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Grant Details

Grant Number: 5R01CA034493-22 Interpret this number
Primary Investigator: Koutsky, Laura
Organization: University Of Washington
Project Title: Etiology and Natural History of Cervical Neoplasia
Fiscal Year: 2007
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Abstract

DESCRIPTION (provided by applicant): Our long-term goal is to develop sensitive, specific, and inexpensive approaches to cervical cancer screening. In our previous proposal, we performed the first U.S.-based study of the accuracy and cost effectiveness of primary screening by traditional Pap and cervical HPV DNA testing. We found that testing for HPV was considerably more sensitive but less specific than Pap testing for detection of cervical intraepithelial neoplasia grade 3 (CIN3). While the role of high sensitivity in detecting disease cannot be disputed, when the trade-offs low specificity there are substantial cost implications, especially for a screening test that is repeated at regular intervals. Preliminary results from our group suggest that testing for the cyclin-dependant kinase inhibitor, p16INK4a, may provide a more accurate indication of disease status than either Pap or HPV DNA testing. Since p16INK4a is protein, there is potential for developing a low cost ELISA assay. Furthermore, our pilot data suggest that p16INK4a is associated with infection by variants of HPV16 that are most strongly linked with CIN3 and cancer. In HPV-associated tumors, levels of p16INK4a increase due to inactivation of Rb by HPV E7. Lastly, our preliminary data suggest that a self-collected vaginal swab for HPV DNA testing may be a viable screening option for women who avoid, or who do not have access to, pelvic examinations. In the proposed project, we plan to define the accuracy and relative cost-effectiveness of p16INK4a testing of a clinician collected sample and HPV DNA testing of a self-collected vaginal swab sample. In addition, we will explore the hypothesis that variation in levels of E7 gene expression defines differences in the oncogenic potential of HPV16 variants. While Pap test screening of healthy women has substantially reduced cervical cancer deaths over the last 50 years, false negative and false positive screening test results have also deprived women of their sense of well-being, initiated potentially harmful diagnostic testing and treatment, and wasted health-care resources. Clear public health benefits will accrue from development of more accurate and less costly screening tests.

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Publications

Inverse association between methylation of human papillomavirus type 16 DNA and risk of cervical intraepithelial neoplasia grades 2 or 3.
Authors: Xi LF, Jiang M, Shen Z, Hulbert A, Zhou XH, Lin YY, Kiviat NB, Koutsky LA
Source: PLoS One, 2011;6(8), p. e23897.
EPub date: 2011 Aug 24.
PMID: 21887341
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Accuracy and cost-effectiveness of cervical cancer screening by high-risk human papillomavirus DNA testing of self-collected vaginal samples.
Authors: Balasubramanian A, Kulasingam SL, Baer A, Hughes JP, Myers ER, Mao C, Kiviat NB, Koutsky LA
Source: J Low Genit Tract Dis, 2010 Jul;14(3), p. 185-95.
PMID: 20592553
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Depot-medroxyprogesterone acetate and combined oral contraceptive use and cervical neoplasia among women with oncogenic human papillomavirus infection.
Authors: Harris TG, Miller L, Kulasingam SL, Feng Q, Kiviat NB, Schwartz SM, Koutsky LA
Source: Am J Obstet Gynecol, 2009 May;200(5), p. 489.e1-8.
PMID: 19375566
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Development and evaluation of a liquid bead microarray assay for genotyping genital human papillomaviruses.
Authors: Feng Q, Cherne S, Winer RL, Balasubramanian A, Lee SK, Hawes SE, Kiviat NB, Koutsky LA
Source: J Clin Microbiol, 2009 Mar;47(3), p. 547-53.
EPub date: 2009 Jan 14.
PMID: 19144800
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Sequence variation of human papillomavirus type 16 and measurement of viral integration by quantitative PCR.
Authors: Jiang M, Baseman JG, Koutsky LA, Feng Q, Mao C, Kiviat NB, Xi LF
Source: J Clin Microbiol, 2009 Mar;47(3), p. 521-6.
EPub date: 2008 Dec 30.
PMID: 19116350
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Cigarette smoking, oncogenic human papillomavirus, Ki-67 antigen, and cervical intraepithelial neoplasia.
Authors: Harris TG, Kulasingam SL, Kiviat NB, Mao C, Agoff SN, Feng Q, Koutsky LA
Source: Am J Epidemiol, 2004 May 1;159(9), p. 834-42.
PMID: 15105176
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p16(INK4a) expression correlates with degree of cervical neoplasia: a comparison with Ki-67 expression and detection of high-risk HPV types.
Authors: Agoff SN, Lin P, Morihara J, Mao C, Kiviat NB, Koutsky LA
Source: Mod Pathol, 2003 Jul;16(7), p. 665-73.
PMID: 12861062
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Do condoms prevent genital HPV infection, external genital warts, or cervical neoplasia? A meta-analysis.
Authors: Manhart LE, Koutsky LA
Source: Sex Transm Dis, 2002 Nov;29(11), p. 725-35.
PMID: 12438912
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The theoretical population-level impact of a prophylactic human papilloma virus vaccine.
Authors: Hughes JP, Garnett GP, Koutsky L
Source: Epidemiology, 2002 Nov;13(6), p. 631-9.
PMID: 12410003
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Determinants of cervical cancer rates in developing countries.
Authors: Drain PK, Holmes KK, Hughes JP, Koutsky LA
Source: Int J Cancer, 2002 Jul 10;100(2), p. 199-205.
PMID: 12115570
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Liquid-based Papanicolaou smears without a transformation zone component: should clinicians worry?
Authors: Baer A, Kiviat NB, Kulasingam S, Mao C, Kuypers J, Koutsky LA
Source: Obstet Gynecol, 2002 Jun;99(6), p. 1053-9.
PMID: 12052599
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The inflammatory Papanicolaou smear: what does it mean?
Authors: Eckert LO, Koutsky LA, Kiviat NB, Krone MR, Stevens CE, Eschenbach DA
Source: Obstet Gynecol, 1995 Sep;86(3), p. 360-6.
PMID: 7651643
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Microbiological, epidemiological and clinical correlates of vaginal colonisation by Mobiluncus species.
Authors: Hillier SL, Critchlow CW, Stevens CE, Roberts MC, Wolner-Hanssen P, Eschenbach DA, Holmes KK
Source: Genitourin Med, 1991 Feb;67(1), p. 26-31.
PMID: 1916772
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Diagnosis and clinical manifestations of bacterial vaginosis.
Authors: Eschenbach DA, Hillier S, Critchlow C, Stevens C, DeRouen T, Holmes KK
Source: Am J Obstet Gynecol, 1988 Apr;158(4), p. 819-28.
PMID: 3259075
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Epidemiology of genital human papillomavirus infection.
Authors: Koutsky LA, Galloway DA, Holmes KK
Source: Epidemiol Rev, 1988;10, p. 122-63.
PMID: 2852116
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