Contribution of gross chromosomal changes to HPV16-induced transformation

Abstract

Cervical cancer is initiated by infection with high-risk human papillomavirus (HPV). The viral E6 and E7 oncogenes are required for the initiation of cervical epithelial cell immortalization, but do not suffice to cause cervical cancer. Human oncogenes and tumor suppressor genes with altered activity in cervical carcinoma have been recognized, but none of these appears to be an absolute precondition for the development of the cancer. To examine the contribution of chromosomal aberrations to the development of cervical carcinoma, we used an in vitro model system consisting of primary keratinocytes (K) and papillomavirus transformed keratinocytes from early (E) and late (L) passages and from benzo[a]pyrene treated L cells (BP). Using DIGMAP software we compared alterations in gene expression as a function of chromosomal location. SKY chromosomal painting confirmed that the alterations identified by DIGMAP include gross chromosomal aberrations. Nearly half of the transcripts that were significantly reduced or increased in BP cells mapped to chromosomal regions showing coordinate changes in expression. These included transcripts involved in previously characterized phenotypic changes involved in transformation, such as the switch from apoptosis to necrosis and the reduction in cap-dependent translation. The global chromosomal changes that occurred during transformation are highly correlated with the phenotypic changes in HPV transformed keratinocytes. Our data are consistent with the theory that global chromosomal change is a necessary step in the process of cervical transformation.