Compositions and methods for characterizing bladder cancer
AssigneesThe Broad Institute, Inc., The General Hospital Corporation, Baylor College of Medicine, The Brigham and Women S Hospital, Inc., Northwestern University, The Johns Hopkins University, United States Government as represented by the U.S. Department of Veterans Affairs
InventorsJaegil Kim, Gad Getz, Seth Paul Lerner, David Kwiatkowski, Joshua Meeks, Joaquim Bellmunt, David McConkey
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Abstract
The present invention features methods for characterizing mutational profiles in patients with bladder cancer.
Claims18
A method of characterizing bladder cancer in a subject, the method comprising detecting in a biological sample of the subject an alteration in the expression of a target selected from
- luminal markers selected from the group consisting of uroplakin genes UPK2, UPK1A, urothelial differentiation markers FOXA1, GATA3, and PPARG, and genes KRT20, and SNX31;
- luminal-papillary markers selected from the group consisting of FGFR, FGFR3-TACC3 fusions, lncRNAs DANCR, GAS5, MALAT1, NEAT1, NORAD (LINC00657), UCA1, ZNF667-AS1 (MORT), LINC00152, GATA3, FOXA1, PPARγ, TP63, sonic-hedgehog signaling (SHH);
- luminal-infiltrated markers selected from the group consisting of CD274 (PD-L1) and PDCD1 (PD-1);
- basal-squamous markers including basal and stem-like markers CD44, KRT5, KRT6A, KRT14, and COL17A1;
- squamous differentiation markers TGM1, DSC3, TP63, GSDMC, and PI3, TP53, CIS signature genes CRTAC1, CTSE, PADI3, MSN, and NR3C1, and immune markers CD274, PDCD1LG2, 1DO1, CXCL11, L1CAM, SAA1 and CTLA4;
- neuronal markers selected from the group consisting of neuronal differentiation and development genes MSI1, PLEKHG4B, GNG4, PEG10, RND2, APLP1, SOX2, TUBB2B, TP53, RB1 and E2F3 and neuroendocrine markers CHGA, CHGB, SCG2, ENO2, SYP, NCAM1;
- and
- targets from among those listed in Tables 2-4.
A method of treating a selected subject for bladder cancer, the method comprising
- (a) administering to the patient a checkpoint inhibitor, wherein the subject is selected by detecting increased expression of uroplakin genes and an umbrella cell phenotype in a biological sample from the subject;
- (b) administering to the subject a tyrosine kinase inhibitor of FGFR3, wherein the subject is selected by identifying a luminal-papillary subtype, wherein the luminal-papillary subtype is characterized by an FGFR3 mutations, a fusion with TACC3, and/or amplification;
- by papillary histology;
- by active sonic hedgehog signaling;
- and by low CIS scores;
- or
- (c) administering to the subject a tyrosine kinase inhibitor of FGFR3, wherein the subject is selected by identifying a luminal-papillary subtype, wherein the luminal-papillary subtype is characterized by an FGFR3 mutations, a fusion with TACC3, and/or amplification;
- by papillary histology;
- by active sonic hedgehog signaling;
- and by low CIS scores;
- or
- (d) administering to the subject an immune checkpoint therapy, wherein the subject is selected by characterizing a biological sample of the subject as having a luminal-infiltrated subtype characterized by increased expression of EMT markers, myofibroblast markers, and of the miR-200s;
- (e) administering to the subject a cisplatin-based NAC or immune checkpoint therapy, wherein the subject is selected by characterizing a biological sample of the subject as having a basal-squamous subtype comprising squamous differentiation, basal keratin expression, and increased expression of CD274 (PD-L1) and CTLA4 immune markers;
- or
- (f) administering to the subject Etoposide-cisplatin therapy, wherein a biological sample from the subject is characterized by expression of neuroendocrine/neuronal markers;
- or
- (g) administering to a selected patient atezolizumab, wherein the subject is selected by detecting increased expression of neuronal markers comprising or consisting of SOX2, TUBB2B, and PEG10 in a biological sample from the subject.
A method of characterizing a neuronal subtype marker in a bladder cancer in a subject, the method comprising detecting in a biological sample of the subject an alteration in the expression of neuronal markers comprising or consisting of SOX2, TUBB2B, and PEG10.
Dependencies are inferred from the claim text.