Mutations of KRAS, NRAS, BRAF, EGFR, and PIK3CA genes in urachal carcinoma: Occurence and prognostic significance

Abstract

PurposeTargeted therapy represents an attractive alternative for rare tumors such as urachal carcinoma (UrC). The aim of this study was to assess the mutations of the most commonly affected 5 genes in the targetable EGFR-pathway in UrC and comapre their frequencies to those of found in urothelial and colorectal cancer.Materials and MethodsMutational hot-spots of selected genes were tested in 22 UrC samples by pyrosequencing. Mutational patterns were compared to those published for colorectal and urothelial cancers. Furthermore, we sought correlations between mutations and clinicopathological and follow-up data.ResultsWe found 11 mutations in 10 of 22 (45%) patients. The most frequently mutated gene was KRAS (27%) followed by BRAF (18%) and NRAS (5%), while no mutations were detected in the EGFR and PIK3CA genes. No correlation was found between the mutation status and clinicopathological parameters (Sheldon/Mayo stage, tumor grade, metastases). Furthermore, none of the mutations correlated with progression-free or overall survival.ConclusionsThe mutation pattern of UrC is more similar to colorectal than to urothelial cancer. However, the mutation characteristics of UrC seems to be unique suggesting that clinical decision-making for UrC cannot be simply adopted from urothelial or colorectal carcinoma. The high occurence of EGFR-pathway mutations warrants the testing for KRAS and BRAF mutations when considering anti-EGFR therapy in UrC.

Telomerase reverse transcriptase (TERT) promoter mutations are rare in urachal cancer

“…Second, the low rates of TERT promoter mutations in urachal adenocarcinomas give further evidence to urachal adenocarcinomas being more closely related to colorectal adenocarcinomas than to UC on the mutational genetic level. We and others have recently reported data showing a similar mutation pattern of EGFR pathway activation between urachal adenocarcinomas and colorectal cancer . The present case with TERT promoter mutation, however, did not exhibit any EGFR/MAPK related mutations, while these are a common event in the remaining cases with hotspot mutations in KRAS (5/10) and BRAF (1/10) .…”

Pathogenic and targetable genetic alterations in 70 urachal adenocarcinomas

“…However, not only similarities but also differences were detected. For example, we identified three non‐classical, BRAF mutations (G469A: n = 1, D594G: n = 2) adding to the four classical V600E mutations reported previously . While the G469A BRAF mutation was relatively common in cancer, the D594G variant has rarely been detected in cancer.…”

“…In addition, we found a subset of UrC characterized by dysfunctional and activated oncogenic MAPK‐ and PI3K‐pathways . As EGFR signaling mainly occurs through these pathways, we grouped together all UrC with any pathogenic mutational event in KRAS, NRAS, BRAF , or PIK3CA ( n = 22; 31%).…”

“…Like in CRC, oncogenic signaling in UrC appears to employ preferably the epidermal growth factor receptor (EGFR)/mitogen‐activated protein kinase (MAPK) and phosphoinositide 3‐kinase (PI3K) pathways. Moreover, anti‐EGFR agents such as cetuximab seem to exert positive effects …”

“…To date, genetic data on UrC still is scant or reported only in few cases . In addition, data on non‐adenocarcinoma UrC is completely lacking.…”