Genetic Variants as Markers for Use in Urinary Bladder Cancer Risk Assessment, Diagnosis, Prognosis and Treatment
AssigneesIllumina, Inc., deCODE Genetics ehf.
InventorsThorunn Rafnar, Patrick Sulem
Life of this patent
Estimating the term…
Abstract
Polymorphic variants that have been found to be associated with risk of urinary bladder cancer are provided herein. Such polymorphic markers are useful for diagnostic purposes, such as in methods of determining a susceptibility, and for prognostic purposes, including methods of predicting prognosis and methods of assessing an individual for probability of a response to therapeutic 5 agents, as further described herein. Further applications utilize the polymorphic markers of the invention include screening and genotyping methods. The invention furthermore provides related kits, and computer-readable media and apparatus.
Claims70
A method of determining a susceptibility to Bladder Cancer, the method comprising:
- analyzing nucleic acid sequence data from a human individual for at least one polymorphic marker in the human SLC14A1 gene;
- wherein different alleles of the at least one polymorphic marker are associated with different susceptibilities to Bladder Cancer in humans, and
- determining a susceptibility to Bladder Cancer from the nucleic acid sequence data.
The method of any one of the preceding claims, wherein the analyzing comprises determining the presence or absence of at least one at-risk allele for Bladder Cancer of the polymorphic marker.
The method of any one of the preceding claims, wherein the determining comprises comparing the sequence data to a database containing correlation data between the at least one polymorphic marker and susceptibility to Bladder Cancer.
The method of any one of the preceding claims, wherein the at least one polymorphic marker encodes a missense substitution, a nonsense substitution, or a truncation in a SLC14A1 protein with sequence as set forth in SEQ ID NO:133.
The method of any one of the preceding claims, wherein the at least one polymorphic marker encodes a defective SLC14A1 protein with impaired function selected from the group consisting of:
- an impaired JK antigen function, and an impaired urea binding function.
The method of any one of the preceding claims, wherein the at least one polymorphic marker in the SLC14A1 gene is selected from the group consisting of rs1058396, rs11877062, rs2298720 and rs2298719, and markers in linkage disequilibrium therewith.
A method of determining whether an individual is at increased risk of developing bladder cancer, the method comprising steps of
- obtaining a biological sample containing nucleic acid from the individual;
- determining, in the biological sample, nucleic acid sequence about the SLC14A1 gene;
- and
- comparing the sequence information to the wild-type nucleic acid sequence of SLC14A1 (SEQ ID NO:134);
- wherein an identification of a mutation in SLC14A1 in the individual is indicative that the individual is at increased risk of developing bladder cancer.
A method of determining a susceptibility to Bladder Cancer, the method comprising:
- obtaining amino acid sequence data about at least one encoded SLC14A1 protein in a human individual;
- and
- analyzing the amino acid sequence data to determine whether at least one amino acid substitution predictive of increased susceptibility of Bladder Cancer is present;
- wherein a determination of the presence of the at least one amino acid substitution is indicative of increased susceptibility of Bladder Cancer for the individual, and wherein a determination of the absence of the at least one amino acid substitution is indicative of the individual not having the increased susceptibility.
The method of any one of the preceding claims, further comprising a step of preparing a report containing results from the determination, wherein said report is written in a computer readable medium, printed on paper, or displayed on a visual display.
The method of any one of the previous claims, further comprising reporting the susceptibility to at least one entity selected from the group consisting of the individual, a guardian of the individual, a genetic service provider, a physician, a medical organization, and a medical insurer.
A method of identification of a marker for use in assessing susceptibility to Bladder Cancer in human individuals, the method comprising
- a. identifying at least one polymorphic marker in the human SLC14A1 gene;
- b. obtaining sequence information about the at least one polymorphic marker in a group of individuals diagnosed with Bladder Cancer;
- and
- c. obtaining sequence information about the at least one polymorphic marker in a group of control individuals;
- wherein determination of a significant difference in frequency of at least one allele in the at least one polymorphism in individuals diagnosed with Bladder Cancer as compared with the frequency of the at least one allele in the control group is indicative of the at least one polymorphism being useful for assessing susceptibility to Bladder Cancer.
A method of predicting prognosis of an individual diagnosed with Bladder Cancer, the method comprising
- obtaining sequence data about a human individual about at least one polymorphic marker in the human SLC14A1 gene, wherein different alleles of the at least one polymorphic marker are associated with different susceptibilities to Bladder Cancer in humans, and
- predicting prognosis of Bladder Cancer from the sequence data.
A method of assessing probability of response of a human individual to a therapeutic measure for preventing, treating and/or ameliorating symptoms associated with Bladder Cancer, comprising:
- obtaining sequence data about a human individual identifying at least one allele of at least one polymorphic marker in the human SLC14A1 gene, wherein different alleles of the at least one polymorphic marker are associated with different probabilities of response to the therapeutic agent in humans, and
- determining the probability of a positive response to the therapeutic agent from the sequence data.
A kit for assessing susceptibility to Bladder Cancer in human individuals, the kit comprising:
- reagents for selectively detecting at least one risk variant for Bladder Cancer in the individual, wherein the at least one risk variant is a marker in the human SLC14A1 gene or an amino acid marker in an encoded SLC14A1 protein, and
- a collection of data comprising correlation data between the at least one at-risk variant and susceptibility to Bladder Cancer.
Use of an oligonucleotide probe in the manufacture of a diagnostic reagent for diagnosing and/or assessing a susceptibility to Bladder Cancer, wherein the probe is capable of hybridizing to a segment of the human SLC14A1 gene with sequence as given by SEQ ID NO:134, and wherein the segment is 15-400 nucleotides in length.
A computer-readable medium having computer executable instructions for determining susceptibility to Bladder Cancer in a human individual, the computer readable medium comprising:
- sequence data identifying at least one allele of at least one polymorphic marker in the individual;
- a routine stored on the computer readable medium and adapted to be executed by a processor to determine risk of developing Bladder Cancer for the at least one polymorphic marker;
- wherein the at least one polymorphic marker is a marker in the human SLC14A1 gene, or an amino acid variant in an encoded SLC14A1 protein, that is predictive of susceptibility of Bladder Cancer in humans.
An apparatus for determining a susceptibility to Bladder Cancer in a human individual, comprising:
- a processor;
- a computer readable memory having computer executable instructions adapted to be executed on the processor to analyze information for at least one human individual with respect to at least one marker in the human SLC14A1 gene that is predictive of susceptibility to Bladder Cancer in humans, or at least one amino acid variation in an encoded SLC14A1 protein, and generate an output based on the marker or amino acid information, wherein the output comprises at least one measure of susceptibility to Bladder Cancer for the human individual.
A system for identifying susceptibility to bladder cancer in a human subject, the system comprising:
- at least one processor;
- at least one computer-readable medium;
- a susceptibility database operatively coupled to a computer-readable medium of the system and containing population information correlating the presence or absence of one or more alleles of the human SLC14A1 gene and susceptibility to bladder cancer in a population of humans;
- a measurement tool that receives an input about the human subject and generates information from the input about the presence or absence of the at least one allele in the human subject;
- and
- an analysis tool that:
- is operatively coupled to the susceptibility database and the measurement tool,
- is stored on a computer-readable medium of the system,
- is adapted to be executed on a processor of the system, to compare the information about the human subject with the population information in the susceptibility database and generate a conclusion with respect to susceptibility to bladder cancer for the human subject.
A system for assessing or selecting a treatment protocol for a subject diagnosed with bladder cancer, comprising:
- at least one processor;
- at least one computer-readable medium;
- a medical treatment database operatively connected to a computer-readable medium of the system and containing information correlating the presence or absence of at least one mutant SLC14A1 allele and efficacy of treatment regimens for bladder cancer;
- a measurement tool to receive an input about the human subject and generate information from the input about the presence or absence of the at least one SLC14A1 allele in a human subject diagnosed with bladder cancer;
- and
- a medical protocol tool operatively coupled to the medical treatment database and the measurement tool, stored on a computer-readable medium of the system, and adapted to be executed on a processor of the system, to compare the information with respect to presence or absence of the at least one SLC14A1 allele for the subject and the medical treatment database, and generate a conclusion with respect to at least one of:
- the probability that one or more medical treatments will be efficacious for treatment of bladder cancer for the patient;
- and
- which of two or more medical treatments for bladder cancer will be more efficacious for the patient.
Dependencies are inferred from the claim text.