Mirabello, L; Nelson, CW; Raine-Bennett, T; Chen, Z; Bass, S; Song, Lei; Yang, Qi; Steinberg, Mia; Burdett, L; Dean, M; Roberson, D; Yeager, M; Mitchell, J; Lorey, T; Franceschi, S; Castle, PE; Walker, J; Zuna, R; Kreimer, AR; Beachler, DC; Hildesheim, A; Gonzalez, P; Yu, Kai; Porras, C; Burk, RD; Schiffman, M; Clifford, GM; Xiao, Y; Zhu, Bin; Cullen, M; Boland, JF; Wentzensen, N; ,
Although most cervical human papillomavirus type 16 (HPV16) infections become undetectable within 1-2 years, persistent HPV16 causes half of all cervical cancers. We used a novel HPV whole-genome sequencing technique to evaluate an exceptionally large collection of 5,570 HPV16-infected case-control samples to determine whether viral genetic variation influences risk of cervical precancer and cancer. We observed thousands of unique HPV16 genomes; very few women shared the identical HPV16 sequence, which should stimulate a careful re-evaluation of the clinical implications of HPV mutation rates, transmission, clearance, and persistence. In case-control analyses, HPV16 in the controls had significantly more amino acid changing variants throughout the genome. Strikingly, E7 was devoid of variants in precancers/cancers compared to higher levels in the controls; we confirmed this in cancers from around the world. Strict conservation of the 98 amino acids of E7, which disrupts Rb function, is critical for HPV16 carcinogenesis, presenting a highly specific target for etiologic and therapeutic research.
