Oncogenic KRAS is not necessary for Wnt signalling activation in APC-associated FAP adenomas.
Recent studies have suggested that APC loss alone may be insufficient to promote aberrant Wnt/beta-catenin signalling. Our aim was to comprehensively characterize Wnt signalling components in a set of APC-associated familial adenomatous polyposis (FAP) tumours. Sixty adenomas from six FAP patients with known pathogenic APC mutations were included. Somatic APC and KRAS mutations, beta-catenin immunostaining, and qRT-PCR of APC, MYC, AXIN2 and SFRP1 were analysed. Array-comparative genomic hybridization (aCGH) was also assessed in 26 FAP adenomas and 24 paired adenoma-carcinoma samples. A somatic APC alteration was present in 15 adenomas (LOH in 11 and four point mutations). KRAS mutations were detected in 10% of the cases. APC mRNA was overexpressed in adenomas. MYC and AXIN2 were also overexpressed, with significant intra-case heterogeneity. Increased cytoplasmic and/or nuclear beta-catenin staining was seen in 94% and 80% of the adenomas. beta-Catenin nuclear staining was strongly associated with MYC levels (p value 0.03) but not with KRAS mutations. Copy number aberrations were rare. However, the recurrent chromosome changes observed more frequently contained Wnt pathway genes (p value 0.012). Based on beta-catenin staining and Wnt pathway target genes alterations the Wnt pathway appears to be constitutively activated in all APC-FAP tumours, with alterations occurring both upstream and downstream of APC. Wnt aberrations are present at both the DNA and the RNA level. Somatic profiling of APC-FAP tumours provides new insights into the role of APC in tumourigenesis.
Obrador-Hevia
Antònia
A
Cancer Cell Biology Group, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS)-Universitat de les Illes Balears, Mallorca, Illes Balears, Spain.
Chin
Suet-Feung
SF
González
Sara
S
Rees
Jonathan
J
Vilardell
Felip
F
Greenson
Joel K
JK
Cordero
David
D
Moreno
Víctor
V
Caldas
Carlos
C
Capellá
Gabriel
G
D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000378:metabolism; D025601:Adenomatous Polyposis Coli Protein / Q000096:biosynthesis / Q000235:genetics; D000328:Adult; D002467:Cell Nucleus / Q000378:metabolism; D055028:Comparative Genomic Hybridization; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000502:physiology*; D055815:Young Adult; D051176:beta Catenin / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000502:physiology*
D025601:Adenomatous Polyposis Coli Protein; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins