A 44-year-old woman, gravida 2, para 2, is being evaluated after having several episodes of painless postcoital bleeding. She emigrated from Guatemala 5 years ago and has not received any preventative health care. The patient is married and gave birth to two girls via vaginal delivery at home in Guatemala. Her menstrual periods have been regular, and she uses barrier contraceptives. Speculum examination reveals an ulcerative lesion at the external cervical os. Cervical biopsy shows malignant squamous cells invading the underlying stroma. Further analysis of the malignant cells reveals that a double-stranded DNA virus, which encodes several proteins including E6 and E7, has integrated into the host genome. Which of the following is the most likely mechanism by which these viral proteins are involved in this patient's condition?

Question

A 44-year-old woman, gravida 2, para 2, is being evaluated after having several episodes of painless postcoital bleeding.  She emigrated from Guatemala 5 years ago and has not received any preventative health care.  The patient is married and gave birth to two girls via vaginal delivery at home in Guatemala.  Her menstrual periods have been regular, and she uses barrier contraceptives.  Speculum examination reveals an ulcerative lesion at the external cervical os.  Cervical biopsy shows malignant squamous cells invading the underlying stroma.  Further analysis of the malignant cells reveals that a double-stranded DNA virus, which encodes several proteins including E6 and E7, has integrated into the host genome.  Which of the following is the most likely mechanism by which these viral proteins are involved in this patient's condition?

Quizplus · Accepted Answer

This patient has biopsy-confirmed squamous cell carcinoma of the cervix as a result of human papillomavirus (HPV) infection. HPV is a small double-stranded DNA virus with multiple genotypes. High-risk subtypes 16 and 18 are most commonly identified in cervical cancers. The oncogenic capability of HPV is dependent on its ability to integrate into the host genome and subsequently produce viral proteins E6 and E7, which interact with cell cycle regulatory proteins p53 and Rb, respectively. E6 binds p53, leading to its ubiquination and subsequent proteasomal degradation. Without p53, the cell is unable to halt cell growth to repair damaged DNA or trigger apoptosis when DNA is damaged beyond repair. Similarly, E7 binds Rb and displaces bound transcription factors, promoting unregulated DNA replication and cyclin-mediated cell cycling. The collective effects of E6 and E7 lead to inhibition of cell cycle regulation and evasion of apoptosis, consequently increasing malignant potential. (Choice A) RAS and BRAF are proto-oncogenes that code for cytoplasmic signal transducer proteins, which upregulate cellular proliferation and differentiation when activated. Mutations causing constitutive activation of these proteins are linked to development of pancreatic cancer (Ras) and malignant melanomas (BRAF). (Choice B) Mutations resulting in upregulation of the epithelial growth factor receptor (EGFR) gene have been implicated in the development of solid tumors (eg, colon, breast, lung). (Choice C) MSH2 is a DNA mismatch repair protein encoded by the MSH2 gene, which leads to ineffective DNA repair when inactivated. This is the pathogenic basis of hereditary nonpolyposis colorectal cancer (HNPCC). (Choice E) Platelet derived growth factor (PDGF) activity is essential for normal development of the central nervous system during the embryonic period. Upregulation of PDGF synthesis and corresponding receptor activation are responsible for the malignant transformation of glial cells in glioblastoma. Educational objective: Human papillomavirus (HPV) oncogenicity relies on the inhibitory effects of viral proteins E6 and E7 on cell cycle regulatory proteins p53 and Rb. This allows cells infected with HPV to undergo unchecked cellular proliferation and evasion of apoptosis, promoting genomic instability and malignant transformation. __________ References: The role of HPV E6 and E7 oncoproteins in HPV-associated cervical carcinogenesis. (http://www.ncbi.nlm.nih.gov/pubmed/19956366)

A 44-Year-Old Woman, Gravida 2, Para 2, Is Being Evaluated