Abstract 1168: Urothelial cell carcinomas harbor very frequent mutations in FGFR3-PI3K-AKT pathway and highest prevalence of mutations is related to low-grade tumors

Abstract

Abstract More than 90% of bladder cancers are urothelial cell carcinomas. Superficial/papillary and invasive tumors progress via different molecular pathways. FGFR3 and PI3KCA mutations are more commonly found in superficial/papillary tumors. The PI3K-AKT pathway emerges as an alternative pathogenic mechanism linked to bladder cancer. We have analyzed the prevalence of mutations in FGFR3, PI3KCA, KRAS, BRAF and AKT1 genes in a set of 61 bladder tumors classified as TaG1 (n=10), TaG2 (n=19), TaG3 (n=8), T1G2 (n= 3), T1G3 (n= 11), T2G2 (n=1) and T2G3 (n=10). We focused on analyzing the hot spot mutation codons and surrounding regions. Mutation analysis of DNA from paraffin-embedded tumors was performed by direct sequencing of PCR products. Thirty-six (60%) tumors presented mutations, 22 cases with only one mutated gene, whereas 14 of 61 cases had mutations in two genes. The most frequently mutated gene was FGFR3 in 25 tumors, followed by PI3KCA in 16 tumors. The distribution and combinations of mutations was: FGFR3 (n= 16), PI3KCA (n= 3), AKT1 (n= 2), KRAS (n= 1), FGFR3-PI3KCA (n= 9), FGFR3-AKT1 (n= 1), and PI3KCA-KRAS (n= 4). No tumor showed BRAF mutations. According to tumor stage, 26 of 37 (70%) Ta tumors, 3 of 13 (23%) T1 tumors and 7 of 11 (63%) of T2 tumors harbored mutations. On the other hand, according to tumor grade, the distribution of mutations was: grade 1, 9 of 11 (82%); grade 2, 15 of 22 (68%); and grade 3, 12 of 28 (43%), with an overall rate of 27 mutations in 50 high grade tumors (54%). In grade 1, 100% of mutations were found in FGFR3 and/or PI3KCA, with FGFR3 mutations in 9 of 10 tumors. In grade 2, 11 of 15 mutated tumors (73%) showed alterations in FGFR3 and/or PI3KCA, and 4 tumors displayed mutations in AKT1 and KRAS (3 of them in combination with FGFR3 or PI3KCA). In grade 3, 8 of 12 mutated tumors (66%) showed mutations in FGFR3 and/or PI3KCA, and 4 tumors harbored mutations in AKT1 and KRAS (2 of them in combination with PI3KCA). Mutations in AKT1 and KRAS were found in grade 2 and 3, but not in grade 1 tumors. Percentage of mutations in the FGFR3-PI3K-AKT1 pathway is inversely proportional to grade, and it is more often associated with low grade tumors. Mutations in FGFR3 are often found alone in bladder tumors, whereas PI3KCA mutations are more frequent in combination with other mutated genes, such as FGFR3 or KRAS. FGFR3 and KRAS mutations seem to be mutually exclusive, but not PI3KCA and KRAS, nor FGFR3 and AKT1 mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1168.