Characterization of sequence variations within HPV16 isolates among Indian women: prediction of causal role of rare non-synonymous variations within intact isolates in cervical cancer pathogenesis.
We re-sequenced HPV16 genome (~6 kb) implicated in cervical carcinogenesis (LCR, E2, E5, E6, E7, L1, L2) to prioritize sequence variants for functional validation as biomarkers, using CaCx cases (n=74) and asymptomatic controls (n=24). Of the nucleotide variations recorded (n=271), non-synonymous changes in L2 region were significantly higher (p=0.005) among cases (2.67%) compared to controls (1.27%). Using SIFT database, 29 non-synonymous changes (frequency=0.01-0.03) predicted as deleterious to protein functions were identified. Haplotype analysis considering 110 polymorphic variations (frequency> or =0.05) within intact viral isolates (53 CaCx cases and 21 controls) using NETWORK software, confirmed Asian-American (AA, 14.86%) and European (E, 85.14%) variants, differing at 78 positions. The E-variants portrayed thirty-six haplotypes, of which, E-12 was most prevalent within cases (38.1%; 16/42) and controls (28.57%; 6/21) harboring polymorphic variations at 10 positions, in contrast to HPV16R. Cases of the E-12 haplotype harbored 7 deleterious mutations distributed within L1 (n=1), E2 (n=1), E5 (n=1), and L2 (n=4), while none within similar controls. Thus rare deleterious variations within genes implicated in productive infection over the E-12 haplotype background of intact HPV16 isolates might be of causal relevance for CaCx development.
Bhattacharjee
Bornali
B
Human Genetics Unit, Indian Statistical Institute, Kolkata, India.
Mandal
Nidhu Ranjan
NR
Roy
Sudipta
S
Sengupta
Sharmila
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D001483:Base Sequence; D016022:Case-Control Studies; D017931:DNA Primers / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D016679:Genome, Viral; D052162:Human papillomavirus 16 / Q000235:genetics* / Q000302:isolation & purification*; D006801:Humans; D007194:India; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000209:etiology* / Q000821:virology*; D020641:Polymorphism, Single Nucleotide; D002583:Uterine Cervical Neoplasms / Q000209:etiology* / Q000821:virology*; D014774:Virulence / Q000235:genetics
D017931:DNA Primers; D004279:DNA, Viral