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  • Introduction Leukaemias lymphomas and multiple myeloma can

    2019-05-15

    Introduction Leukaemias, lymphomas and multiple myeloma can be the dreadful sequelae of viral infections. RNA oncogenic viruses, which are also known as retroviruses, were initially known to cause lymphoproliferative disorders only in animals, but have also been reported to demonstrate their transforming ability in humans. Retroviruses are capable of integrating their proviral DNA into the host genome, which may in turn, mediate leukemogenesis via insertional mutagenesis. For instance, human T-cell lymphotropic virus type 1 is the causative agent of adult T-cell leukaemia–lymphoma [1]. Akin to exogenous retroviruses, human endogenous retroviruses (HERVs) have integrated into the human DIG-11-dUTP since at least 30 million years ago and are transmitted vertically via the germ line [2]. Some family members of HERVs (HERV-K and HERV-H) are implicated in leukaemias and lymphomas, although the precise molecular mechanism underlying HERV-mediated carcinogenesis remains to be elucidated [3]. While seroprevalence to exogenous viral infections in endemic regions have been shown to be associated with the incidence rate of lymphoid cancers [1,4], information about the prevalence of HERV-H in different populations in relation to lymphoid neoplasms remains unknown. Of interest, a recent study reported that endogenous LTR derepression is involved in the pathogenesis of Hodgkin\'s lymphoma [5]. This provide the impetus for us to determine the prevalence of HERV-H in the three major ethnic groups (Chinese, Malays and Indians) residing in Singapore, and examine the association between the prevalence rate of each of these ethnic group with the reported incidence rate of Hodgkin\'s lymphoma retrieved from the Singapore Cancer Registry.
    Materials and methods
    Results Of 808 subjects recruited, 785 were successfully analysed for HERV-H element. The prevalence rates of HERV-H positivity, based on gender as well as categorised by their ethnic descent, are shown in Table 1. 89.9% (381/427) females and 88.6% (320/361) males were found to possess HERV-H in their genome, resulting in a total of 89.3% HERV-H positivity overall. With respect to gender, there is no statistical difference between males and females (P>0.05). The prevalence rates of HERV-H positivity for Chinese, Malays and Indians are 86.1%, 95.4%, and 96.8%, respectively. To examine the significance of ethnic disparities, we performed a Chi-square test. Compared to Chinese, both Malays and Indians were found to possess statistically higher prevalence rates (P<0.01). In addition, Malays were also found to be 1.11 times likely (95% CI=1.05–1.17; P<0.01), and Indians 1.12 times likely (95% CI=1.07–1.18; P<0.01) to be HERV-H positive when compared to Chinese. Fig. 1 depicts the strong association between the Hodgkin\'s lymphoma incidence rates and the prevalence rate for HERV-H positivity in three major ethnic groups of Singapore (1A: r=0.9921 for male; 1B: r=0.9801 for female). The age standardised rate risks data was obtained from the Singapore Cancer Registry Report No. 7 [7].
    Discussion HERVs represent the trail of successful ancient retroviral infection of the human germ line. As a consequence to the persistence of vertical transmission, about 8% of the human genome is occupied by HERVs [2]. Their existence, through millions of years of evolution, implies that HERVs have overcome the stringent evolutionary selection and their genomes have been successfully domesticated and incorporated into the host genomes, although the accumulative effects of mutations, deletions, frame shifts, premature stop codons and hypermethylation of the promoter sites may have rendered them defective or inactive. While retroelements such as Alu (in SINE) is implicated in pathogenesis of autoimmune lymphoproliferative syndrome and X-linked agammaglobulinemia, and L1 (in LINE) in haemophilia A and B [8], the role of HERV in carcinogenesis remains poorly understood. Interestingly, our analysis reveals strong positive correlation between age standardized incidence rate of Hodgkin\'s lymphoma and prevalence rate for HERV-H positivity. Based on genetic similarity in the pol region, HERV-H belongs to Class I of the Gammaretrovirus-like family. Apart from possessing long terminal repeats (LTR)s, HERV-H is also known to utilise histidine (H) transfer RNA (tRNA) at its primer binding site to initiate reverse transcription [2]. A previous study demonstrated that derepression of endogenous LTR due to hypomethylation results in up-regulation of CSF1R proto-oncogene expression, which in turn contributes to the pathogenesis of Hodgkin\'s lymphoma [5]. In addition, endogenous retroviral Np9 and Rec were identified as oncogenic players in leukaemia [2]. Expression of HERV-H was also shown to contribute to pluripotency in human cells [9]. Perturbation to HERV-H-mediated pluripotency regulation may lead to deregulation in self-renewal control and emergence of cancer stem cell, though this hypothesis remains to be proven.