Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Mar 21;10(433):eaap8793.
doi: 10.1126/scitranslmed.aap8793.

Evaluation of liquid from the Papanicolaou test and other liquid biopsies for the detection of endometrial and ovarian cancers

Yuxuan Wang  1 , Lu Li  2 , Christopher Douville  1 , Joshua D Cohen  1   3 , Ting-Tai Yen  4 , Isaac Kinde  5 , Karin Sundfelt  6 , Susanne K Kjær  7   8 , Ralph H Hruban  9 , Ie-Ming Shih  9 , Tian-Li Wang  9 , Robert J Kurman  9 , Simeon Springer  1 , Janine Ptak  1 , Maria Popoli  1 , Joy Schaefer  1 , Natalie Silliman  1 , Lisa Dobbyn  1 , Edward J Tanner  4 , Ana Angarita  4 , Maria Lycke  6 , Kirsten Jochumsen  10 , Bahman Afsari  2 , Ludmila Danilova  2 , Douglas A Levine  11 , Kris Jardon  12 , Xing Zeng  12 , Jocelyne Arseneau  12 , Lili Fu  12 , Luis A Diaz Jr  1 , Rachel Karchin  13 , Cristian Tomasetti  14 , Kenneth W Kinzler  15 , Bert Vogelstein  15   16 , Amanda N Fader  17 , Lucy Gilbert  18 , Nickolas Papadopoulos  15
Affiliations

Evaluation of liquid from the Papanicolaou test and other liquid biopsies for the detection of endometrial and ovarian cancers

Yuxuan Wang et al. Sci Transl Med. .

Abstract

We report the detection of endometrial and ovarian cancers based on genetic analyses of DNA recovered from the fluids obtained during a routine Papanicolaou (Pap) test. The new test, called PapSEEK, incorporates assays for mutations in 18 genes as well as an assay for aneuploidy. In Pap brush samples from 382 endometrial cancer patients, 81% [95% confidence interval (CI), 77 to 85%] were positive, including 78% of patients with early-stage disease. The sensitivity in 245 ovarian cancer patients was 33% (95% CI, 27 to 39%), including 34% of patients with early-stage disease. In contrast, only 1.4% of 714 women without cancer had positive Pap brush samples (specificity, ~99%). Next, we showed that intrauterine sampling with a Tao brush increased the detection of malignancy over endocervical sampling with a Pap brush: 93% of 123 (95% CI, 87 to 97%) patients with endometrial cancer and 45% of 51 (95% CI, 31 to 60%) patients with ovarian cancer were positive, whereas none of the samples from 125 women without cancer were positive (specificity, 100%). Finally, in 83 ovarian cancer patients in whom plasma was available, circulating tumor DNA was found in 43% of patients (95% CI, 33 to 55%). When plasma and Pap brush samples were both tested, the sensitivity for ovarian cancer increased to 63% (95% CI, 51 to 73%). These results demonstrate the potential of mutation-based diagnostics to detect gynecologic cancers at a stage when they are more likely to be curable.

PubMed Disclaimer

Conflict of interest statement

Competing interests: Under agreements between the Johns Hopkins University (JHU), Genzyme, Sysmex Inostics, Qiagen, Invitrogen, and Personal Genome Diagnostics, B.V., K.W.K., N.P., and L.A.D. are entitled to a share of the royalties received by the university on the sales of products related to genes and technologies described in this manuscript. B.V., K.W.K., N.P., and L.A.D. are cofounders of Personal Genome Diagnostics and PapGene Inc., are members of the Scientific Advisory Boards of Sysmex Inostics, Personal Genome Diagnostics, and PapGene Inc., and own Personal Genome Diagnostics and PapGene Inc. stock, which is subject to certain restrictions under JHU policy. I.K. is a cofounder and chief scientific officer of PapGene Inc. The company has licensed previously described technologies related to the work described in this paper. The terms of these arrangements are managed by the JHU in accordance with its conflict of interest policies. Part of the technology described in U.S. Patent 20150292027 (Papanicolaou Test for Ovarian and Endometrial Cancers) was applied in this study. Y.W., K.W.K., N.P., C.T., and B.V. are inventors on a patent application on the use of biomarker combinations for the detection of gynecologic cancers. This application will be submitted by the JHU and managed in accordance with its conflict of interest policies. Y.W., K.W.K., N.P., B.V., R.K., I.K., L.D., and C D. are inventors of technologies that are related to those described in this paper and that are associated with equity or royalty payments to the inventors. The terms of these arrangements are being managed by JHU in accordance with its conflict of interest policies. L.G. is listed as a co-inventor on U.S. Provisional Patent application no. 62/656,525 (Uterine Brush and Sample Collection Kit, and Method of Collecting Endometrial Cells from the Uterus) that partially describes the intrauterine sampling method outlined in this paper.

Figures

Fig. 1.
Fig. 1.. Detection of aneuploidy and somatic mutations (PapSEEK) in Pap or Tao brush samples from healthy controls and patients with endometrial or ovarian cancers.
Data shown as means ± 95% confidence intervals.
Fig. 2.
Fig. 2.. Venn diagrams showing increased detection with combined testing for somatic mutations and aneuploidy, as well as combined testing of Pap brush and plasma samples.
For both endometrial and ovarian cancers, combined testing for somatic mutations and aneuploidy increased sensitivity in the Pap and Tao brush samples. For ovarian cancer, combined testing of Pap brush and plasma samples also increased sensitivity compared to testing either sample type alone.
Fig. 3.
Fig. 3.. Detection of endometrial or ovarian cancers In Pap or Tao brush samples with PapSEEK by stage.
Data shown as means ± 95% confidence intervals.
Fig. 4.
Fig. 4.. Detection of ovarian cancer in Pap and plasma samples.
Data shown as means ± 95% confidence intervals.
Fig. 5.
Fig. 5.. PapSEEK test for the detection of tumor DNA in the Pap brush, Tao brush, and plasma samples of patients with endometrial or ovarian cancers.
Tumor cells shed from ovarian or endometrial cancers are carried into the uterine cavity, where they can be collected by the Tao brush. The tumor cells that pass down into the endocervical canal can be captured by the Pap brush used in the routine Pap test. These brushes are dipped into a liquid fixative, from which DNA is isolated and sequenced. The sequences are analyzed for somatic mutations and aneuploidy. In addition, tumor DNA shed into the bloodstream can be detected by circulating tumor DNA (ctDNA) analysis. Detection of endometrial and ovarian cancers with PapSEEK in the Pap brush, Tao brush, and plasma samples is shown as means ± 95% confidence intervals.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Geldenhuys L, Murray ML, Sensitivity and specificity of the Pap smear for glandular lesions of the cervix and endometrium. Acta Cytol 51, 47–50 (2007). - PubMed
    1. Ng AB, Reagan JW, Hawliczek S, Wentz BW, Significance of endometrial cells in the detection of endometrial carcinoma and its precursors. Acta Cytol 18, 356–361 (1974). - PubMed
    1. Schnatz PF, Guile M, O’Sullivan DM, Sorosky JI, Clinical significance of atypical glandular cells on cervical cytology. Obstet. Gynecol. 107, 701–708 (2006). - PubMed
    1. Zhao C, Florea A, Onisko A, Austin RM, Histologic follow-up results in 662 patients with Pap test findings of atypical glandular cells: Results from a large academic womens hospital laboratory employing sensitive screening methods. Gynecol. Oncol. 114, 383–389 (2009). - PubMed
    1. Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA, SEER Cancer Statistics Review, 1975–2014 (National Cancer Institute, 2017).

Publication types