Open AccessMolecular subtype classification of urothelial carcinoma in Lynch syndrome
Author(s) -
Therkildsen Christina,
Eriksson Pontus,
Höglund Mattias,
Jönsson Mats,
Sjödahl Gottfrid,
Nilbert Mef,
Liedberg Fredrik
Publication year - 2018
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12325
Subject(s) - lynch syndrome , microsatellite instability , cdkn2a , colorectal cancer , bladder cancer , medicine , immunohistochemistry , pathology , cancer , cancer research , oncology , dna mismatch repair , biology , microsatellite , genetics , gene , allele
Lynch syndrome confers an increased risk for urothelial carcinoma ( UC ). Molecular subtypes may be relevant to prognosis and therapeutic possibilities, but have to date not been defined in Lynch syndrome‐associated urothelial cancer. We aimed to provide a molecular description of Lynch syndrome‐associated UC . Thus, Lynch syndrome‐associated UC s of the upper urinary tract and the urinary bladder were identified in the Danish hereditary nonpolyposis colorectal cancer ( HNPCC ) register and were transcriptionally and immunohistochemically profiled and further related to data from 307 sporadic urothelial carcinomas. Whole‐genome mRNA expression profiles of 41 tumors and immunohistochemical stainings against FGFR 3, KRT 5, CCNB 1, RB 1, and CDKN 2A (p16) of 37 tumors from patients with Lynch syndrome were generated. Pathological data, microsatellite instability, anatomic location, and overall survival data were analyzed and compared with sporadic bladder cancer. The 41 Lynch syndrome‐associated UC developed at a mean age of 61 years with 59% women. mRNA expression profiling and immunostaining classified the majority of the Lynch syndrome‐associated UC as urothelial‐like tumors with only 20% being genomically unstable, basal/SCC‐like, or other subtypes. The subtypes were associated with stage, grade, and microsatellite instability. Comparison to larger datasets revealed that Lynch syndrome‐associated UC shares molecular similarities with sporadic UC . In conclusion, transcriptomic and immunohistochemical profiling identifies a predominance of the urothelial‐like molecular subtype in Lynch syndrome and reveals that the molecular subtypes of sporadic bladder cancer are relevant also within this hereditary, mismatch‐repair defective subset.