TY - JOUR
T1 - Claudin-low bladder tumors are immune infiltrated and actively immune suppressed
AU - Kardos, Jordan
AU - Chai, Shengjie
AU - Mose, Lisle E.
AU - Selitsky, Sara R.
AU - Krishnan, Bhavani
AU - Saito, Ryoichi
AU - Iglesia, Michael D.
AU - Milowsky, Matthew I.
AU - Parker, Joel S.
AU - Kim, William Y.
AU - Vincent, Benjamin G.
N1 - Publisher Copyright:
© 2016 American Society for Clinical Investigation. All rights reserved.
PY - 2016/3/17
Y1 - 2016/3/17
N2 - We report the discovery of a claudin-low molecular subtype of high-grade bladder cancer that shares characteristics with the homonymous subtype of breast cancer. Claudin-low bladder tumors were enriched for multiple genetic features including increased rates of RB1, EP300, and NCOR1 mutations; increased frequency of EGFR amplification; decreased rates of FGFR3, ELF3, and KDM6A mutations; and decreased frequency of PPARG amplification. While claudin-low tumors showed the highest expression of immune gene signatures, they also demonstrated gene expression patterns consistent with those observed in active immunosuppression. This did not appear to be due to differences in predicted neoantigen burden, but rather was associated with broad upregulation of cytokine and chemokine levels from low PPARG activity, allowing unopposed NFKB activity. Taken together, these results define a molecular subtype of bladder cancer with distinct molecular features and an immunologic profile that would, in theory, be primed for immunotherapeutic response.
AB - We report the discovery of a claudin-low molecular subtype of high-grade bladder cancer that shares characteristics with the homonymous subtype of breast cancer. Claudin-low bladder tumors were enriched for multiple genetic features including increased rates of RB1, EP300, and NCOR1 mutations; increased frequency of EGFR amplification; decreased rates of FGFR3, ELF3, and KDM6A mutations; and decreased frequency of PPARG amplification. While claudin-low tumors showed the highest expression of immune gene signatures, they also demonstrated gene expression patterns consistent with those observed in active immunosuppression. This did not appear to be due to differences in predicted neoantigen burden, but rather was associated with broad upregulation of cytokine and chemokine levels from low PPARG activity, allowing unopposed NFKB activity. Taken together, these results define a molecular subtype of bladder cancer with distinct molecular features and an immunologic profile that would, in theory, be primed for immunotherapeutic response.
UR - http://www.scopus.com/inward/record.url?scp=85117772309&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.85902
DO - 10.1172/jci.insight.85902
M3 - Article
C2 - 27699256
AN - SCOPUS:85117772309
SN - 2379-3708
VL - 1
JO - JCI Insight
JF - JCI Insight
IS - 3
M1 - e85902
ER -