Abstract
ObjectivesHuman papillomavirus (HPV) causes tumors primarily Cervical cancer. Recently, inconsistent reports came up in Breast cancer (BC) too. In India, despite treatment 70,218 BC patients die each year. So, we explored the association of HPV, if any, with BC prognosis in Indian pre-therapeutic (PT) and Neo-adjuvant chemotherapy (NACT) patients with subsequent analysis of HPV profile.MethodsHPV prevalence was checked and analysis of physical status, copy number, genome variation, promoter methylation and expression (mRNA and protein) of the prevalent subtype was done.ResultsHigh prevalence of HPV was observed in both PT (64.0%) and NACT (71.0%) cases with significant association with younger (20–45 yrs) PT patients. Interestingly, HPV infection was significantly increased from adjacent normal breast (9.5%, 2/21), fibro adenomas (30%, 3/10) to tumors (64.8%, 203/313) samples. In both PT and NACT cases, HPV16 was the most prevalent subtype (69.0%) followed by HPV18 and HPV33. Survival analysis illustrated hrHPV infected PT patients had worst prognosis. So, detailed analysis of HPV16 profile was done which showed Europian-G350 as the most frequent HPV16 variant along with high rate of integration. Moreover, low copy number and hyper-methylation of P97 early promoter were concordant with low HPV16 E6 and E7 mRNA and protein expression. Notably, four novel variations (KT020838, KT020840, KT020841 and KT020839) in the LCR region and two (KT020836 and KT020837) in the E6 region were identified for the first time along with two novel E6^E7*I (KU199314) and E6^E7*II (KU199315) fusion transcript variants.ConclusionThus, significant association of hrHPV with prognosis of Indian BC patients led to additional investigation of HPV16 profile. Outcomes indicated a plausible role of HPV in Indian BC patients.
Highlights
Human papillomavirus (HPV) is a DNA virus having a 9.2Kb genome
Low copy number and hyper-methylation of Early promoter (P97) early promoter were concordant with low HPV16 E6 and E7 mRNA and protein expression
Significant association of High risk HPV (hrHPV) with prognosis of Indian Breast cancer (BC) patients led to additional investigation of HPV16 profile
Summary
Human papillomavirus (HPV) is a DNA virus having a 9.2Kb genome. The high-risk (hr) subtypes were frequently associated with different cancers, primarily cervical cancer (CACX) and Head and neck squamous cell carcinoma (HNSCC) [1]. The transformation HPV depends on expression of E6/E7 oncoproteins which contributes to the process of carcinogenesis by increasing cellular proliferation leading to more genomic instability and inhibition of apoptosis [4]. The expression of both the oncoproteins is controlled by viral protein E2, which often gets abrogated due to viral integration in the host genome through the E2 region [5]. Expression of E6 and E7 has been regulated by the long control region (LCR) harboring different transcription factors binding sites along with the viral copy number variation though the activity of P97 promoter and enhancer [6, 7] The activity of this promoter and enhancer were further controlled by methylation though host DNA Methyltransferase enzymes [8]. It was reported that RNA splicing may control the expression of these oncoproteins as well [9]
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