KRAS mutations in microsatellite instable gastric tumours: impact of targeted treatment and intratumoural heterogeneity

• Type: Article in International Scientific Journal
• Date: 2015

Authors

Queiros, P (Author) Other; Pinheiro, H (Author) Other; Carvalho, J (Author) Other; Oliveira, P (Author) Other; Gullo, I (Author) FMUP; Carneiro F (Author) FMUP; Almeida, GM (Author) Other; Oliveira C (Author) FMUP

Journal

Title: Virchows Archiv

Vol. 467

Pages: 383-392

ISSN: 0945-6317

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 5 Citations

Scopus - 5 Citations

Other information

Authenticus ID: P-00G-MEC

DOI: 10.1007/s00428-015-1823-7

Abstract (EN): In gastric cancer (GC), epidermal growth factor receptor (EGFR) overexpression associates with poor prognosis. Addition of a chimeric monoclonal antibody against EGFR (cetuximab) to first-line treatment of metastatic colorectal tumours improved outcomes of patients (stratified for KRAS wild-type cancers), whereas GC patients did not benefit from this approach. In GC, however, stratification based on KRAS mutations was not performed, and the 30 % KRAS mutation frequency in microsatellite instable cancers (MSI), which represents similar to 4 % of total GC, was disregarded. Further, intratumoural heterogeneity regarding KRAS mutant subpopulations might also contribute to anti-EGFR therapy failure. We assessed the mutational status of the entire KRAS coding sequence in 19 MSI-GC cases by multiplex PCR/sequencing and used peak height ratio determined from electropherograms from KRAS heterozygous mutants and histopathological evaluation to infer tumour heterogeneity in GC. Using 2 multiplex reactions per sample, we found that 26 % (5/19) of MSI-GC cases harboured KRAS mutations (2 G12D, 2 G13D, 1 G12V). No mutations were found outside the codon 12 and 13 hotspots. Our analysis supported the co-existence of KRAS-positive and KRAS-negative tumour populations in 4/5 MSI-GC cases. In conclusion, the method developed stands as a cost-effective and practical way for mutation screening of the entire KRAS coding sequence. KRAS mutations are frequent in our series of MSI cases and are often found in a subpopulation of the tumour and not in the whole tumour. Further studies are needed to access the implications of this heterogeneity in KRAS mutant and wild-type tumour clones in anti-EGFR therapy response.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 10