Molecular subtyping, prognosis, and treatment of bladder cancer

Abstract

The present invention relates to methods, systems and kits for the diagnosis, prognosis, and treatment of bladder cancer in a subject. The invention also provides biomarkers that define subgroups of bladder cancer, clinically useful classifiers for distinguishing bladder cancer subtypes, bioinformatic methods for determining clinically useful classifiers, and methods of use of each of the foregoing. The methods, systems and kits can provide expression-based analysis of biomarkers for purposes of subtyping bladder cancer in a subject. Further disclosed herein, in certain instances, are probe sets for use in subtyping bladder cancer in a subject. Classifiers for subtyping a bladder cancer are provided. Methods of treating bladder cancer based on molecular subtyping are also provided.

1 . A method comprising:
 providing a biological sample from a subject having bladder cancer;   measuring levels of expression in the biological sample of a plurality of genes selected from Table 3, Table 5, Table 13 or SEQ ID Nos: 1-4050; and   subtyping the bladder cancer of the subject according to a genomic subtyping classifier based on the levels of expression of the plurality of genes, wherein said subtyping comprises assigning the bladder cancer to one of four subtypes selected from the group consisting of a claudin-low subtype, a basal subtype, a luminal-infiltrated subtype, and a luminal non-infiltrated subtype.   
     
     
         2 . The method of  claim 1 , further comprising administering neoadjuvant chemotherapy to the subject if the subtyping indicates that the subject has the basal subtype and administering an anti-cancer treatment other than the neoadjuvant chemotherapy to the subject if the subtyping indicates that the subject has the luminal-infiltrated subtype, the luminal non-infiltrated subtype, or the claudin-low subtype, wherein the anti-cancer treatment other than neoadjuvant chemotherapy is selected from the group consisting of surgery, radiation therapy, immunotherapy, biological therapy, hormonal therapy, and photodynamic therapy. 
     
     
         3 . The method of  claim 1 , wherein the neoadjuvant chemotherapy comprises administering cisplatin. 
     
     
         4 . The method of  claim 1 , wherein the method is performed prior to treatment of the patient with the neoadjuvant chemotherapy. 
     
     
         5 . The method of  claim 1 , wherein the subject is undergoing the neoadjuvant chemotherapy. 
     
     
         6 . The method of  claim 1 , wherein the subject has muscle-invasive bladder cancer. 
     
     
         7 - 13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein said measuring the level of expression comprises measuring the level of an RNA transcript. 
     
     
         15 . (canceled) 
     
     
         16 . A method for determining a treatment for a subject who has bladder cancer, the method comprising:
 providing a biological sample from the subject;   measuring levels of expression in the biological sample of a plurality of genes selected from Table 3, Table 5, Table 13 or SEQ ID Nos: 1-4050;   subtyping the bladder cancer in the subject according to a genomic subtyping classifier based on the levels of expression of the plurality of genes, wherein said subtyping comprises assigning the bladder cancer to one of four subtypes selected from the group consisting of a claudin-low subtype, a basal subtype, a luminal-infiltrated subtype, and a luminal non-infiltrated subtype; and   determining whether or not the subject is likely to be responsive to neoadjuvant chemotherapy based on the subtype of the bladder cancer in the subject; and   prescribing neoadjuvant chemotherapy to the subject if the patient is identified as likely to be responsive to neoadjuvant chemotherapy, or prescribing a cancer treatment other than neoadjuvant chemotherapy to the subject if the subject is not identified as likely to be responsive to neoadjuvant chemotherapy.   
     
     
         17 - 24 . (canceled) 
     
     
         25 . A probe set for predicting benefit from neoadjuvant chemotherapy in a subject who has bladder cancer, the probe set comprising a plurality of probes for detecting a plurality of target nucleic acids, wherein the plurality of target nucleic acids comprises one or more gene sequences, or complements thereof, of genes selected from Table 3, Table 5, or Table 13. 
     
     
         26 - 27 . (canceled) 
     
     
         28 . A system for analyzing a bladder cancer to predict response of a subject to neoadjuvant chemotherapy, the system comprising:
 the probe set of  claim 25 ; and   a computer model or algorithm for analyzing an expression level or expression profile of the plurality of target nucleic acids hybridized to the plurality of probes in a biological sample from a subject who has bladder cancer and subtyping the bladder cancer of the subject according to a genomic subtyping classifier based on the expression level or expression profile, wherein said subtyping comprises assigning the bladder cancer to one of four subtypes selected from the group consisting of a claudin-low subtype, a basal subtype, a luminal-infiltrated subtype, and a luminal non-infiltrated subtype.   
     
     
         29 - 34 . (canceled)