Genomic landscape of human papillomavirus-associated cancers

Abstract

Recent next-generation sequencing studies have generated a comprehensive overview of the genomic landscape of human papillomavirus (HPV)-associated cancers. This review summarizes these findings to provide insight into the tumor biology of these cancers and potential therapeutic opportunities for HPV-driven malignancies. In addition to the tumorigenic properties of the HPV oncoproteins, integration of HPV DNA into the host genome is suggested to be a driver of the neoplastic process. Integration may confer a growth and survival advantage via enhanced expression of viral oncoproteins, alteration of critical cellular genes, and changes in global promoter methylation and transcription. Alteration of cellular genes may lead to loss of function of tumor suppressor genes, enhanced oncogene expression, loss of function of DNA repair genes, or other vital cellular functions. Recurrent integrations in RAD51B, NR4A2, and TP63, leading to aberrant forms of these proteins, are observed in both HPV-positive head and neck squamous cell carcinoma (HNSCC) and cervical carcinoma. Additional genomic alterations, independent of integration events, include recurrent PIK3CA mutations (and aberrations in other members of the PI3K pathway), alterations in receptor tyrosine kinases (primarily FGFR2 and FGFR3 in HPV-positive HNSCC, and ERBB2 in cervical squamous cell carcinoma), and genes in pathways related to squamous cell differentiation and immune responses. A number of the alterations identified are potentially targetable, which may lead to advances in the treatment of HPV-associated cancers.

Figure 1

Distribution of breakpoints across the HPV genome. The histogram (in red) indicates the number of tumors with a breakpoint in that particular gene. L2/L1 indicates a region of overlap between L2 and L1. E7-E1 refers to the area between the E7 and E1 genes, and likewise for E5-E2. Counts are based on data from the 25 HPV-positive HNSCC primary tumors with integrations analyzed by Parfenov et al. (22). Please note the HPV16 genome is depicted here, however three of the tumors had HPV33 and one had HPV35 (the structure of these is highly similar to HPV16).

Figure 2

Integration sites of HPV into the human genome. a) Integration sites in head and neck squamous cell carcinomas, based on data from the HPV-positive tumors analyzed by Parfenov et al. (22), and b) Integration sites in cervical carcinomas, based on data from Ojesina et al. (24). In both panels, integrations into coding regions are represented by red dots, and noncoding regions by blue dots. If a tumor had multiple insertions at the same locus it is only represented once in the diagram. Several cases had multiple genes in the region involved in the integration event: ^a PARN, BFAR, PLA2G10 ^b ERBB2, STARD3, TCAP, PNMT, PGAP3, C17orf37, GRB7, IKZF3 ^c ERBB2, C17orf37, GRB7 ^d MIRLET7B, MIRLET7BHG, MIRLET7A3, MIR4763

Figure 2

Integration sites of HPV into the human genome. a) Integration sites in head and neck squamous cell carcinomas, based on data from the HPV-positive tumors analyzed by Parfenov et al. (22), and b) Integration sites in cervical carcinomas, based on data from Ojesina et al. (24). In both panels, integrations into coding regions are represented by red dots, and noncoding regions by blue dots. If a tumor had multiple insertions at the same locus it is only represented once in the diagram. Several cases had multiple genes in the region involved in the integration event: ^a PARN, BFAR, PLA2G10 ^b ERBB2, STARD3, TCAP, PNMT, PGAP3, C17orf37, GRB7, IKZF3 ^c ERBB2, C17orf37, GRB7 ^d MIRLET7B, MIRLET7BHG, MIRLET7A3, MIR4763

Figure 3

Mechanisms by which integration may lead to the deregulation of key cellular genes. The figure highlights mechanisms by which integration of HPV DNA into the host genome may lead to alteration of critical cellular genes. These include: (1) disruption of a tumor suppressor gene, (2a) by amplification of an oncogene, or (2b) by enhanced expression of an oncogene from a viral promoter. Integration may also cause (3) more extensive intra- or inter-chromosomal rearrangements, resulting in altered expression of multiple genes in the involved regions.

Figure 4

Signaling pathways deregulated in HPV-associated HNSCC. Red boxes highlight the most frequently altered components. Pathway alterations include homozygous deletions, focal amplifications and somatic mutations. Data is based on results from TCGA (20) and Seiwert and colleagues (21).