Analysis of Several Common APOBEC-type Mutations in Bladder Tumors Suggests Links to Viral Infection.
Journal
Cancer prevention research (Philadelphia, Pa.)
ISSN: 1940-6215
Titre abrégé: Cancer Prev Res (Phila)
Pays: United States
ID NLM: 101479409
Informations de publication
Date de publication:
02 10 2023
02 10 2023
Historique:
received:
30
03
2023
revised:
16
06
2023
accepted:
18
07
2023
pmc-release:
02
04
2024
medline:
6
10
2023
pubmed:
21
7
2023
entrez:
21
7
2023
Statut:
ppublish
Résumé
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. 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.
Identifiants
pubmed: 37477495
pii: 727879
doi: 10.1158/1940-6207.CAPR-23-0112
pmc: PMC10592262
mid: NIHMS1920861
doi:
Substances chimiques
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
561-570Subventions
Organisme : NCI NIH HHS
ID : R21 CA266660
Pays : United States
Organisme : Intramural NIH HHS
ID : Z99 CA999999
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA CP010125
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA CP010201
Pays : United States
Informations de copyright
©2023 American Association for Cancer Research.
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