Hepatitis b virus-related hepatocellular carcinoma in south africa: investigations into the risk profile of a previously unscreened population from the Western Cape

Chotun, Bibi Nafiisah (2018-12)

Thesis (PhD)--Stellenbosch University, 2018.

Thesis

ENGLISH ABSTRACT: Hepatocellular carcinoma (HCC) is a neglected major public health problem worldwide. In SubSaharan Africa (SSA), most HCC cases are diagnosed with advanced disease, well past the timing of possible treatment. Most HCC cases worldwide are caused by chronic infection with hepatitis B virus (HBV). Although the bulk of the burden of HBV is in SSA, there are no screening programmes implemented in the general African population so only 0.8% of HBV-infected individuals are diagnosed. Most research on HBV-related HCC has been conducted in Asia, where HBV is also endemic, but where there are differences in disease progression and presentation. The present study investigated HBV and HCC from an African perspective and tackled these public health issues by incorporating three key components for early diagnosis of HBV-related HCC: HBV screening, HCC biomarkers, and HBV-related HCC genomics. The HBV screening study found the prevalence of HBV in a South African community-based cohort using a validated point-of-care test to be 2.2% (95% CI: 1.4%–3.3%). The test performed well in the field and had a sensitivity, specificity, negative and positive predictive values of 100%. The test was also accepted by the community (93% uptake) and health care providers. The results of the present study support the case for the implementation of HBV screening in South Africa by demonstrating the magnitude of the HBV health problem in South Africa and new evidence that the POCT test performs well in the field, is accepted by the community and health care providers, and that patients diagnosed with the test can be successfully linked to treatment and long-term follow-up. The HCC biomarker study found significant differences in methylation expression levels in CpG islands in the promoter region of the tumour suppressor gene RASSF1A between HCC cases and normal liver tissue controls as well as a significant association between HBV genotype A and HCC. Although the sample size was small, it showed that there are biomarkers that may be used to identify HCC, paving the way for future studies looking into developing HCC risk scores for early diagnosis of HCC. Using whole-exome sequencing, the HBV-related HCC genomics study identified two novel germline variants in the SMARCA1 and RAB19 genes that in the absence of other risk factors besides HBV infection, could have contributed to early-onset HBV-related HCC in their respective hosts. Overall, these data provide evidence that early diagnosis of HBV-related HCC in an African setting is possible especially if a multi-targeted approach is taken. The simplest approach to minimise the incidence of HCC in SSA would be to implement HBV screening, at the very least in pregnant women, to break the transmission cycle of HBV. Moreover, the biomarkers of interest identified in the present study should be investigated further in larger cohorts and non-invasive patient samples to determine their utility in stratifying HCC risk. Lastly, the WES study showed that there are germline variants that could predispose carriers to HCC although these results need to be further investigated in in-silico and proteomic studies.

AFRIKAANSE OPSOMMING: Hepatosellulêre karsinoom (HCC) is ‘n omvangryke maar verontagsame publieke gesondheid probleem wêreldwyd. In sub-Sahara Afrika (SSA) word meeste HCC gevalle eers gediagnoseer met reeds-gevorderde siekte, lank nadat moontlike behandeling toegepas kon word. Meeste HCC gevalle word deur kroniese hepatitis B virus (HBV) infeksie veroorsaak. Alhoewel die grootste HBV las op SSA is, bestaan daar geen siftingsprogramme vir die algemene populasie in Afrika nie, wat veroorsaak dat slegs 0.8% van HBV positiewe individuele gediagnoseer word. Meeste HBV verwante HCC navorsing is tot dusvêr in Asië uitgevoer waar HBV ook endemies is, maar daar is verskille in siekte ontwikkeling en voordoening. Hierdie studie het HBV en HCC uit ‘n Akrika perspektief benader en die publieke gesondheid kwessies ondersoek deur drie sleutelkomponente in ag te neem om HBV verwante HCC vroeg te identifiseer, naamlik: HBV sifting, HCC biomerkers en HBV verwante HCC genomika. In die HBV sifting studie, het ‘n geverifieërde punt-van-sorg toets gevind dat die voorkoms van HBV in ‘n Suid Afrikaanse gemeenskap gebaseerde kohort 2.2% (95% CI: 1.4%–3.3%) is. Die toets was suksesvol uitgevoer en het sensitiwiteit, spesifisiteit, negatiewe en positiewe voorspellende waardes van 100% behaal. Die toets is ook deur die gemeenskap (93% opname) en gesondheidsorgverskaffers aanvaar. Die bevindings van die huidige studie ondersteun die implementering van HBV sifting in Suid Afrika deur die omvang van HBV as ‘n meenigte gesondheids probleem te bevestug is en deur nuwe bevindings dat the punt-van-sorg toets gebruiklik in die veld is en aanvaar word deur die gemeenskap en gesondheidsorgverskaffers. Pasiënte gediagnoseer met die toets kan ook behandeling en langtermyn nasorg ontvang. Die HCC biomerker studie het bekenisvolle verskille in metilering uitdrukking-vlakke in CpG eilande in die promotor area van die tumor onderdrukking geen RASSFIA tussen HCC gevalle en normale lewer weefsel kontroles gevind, asook ‘n betekenisvolle verwantskap tussen HBV genotype A en HCC. Alhoewel die steekproefgrootte klein was, het dit daartoe aanduiding gegee dat sekere biomerkers gebruik kan word vir die identifikasie van HCC, wat die pad voorberei vir verdere studies om HCC risiko-gradering te gebruik om HCC vroegtydig te diagnoseer. Met die gebruik van heel-eksoom nukleïensuurvolgordebepaling het die HBV-verwante HCC genomika studie twee nuwe kiemlyn variante in die SMARCA1 en RAB19 gene geïdentifiseer, wat onafhanklik van ander risiko faktore, HBV uitgesluit, kon bydra tot vroeë HBV-verwante HCC aanvang in hulle onderskeie gashere. In samevatting, verskaf hierdie data bewyse dat vroeë diagnose van HBV-verwante HCC in ‘n Afrika-omgewing moontlik is, veral wanneer ‘n multi-geteikende benadering geneem word. Die eenvoudigste benadering tot die vermindering van HCC in SSA is om HBV-sifting te implementer, minstens in swanger vroue om die oordragsiklus te verhoed. Verder moet die biomerkers wat in hierdie studie geïdentifiseer is, in meer omvattende studies ondersoek met gebruik van nie-indringende pasiënt monsters. Laastens het die WES studie aangedui dat daar sekere kiemlyn variante is wat draers kan vatbaar maak aan HCC, hoewel hierdie resultate verder ondersoek moet word in ‘in-silico’ en proteomiese studies.

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