title: Combined analysis of specific KRAS mutation, BRAF and microsatellite instability identifies prognostic subgroups of sporadic and hereditary colorectal cancer.
abstract: Confounding effects of specific KRAS gene alterations on colorectal cancer (CRC) prognosis stratified by microsatellite instability (MSI) and BRAF(V600E) have not yet been investigated. The aim of our study was to evaluate the combined effects of MSI, BRAF(V600E) and specific KRAS mutation (Gly → Asp; G12D, Gly → Asp, G13D; Gly → Val; G12V) on prognosis in 404 sporadic and 94 hereditary CRC patients. MSI status was determined according to the Bethesda guidelines. Mutational status of KRAS and BRAF(V600E) was assessed by direct DNA sequencing. In sporadic CRC, KRAS G12D mutations had a negative prognostic effect compared to G13D and wild-type cancers (p = 0.038). With MSI, specific KRAS and BRAF(V600E) mutations, 3 distinct prognostic subgroups were observed in univariate (p = 0.006) and multivariable (p = 0.051) analysis: patients with (i) KRAS mutation G12D, G12V or BRAF(V600E) mutation, (ii) KRAS/BRAF(V600E) wild-type or KRAS G13D mutations in MSS/MSI-L and (iii) MSI-H and KRAS G13D mutations. Moreover, none of the sporadic MSI-H or hereditary patients with KRAS G13 mutations had a fatal outcome. Specific KRAS mutation is an informative prognostic factor in both sporadic and hereditary CRC and applied in an algorithm with BRAF(V600E) and MSI may identify sporadic CRC patients with poor clinical outcome.
authors.affiliation: Institute for Pathology, University of Basel, Basel, Switzerland. izlobec@uhbs.ch
authors.forename: Inti
authors.initials: I
authors.lastname: Zlobec
authors.forename: Michal
authors.initials: M
authors.lastname: Kovac
authors.forename: Priska
authors.initials: P
authors.lastname: Erzberger
authors.forename: Francesca
authors.initials: F
authors.lastname: Molinari
authors.forename: Michel P
authors.initials: MP
authors.lastname: Bihl
authors.forename: Alexander
authors.initials: A
authors.lastname: Rufle
authors.forename: Anja
authors.initials: A
authors.lastname: Foerster
authors.forename: Milo
authors.initials: M
authors.lastname: Frattini
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.forename: Karl
authors.initials: K
authors.lastname: Heinimann
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lugli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D005260:Female; D011905:Genes, ras; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D017354:Point Mutation; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf