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Methods of diagnosing, classifying and treating endometrial cancer and precancer

a technology applied in the field of precancer and endometrial cancer diagnostic and treatment methods, can solve problems such as poor survival

Inactive Publication Date: 2014-02-27
TRANSLATIONAL GENOMICS RESEARCH INSTITUTE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention is a method to detect and diagnose endometrial cancer or precancer in a human by detecting a mutation in a specific gene called FGFR2. This mutation is associated with enhanced ligand binding, which can activate the receptor and lead to increased signaling, even without the need for additional ligand stimulation. This method can provide a reliable diagnostic tool for endometrial cancer and precancer.

Problems solved by technology

For those women with advanced stage, progressive, or recurrent disease, survival is poor as there are no adjuvant therapies proven to be effective.
Although much progress has been made toward understanding the biological basis of cancer and in its diagnosis and treatment, it is still one of the leading causes of death in the United States.
Inherent difficulties in the diagnosis and treatment of cancer include among other things, the existence of many different subgroups of cancer and the concomitant variation in appropriate treatment strategies to maximize the likelihood of positive patient outcome.

Method used

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  • Methods of diagnosing, classifying and treating endometrial cancer and precancer
  • Methods of diagnosing, classifying and treating endometrial cancer and precancer
  • Methods of diagnosing, classifying and treating endometrial cancer and precancer

Examples

Experimental program
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Effect test

example 1

Detection of Activating FGFR2 Mutations in Endometrial Cancer

[0132]Our findings show that activation and overexpression of FGFR2 plays a role in endometrial tumorigenesis. Exon 8 is three nucleotides longer than exon 9, hence the FGFR2b isoform is one codon longer than the FGFR2c isoform. Specificity of signaling is also provided by tissue specific expression of receptors, ligands and heparin sulphate proteoglycans (Allen et al., 2001; Fiore, 2001). Due to the differences in length of the FGFR2 “b” and “c” isoforms, all mutations will be numbered relative to the epithelially expressed FGFR2b isoform (SEQ ID NO:2; NP—075259.2). For those occurring downstream of exon 8 we provide herein the equivalent mutation numbered relative to the FGFR2c isoform (SEQ ID NO:3; NP—000132.1) in brackets and in Table 2. The N550K (N549K) variant identified in two of the endometrial cell lines was likely to result in receptor activation as identical or similar germline missense changes had been reporte...

example 2

Treatment of Endometrial Cancer by Inhibition of FGFR2

Materials and Methods

Sequencing Analysis

[0145]Mutation analysis was performed as previously described (8). PCR primer sequences were M13 tailed and sequencing performed in two directions. Primer sequences are available by request from the author.

Cell Culture and Reagents

[0146]The human endometrial MFE296 cell line was purchased from the European Collection of Cell Cultures (Salisbury, Wiltshire, UK). The human endometrial cell lines AN3CA, HEC1A, Ishikawa, RL952, and KLE were provided by Dr. Paul Goodfellow (Washington University, St. Louis, Mo.). MFE296 cells were grown in MEM supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine, and penicillin-streptomycin. AN3CA cells were cultured in DMEM supplemented with 10% FBS, non-essential amino acids, 2 mM L-glutamine, and penicillin-streptomycin. HEC1A cells were cultured in 50% DMEM and 50% RPMI 1640, supplemented with 10% FBS and penicillin-streptomycin. Ishikawa and RL9...

example 3

Activating-FGFR2 Mutations Promote Endometrial Cell Migration

Materials and Methods

[0171]To determine the ability of FGFR2 mutations to alter the phenotype of primary endometrial epithelial cells, HPV / TERT immortalized primary human endometrial epithelial cells were transduced with wild type FGFR2b or mutant FGFR2b (N550K) and FGF-stimulated migration evaluated.

[0172]Briefly, 3×105 cells were seeded on top of 8 μm pore size polycarbonate membranes (Cell Biolabs, Inc) in full growth media containing 1 nM FGF10. 24 hours later, the media was aspirated from inside the insert and non-migratory cells were removed from the top of the insert using cotton-tipped swabs. Migratory cells (those that had passed through the membrane) were stained and the membranes were photographed (5 random fields per insert). The stained cells on the inserts were then solubilized and quantified by measuring absorbance at 570 nm.

Results

[0173]Each FGFR2 construct was assessed in quadruplicate and the results are ...

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Abstract

Diagnostic and therapeutic applications for endometrial cancer are described. The diagnostic and therapeutic applications are based on certain activation mutations in the FGFR2 gene and its expression products. The present invention is directed to nucleotide sequences, amino acid sequences, probes, and primers related to FGFR2 activation mutants and kits comprising these mutants to diagnosis and classify endometrial cancer in a subject.

Description

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS[0001]This patent application is a continuation-in-part of U.S. application Ser. No. 12 / 532,563 filed Sep. 22, 2009, which is a National Stage Entry of International Patent Application No. PCT / US2008 / 058065 filed Mar. 24, 2008, which claims priority to U.S. provisional application Ser. No. 60 / 896,884, filed Mar. 23, 2007 and U.S. provisional application Ser. No. 60 / 982,093, filed Oct. 23, 2007. Each of the foregoing applications is hereby incorporated by reference in its entirety.INCORPORATION-BY-REFERENCE OF MATERIAL ELECTRONICALLY FILED[0002]Incorporated by reference in its entirety herein is a computer-readable nucleotide / amino acid sequence listing submitted concurrently herewith and identified as follows: One 27,199 byte ASCII (text) file named “Seq_list” created on Aug. 22, 2013.FIELD OF THE INVENTION[0003]The present invention is directed to methods and kits for diagnosing, classifying, and treating endometrial cancer.BACKGROUND O...

Claims

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Application Information

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IPC IPC(8): G01N33/68
CPCG01N33/6893G01N33/57442A61K31/519A61K35/00C12N15/1138C12N2310/14C12N2310/531C12N2320/30C12Q1/6886C12Q2600/106C12Q2600/156G01N2333/71
Inventor POLLOCK, PAMELAGOODFELLOW, PAUL
Owner TRANSLATIONAL GENOMICS RESEARCH INSTITUTE
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