Genomic case report of a low grade bladder tumor metastasis to lung

Abstract

BackgroundWe present a rare case where distant metastasis of a low grade bladder tumor was observed. We carried out detailed genomic analysis and cell based experiments on patient tumor samples to study tumor evolution, possible cause of disease and provide personalized treatment strategies.Case presentationA man with a smoking history was diagnosed with a low-grade urothelial carcinoma of the bladder and a concurrent high-grade upper urinary tract tumor. Seven years later he had a lung metastasis. We carried out exome sequencing on all the patient’s tumors and peripheral blood (germline) to identify somatic variants. We constructed a phylogenetic tree to capture how the tumors are related and to identify somatic changes important for metastasis. Although distant metastasis of low-grade bladder tumor is rare, the somatic variants in the tumors and the phylogenetic tree showed that the metastasized tumor had a mutational profile most similar to the low grade urothelial carcinoma. The primary and the metastatic tumors shared several important mutations, including in the KMT2D and the RXRA genes. The metastatic tumor also had an activating MTOR mutation, which may be important for tumor metastasis. We developed a mutational signature to understand the biologic processes responsible for tumor development. The mutational signature suggests that the tumor mutations are associated with tobacco carcinogen exposure, which is concordant with the patient’s smoking history. We cultured cells from the lung metastasis to examine proliferation and signaling mechanisms in response to treatment. The mTOR inhibitor Everolimus inhibited downstream mTOR signaling and induced cytotoxicity in the metastatic tumor cells.ConclusionWe used genomic analysis to examine a rare case of low grade bladder tumor metastasis to distant organ (lung). Our analysis also revealed exposure to carcinogens found is tobacco as a possible cause in tumor development. We further validated that the patient might benefit from mTOR inhibition as a potential salvage therapy in an adjuvant or recurrent disease setting.Electronic supplementary materialThe online version of this article (10.1186/s12894-018-0386-8) contains supplementary material, which is available to authorized users.

20(S)‐Protopanaxadiol inhibits epithelial‐mesenchymal transition by promoting retinoid X receptor alpha in human colorectal carcinoma cells

“…24 The abnormal expression of RXRα was reported in a variety of cancers such as bladder cancer, renal cancer and oesophageal cancer. [25][26][27] Furthermore, RXRα promotes the proliferation and inhibits the apoptosis of pancreatic cancer cells through TGF-β/Smad pathway. 28 It also reported that RXRα was bound by berberine to suppressed β-catenin in colon cancer.…”

“…RXRs belong to the NR superfamily and have 3 isoforms: α, β and γ. RXR interacts with several other NRs and plays a central role in the hormonal gene network that regulates many pathways 24 . The abnormal expression of RXRα was reported in a variety of cancers such as bladder cancer, renal cancer and oesophageal cancer 25‐27 . Furthermore, RXRα promotes the proliferation and inhibits the apoptosis of pancreatic cancer cells through TGF‐β/Smad pathway 28 .…”

Diagnostic Immunocytostaining with Peroxisome Proliferator-Activated Receptor-Gamma in Urine Cytology Samples

“…Our study reported that PPAR-γ immunocytostaining stained both HGUC and LGUC. Although the purpose of urine cytology is to detect HGUC, LGUC have a lower likelihood of metastasis and are often recurrent [24,25]. Such cases should be reliably diagnosed by cytological follow-up and PPARγ immunocytostaining would assist in this regard.…”