Fundamental Differences in Cell Cycle Deregulation in Human Papillomavirus–Positive and Human Papillomavirus–Negative Head/Neck and Cervical Cancers

TLDR

Human papillomaviruses (HPV) are linked to nearly all cervical cancers, 20–30 % of head and neck cancers, and other malignancies. Because head and neck cancers also arise in HPV‑negative patients, this setting allows comparison of HPV‑positive versus HPV‑negative tumors within the same tissue. The study performed genome‑wide expression profiling of 84 head and neck cancers, cervical cancers, and matched normal epithelium, using laser capture microdissection to isolate tumor versus normal cells. HPV‑positive head and neck cancers and cervical cancers share many gene‑expression changes relative to HPV‑negative head and neck cancers, including a larger up‑regulation of cell‑cycle genes and novel overexpression of testis‑specific genes driven by E6/E7, providing new biomarkers for early detection and suggesting E6/E7 as therapeutic targets alone or with radiation/chemotherapy. Published in Cancer Research 2007;67(10):4605–19.

Abstract

Abstract Human papillomaviruses (HPV) are associated with nearly all cervical cancers, 20% to 30% of head and neck cancers (HNC), and other cancers. Because HNCs also arise in HPV-negative patients, this type of cancer provides unique opportunities to define similarities and differences of HPV-positive versus HPV-negative cancers arising in the same tissue. Here, we describe genome-wide expression profiling of 84 HNCs, cervical cancers, and site-matched normal epithelial samples in which we used laser capture microdissection to enrich samples for tumor-derived versus normal epithelial cells. This analysis revealed that HPV+ HNCs and cervical cancers differed in their patterns of gene expression yet shared many changes compared with HPV− HNCs. Some of these shared changes were predicted, but many others were not. Notably, HPV+ HNCs and cervical cancers were found to be up-regulated in their expression of a distinct and larger subset of cell cycle genes than that observed in HPV− HNC. Moreover, HPV+ cancers overexpressed testis-specific genes that are normally expressed only in meiotic cells. Many, although not all, of the hallmark differences between HPV+ HNC and HPV− HNC were a direct consequence of HPV and in particular the viral E6 and E7 oncogenes. This included a novel association of HPV oncogenes with testis-specific gene expression. These findings in primary human tumors provide novel biomarkers for early detection of HPV+ and HPV− cancers, and emphasize the potential value of targeting E6 and E7 function, alone or combined with radiation and/or traditional chemotherapy, in the treatment of HPV+ cancers. [Cancer Res 2007;67(10):4605–19]