title: p53 mutation is common in microsatellite stable, BRAF mutant colorectal cancers.
abstract: The majority of "serrated pathway" colorectal cancers have mutation of the BRAF oncogene and display the CpG island methylator phenotype (CIMP). Half these cancers have microsatellite instability (MSI) and an excellent prognosis. In the absence of MSI (microsatellite stable, MSS), BRAF mutation has been associated with a particularly poor prognosis. "Traditional pathway" cancers are BRAF wild type. Mutation of p53 is common and this correlates with advanced stage. We therefore hypothesized that p53 mutation would be common in MSS/BRAF mutant colorectal cancer. One thousand and eighty-one colorectal cancers were screened for BRAF mutation to identify two BRAF mutant study groups (MSI: n = 77; MSS: n = 69) and a BRAF wild type control group (n = 101). These were screened for p53 mutation by high resolution melt analysis and classified for CIMP and MGMT methylation by quantitative methylation specific PCR. Molecular data were compared to patient age, gender, tumor location and stage. p53 was mutated significantly more frequently in MSS/BRAF mutant (28/69, 40.6%) compared to MSI/BRAF mutant cancers (13/77, 16.9%), but this mutation rate did not differ from MSS/BRAF wild type cancers (47/101, 46.5%)(p < 0.0001). CIMP was less common in MSS/BRAF mutant (26/47, 55.3%) compared to MSI/BRAF mutant cancers (41/54, 75.9%), but was more common than in MSS/BRAF wild type cancers (3/85, 3.5%) (p < 0.0001). MSS/BRAF mutant cancers were more commonly proximal (38/54, 70.3%), but were similar to MSS/BRAF wild type cancers in terms of patient age, gender distribution and stage at presentation. MSS/BRAF mutant cancers share molecular and clinical features of both the serrated and traditional pathways of colorectal tumorigenesis.
authors.affiliation: Conjoint Gastroenterology Laboratory, Royal Brisbane and Women's Hospital Research Foundation, Clinical Research Centre and the Queensland Institute of Medical Research, Brisbane, Australia. catherine.bond@qimr.edu.au
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Bond
authors.forename: Aarti
authors.initials: A
authors.lastname: Umapathy
authors.forename: Ingunn
authors.initials: I
authors.lastname: Ramsnes
authors.forename: Sonia A
authors.initials: SA
authors.lastname: Greco
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhen Zhao
authors.forename: Kylie-Ann
authors.initials: KA
authors.lastname: Mallitt
authors.forename: Ron L
authors.initials: RL
authors.lastname: Buttenshaw
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Leggett
authors.forename: Vicki L J
authors.initials: VL
authors.lastname: Whitehall
mesh_terms: D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D005260:Female; D016158:Genes, p53; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D009154:Mutation; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D045643:DNA Repair Enzymes