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

• Published in: BMC urology Vol. 18; no. 1; pp. 74 - 7
• Main Authors: Van Every, Marvin J, Dancik, Garrett, Paramesh, Venki, Gurda, Grzegorz T, Meier, David R, Cash, Steven E, Richmond, Craig S, Guin, Sunny
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 03-09-2018; BioMed Central; BMC
• Subjects: Biopsy; Bladder cancer; Cancer patients; Carcinogens; Carcinoma, Transitional Cell - genetics; Carcinoma, Transitional Cell - pathology; Carcinoma, Transitional Cell - secondary; Case Report; Case reports; Cell proliferation; Cytotoxicity; Diagnosis; Exome; Exome sequencing; Gene expression; Genetic aspects; Genomic analysis; Genomics; Health aspects; Humans; KMT2D; Lung - pathology; Lung cancer; Lung metastasis; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Lungs; Male; Medical research; Metastases; Metastasis; Middle Aged; MTOR; Mutation; Pathology; Patient outcomes; Patients; Peripheral blood; Phylogenetics; Phylogeny; Retinoid X receptor α; RXRA; Sequence Analysis, DNA; Smoking; Tobacco; TOR protein; TOR Serine-Threonine Kinases - genetics; Tumor cells; Tumors; Urinary Bladder - pathology; Urinary Bladder Neoplasms - pathology; Urinary tract; Urogenital system; Urology; Urothelial carcinoma; United States; KMT2D; RXRA; Lung metastasis; Bladder cancer; MTOR; Exome sequencing
• ISSN: 1471-2490; 1471-2490
• DOI: 10.1186/s12894-018-0386-8

We 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.
A 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.
We 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.