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.

A clinicopathological and molecular analysis of 200 traditional serrated adenomas

“…True sessile serrated adenomas with dysplasia have been demonstrated to show Wnt pathway activation, 23 loss of mismatch repair function, 32 CDKN2A silencing, 24 and sometimes TP53 mutation. 33 In contrast, from our data, ordinary traditional serrated adenomas arising in a sessile serrated adenoma do not have these advanced features. Thus, in our opinion, calling these lesions sessile serrated adenoma with dysplasia risks diminishing the significance of true sessile serrated adenoma with dysplasia and potentially leads to erroneous conclusions regarding surveillance.…”

“…TP53 mutation has been reported previously, both as a feature of BRAF mutant, microsatellite-stable colorectal carcinoma and specifically in advanced traditional serrated adenomas. 14,15,33 However, to the best of our knowledge, loss of p16 staining has not previously been reported in advanced traditional serrated adenomas. A detailed outline of the proposed molecular pathways by which traditional serrated adenomas progress to carcinoma is provided in Figure 4.…”

RNF43 and ZNRF3 are commonly altered in serrated pathway colorectal tumorigenesis

“…Cancers displayed typical clinicopathological features when stratified for molecular subtype as previously described [21–23]. Patients with BRAF mutant/MSI cancers presented at significantly older ages compared to both MSS subtypes.…”

“…DNA from the FFPE cancers was extracted by the Chelex-100 method (Bio-Rad Laboratories, CA, USA). The presence of MSI had been previously analysed for the RBWH cancer samples using the National Cancer Institute's 5 marker panel [21, 36, 37]. Cancers from Envoi Specialist Pathologists were evaluated for immunohistochemical loss of MLH1 mismatch repair protein expression as a surrogate for MSI.…”

Clinicopathological and molecular features of sessile serrated adenomas with dysplasia or carcinoma

“…Overall, p53 immunohistochemistry has a specificity of 90% and a sensitivity of 67% for detecting TP53 mutation 52. Bond et al ,53 have demonstrated significant differences in TP53 mutation rates between BRAF -mutated microsatellite stable and unstable carcinomas (40.6% vs 16.9%), with the microsatellite stable group having more frequent mutations. Our study is in agreement with this finding and the presence of a TP53 mutation may be part of the explanation for the poor prognosis associated with the MMRP cancers.…”