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Papanicolaou test for ovarian and endometrial cancers

A technology for endometrial cancer and ovarian cancer, which is applied in the field of ovarian cancer and endometrial cancer, and can solve problems such as differentiation

Active Publication Date: 2019-03-12
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although in some cases AGCs have been associated with premalignant or malignant disease (18-22), it is often difficult to distinguish AGCs arising from endocervical, endometrial, and ovarian cancers from each other or from more benign conditions

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  • Papanicolaou test for ovarian and endometrial cancers
  • Papanicolaou test for ovarian and endometrial cancers
  • Papanicolaou test for ovarian and endometrial cancers

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Embodiment 1

[0046] The inventors speculate that more sophisticated molecular methods may be able to detect the presence of cancer cells in endocervical samples with greater sensitivity and specificity than conventional methods. In particular, the present invention hypothesizes that somatic mutations characteristic of endometrial and ovarian cancers will be detected in conventional fluid-based Pap smears (hereinafter referred to as "Pap smears"; figure 1 ) found in purified DNA. Unlike cytologically abnormal cells, this oncogenic DNA mutation is a specific clonal marker of neoplasia that should be absent in non-neoplastic cells. However, the inventors do not know whether such DNA is actually present in the endocervical sample, and the inventors do not know whether they are present in sufficient quantities to detect them. The experiments described herein were performed to test the hypothesis of the present invention.

[0047]There were four parts to this study: I. Identification of somati...

Embodiment 2

[0049] Incidence of somatically mutated genes in endometrial and ovarian cancer

[0050] There are five major histopathological subtypes of ovarian cancer. The most prevalent subtype was high-grade serous (60% of the total), followed by endometrioid (15%), clear cell (10%), and low-grade serous carcinoma (8%) (Table 1). Genome-wide studies have identified the most frequently mutated genes in the most prevalent subtypes of ovarian cancer (Table 2) (23-25).

[0051] Such a comprehensive study of the endometrioid and mucinous subtypes, which together represent ~20% of ovarian cancer cases (Table 1 ), has not been reported. However, genes that are commonly mutated in the endometrioid and mucinous subtypes have been reported (26). Overall, the most commonly mutated gene in epithelial ovarian cancer was TP53, which was mutated in 69% of these cancers (Table 2). Other highly mutated genes included ARID1A, BRAF, CTNNB1, KRAS, PIK3CA, and PPP2R1A (Table 2).

[0052] In endometrial ...

Embodiment 3

[0058] Identify mutations in tumor tissue

[0059] The inventors obtained tumors from 46 cancer patients for whom Pap smears were available. This included 24 patients with endometrial cancer and 22 patients with ovarian cancer; clinical and histopathological features are listed in Table S3.

[0060] Somatic mutations were identified in 46 tumors by whole-exome sequencing as described above or by targeted sequencing of genes frequently mutated in the most common subtypes of ovarian or endometrial cancer (Table 2). Enrichment of these genes is achieved using a custom solid-phase capture assay comprising oligonucleotides ("capture probes") complementary to a panel of gene regions of interest. For oncogenes, the inventors only targeted their commonly mutated exons, but the inventors targeted the entire coding region of tumor suppressor genes.

[0061] Illumina DNA sequencing libraries were generated from tumors and their matched non-neoplastic tissues, which were then captured u...

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Abstract

The invention relates to papanicolaou test for ovarian and endometrial cancers. The recently developed liquid-based Papanicolaou (Pap) smear allows not only cytologic evaluation but also collection ofDNA for detection of HPV, the causative agent of cervical cancer. We tested these samples to detect somatic mutations present in rare tumor cells that might accumulate in the cervix once shed from endometrial and ovarian cancers. A panel of commonly mutated genes in endometrial and ovarian cancers was assembled and used to identify mutations in all 46 endometrial or cervical cancer tissue samples. We were able also able to identify the same mutations in the DNA from liquid Pap smears in 100% of endometrial cancers (24 of 24) and in 41% of ovarian cancers (9 of 22). We developed a sequence-based method to query mutations in 12 genes in a single liquid Pap smear without prior knowledge of the tumor's genotype.

Description

[0001] This application is a divisional application, the filing date of the original application is October 17, 2013, the application number is 201380068411.8, and the invention name is "Papanicolaou test for ovarian and endometrial cancer". [0002] This invention was made with funding from the National Cancer Institute and the National Institutes of Health. The US government reserves certain rights under the terms of NCI agreement N01-CN-43309 and NIH grants CA129825 and CA43460. technical field [0003] The present invention relates to the field of cancer screening. In particular, it relates to ovarian and endometrial cancers. Background technique [0004] Since the introduction of the Papanicolaou test (Pap test), the incidence and mortality of cervical cancer in the screened population has been reduced by more than 75% (1, 2). In contrast, the number of deaths from ovarian and endometrial cancers did not decrease significantly during the same period. As a result, mor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/6886G01N33/574
CPCC12Q1/6886G01N33/57442G01N33/57449C12Q2600/154C12Q2600/16C12Q1/6851C12Q2600/156C12Q2600/158
Inventor I·金德K·W·肯斯勒B·沃格尔斯坦N·帕帕佐普洛斯L·迪亚斯C·贝蒂加高达Y·王
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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