Analysis of Several Common APOBEC-type Mutations in Bladder Tumors Suggests Links to Viral Infection.

Autor:	Rao N; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.; Department of Biology, Johns Hopkins University, Baltimore, Maryland., Starrett GJ; Laboratory of Cellular Oncology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Piaskowski ML; Laboratory of Cellular Oncology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Butler KE; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland., Golubeva Y; Molecular Digital Pathology Laboratory, Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland., Yan W; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland., Lawrence SM; Molecular Digital Pathology Laboratory, Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland., Dean M; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland., Garcia-Closas M; Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland., Baris D; Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland., Johnson A; Vermont Department of Health, Burlington, Vermont., Schwenn M; Maine Cancer Registry, Augusta, Maine., Malats N; CNIO, Madrid, Spain.; CIBERONC, Madrid, Spain., Real FX; CNIO, Madrid, Spain.; CIBERONC, Madrid, Spain.; Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain., Kogevinas M; Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain., Rothman N; Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland., Silverman DT; Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland., Dyrskjøt L; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.; Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark., Buck CB; Laboratory of Cellular Oncology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Koutros S; Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland., Prokunina-Olsson L; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.
Jazyk:	angličtina
Zdroj:	Cancer prevention research (Philadelphia, Pa.) [Cancer Prev Res (Phila)] 2023 Oct 02; Vol. 16 (10), pp. 561-570.
DOI:	10.1158/1940-6207.CAPR-23-0112
Abstrakt:	FGFR3 and PIK3CA are among the most frequently mutated genes in bladder tumors. We hypothesized that recurrent mutations in these genes might be caused by common carcinogenic exposures such as smoking and other factors. We analyzed 2,816 bladder tumors with available data on FGFR3 and/or PIK3CA mutations, focusing on the most recurrent mutations detected in ≥10% of tumors. Compared to tumors with other FGFR3/PIK3CA mutations, FGFR3-Y375C was more common in tumors from smokers than never-smokers (P = 0.009), while several APOBEC-type driver mutations were enriched in never-smokers: FGFR3-S249C (P = 0.013) and PIK3CA-E542K/PIK3CA-E545K (P = 0.009). To explore possible causes of these APOBEC-type mutations, we analyzed RNA sequencing (RNA-seq) data from 798 bladder tumors and detected several viruses, with BK polyomavirus (BKPyV) being the most common. We then performed IHC staining for polyomavirus (PyV) Large T-antigen (LTAg) in an independent set of 211 bladder tumors. Overall, by RNA-seq or IHC-LTAg, we detected PyV in 26 out of 1,010 bladder tumors with significantly higher detection (P = 4.4 × 10-5), 25 of 554 (4.5%) in non-muscle-invasive bladder cancers (NMIBC) versus 1 of 456 (0.2%) of muscle-invasive bladder cancers (MIBC). In the NMIBC subset, the FGFR3/PIK3CA APOBEC-type driver mutations were detected in 94.7% (18/19) of PyV-positive versus 68.3% (259/379) of PyV-negative tumors (P = 0.011). BKPyV tumor positivity in the NMIBC subset with FGFR3- or PIK3CA-mutated tumors was also associated with a higher risk of progression to MIBC (P = 0.019). In conclusion, our results support smoking and BKPyV infection as risk factors contributing to bladder tumorigenesis in the general patient population through distinct molecular mechanisms. Prevention Relevance: Tobacco smoking likely causes one of the most common mutations in bladder tumors (FGFR3-Y375C), while viral infections might contribute to three others (FGFR3-S249C, PIK3CA-E542K, and PIK3CA-E545K). Understanding the causes of these mutations may lead to new prevention and treatment strategies, such as viral screening and vaccination. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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