond only reporting disparities and identify and target the specific determinants that impact the incidence and

CONFLICT OF INTEREST STATEMENT
The authors have stated explicitly that there are no conflicts of interest in connection with this article.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.

ETHICS STATEMENT
The work submitted to Cancer Reports has been done in accordance with these guidelines and that is has been performed in an ethical and responsible way, with no research misconduct, which includes, but is not limited to data fabrication and falsification, plagiarism, image manipulation, unethical research, biased reporting, authorship abuse, redundant or duplicate publication, and undeclared conflicts of interest.