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 fi Asp; G12D, Gly fi Asp, G13D; Gly fi 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 5 0.038). With MSI, specific KRAS and BRAF V600E mutations, 3 distinct prognostic subgroups were observed in univariate (p 5 0.006) and multivariable (p 5 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.Sporadic colorectal cancer (CRC) is a heterogeneous disease arising from at least 2 different and seemingly independent pathways, namely the chromosomal instability (CIN, or microsatellite stable, MSS) and microsatellite instability (MSI) pathways. 1 CRCs from the MSS pathway are thought to originate from a relatively uniform and linear accumulation of genetic changes in APC, KRAS and TP53. 2 However, in practice, only 10% of these tumors are characterized by this classic genotype. 3,4 Sporadic MSI-high (MSI-H) cancers occur through promoter hypermethylation of the MLH1 gene, more frequently found in females, and tend to be poorly differentiated tumors, of mucinous subtype, associated with a Crohn's like reaction at the invasive tumor front and often harboring somatic mutations in BRAF V600E . 5-7 MSI-H CRCs can also arise in the context of Lynch syndrome/hereditary nonpolyposis CRC (HNPCC), an autosomal dominant disorder, accounting for 3% of all CRC cases, characterized by germline mutations of mismatch-repair genes. 8 Both sporadic and Lynch syndrome-associated MSI-H tumors are characterized by dense tumor-infiltrating lymphocyte populations and less frequent metastases suggesting enhanced immunogenicity irrespective of the mechanism of DNA mismatch repair inactivation. 9,10 Recently, MSI status, BRAF V600E and KRAS mutation status have attracted significant attention due to their potential prognostic and predictive role in CRC. 11 On one hand, patients with MSI-H cancers are specifically thought to have a favorable outcome; yet on the other hand, they are generally nonresponsive to certain chemotherapeutic agents such as 5-flurouracil (5-FU). 6,12 The prognostic effect of somatic KRAS mutations, described in 30...

Sessile serrated adenoma shares similar genetic and epigenetic features with microsatellite unstable colon cancer in a location-dependent manner

“…There are several reports with similar results for the frequency of the BRAF mutation in MSI and MSS cancers (29)(30)(31). Lubomierski et al (31) suggested that there were two genetically distinct entities of MSI cancer with and without the BRAF mutation, which is consistent with our data.…”

Caracterización de pacientes con cáncer colorrectal esporádico basado en la nueva subclasificación molecular de consenso

“…Se ha descrito que la sobrevida de pacientes en etapas tempranas supera 90%, pero en estadios metastásicos es inferior a 10% 30 . En los últimos años, la incorporación de terapias moleculares ha permitido mejorar la sobrevida de estos pacientes, sin embargo, debido a la heterogeneidad de los tumores, no tienen la misma efectividad en todos los pacientes [31][32][33][34] . Considerando lo anterior, el año 2015 se estableció un grupo internacional de subtipificación del CCR , The CRC Subtyping Consortium, basado en datos provenientes de The Cancer Genome Atlas complementados con análisis moleculares y mutacionales 19 .…”

Implication of RAF and RKIP Genes in Urinary Bladder Cancer

“…The vast majority of the studies investigating B-RAF mutation frequency in different types of cancer, including melanoma and colorectal adenocarcinoma [22][23][24][25][26][27][28][29], focus mainly at the thymine (T) 1799 nucleotide. This is the first study measuring the expression status of B-RAF in TCC of the urinary bladder.…”