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HPV16 E7 Genetic Conservation Is Critical to Carcinogenesis

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.

Authors: Mirabello L; Yeager M; Yu K; Clifford GM; Xiao Y; Zhu B; Cullen M; Boland JF; Wentzensen N; Nelson CW; Raine-Bennett T; Chen Z; Bass S; Song L; Yang Q; Steinberg M; Burdett L; Dean M; Roberson D; Mitchell J; Lorey T; Franceschi S; Castle PE; Walker J; Zuna R; Kreimer AR; Beachler DC; Hildesheim A; Gonzalez P; Porras C; Burk RD; Schiffman M

Cell. 2017 Sep 07;170(6):1164-1174.e6.

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